1
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Thibaut MM, Roumain M, Piron E, Gillard J, Loriot A, Neyrinck AM, Rodriguez J, Massart I, Thissen JP, Huot JR, Pin F, Bonetto A, Delzenne NM, Muccioli GG, Bindels LB. The microbiota-derived bile acid taurodeoxycholic acid improves hepatic cholesterol levels in mice with cancer cachexia. Gut Microbes 2025; 17:2449586. [PMID: 39780051 PMCID: PMC11730681 DOI: 10.1080/19490976.2025.2449586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/20/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025] Open
Abstract
Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA). This reduction in hepatic TDCA occurred before the appearance of cachexia. Longitudinal analysis of the gut microbiota pinpointed an ASV, identified as Xylanibacter rodentium, as a bacterium potentially involved in the reduced production of TDCA. Coherently, stable isotope-based experiments highlighted a robust decrease in the microbial 7α-dehydroxylation (7α-DH) activity with no changes in the bile salt hydrolase (BSH) activity in cachectic mice. This approach also highlighted a reduced microbial 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 12α-hydroxysteroid dehydrogenase (12α-HSDH) activities in these mice. The contribution of the lower production of TDCA to cancer cachexia was explored in vitro and in vivo. In vitro, TDCA prevented myotube atrophy, whereas in vivo hepatic whole transcriptome analysis revealed that TDCA administration to cachectic mice improved the unfolded protein response and cholesterol homeostasis pathways. Coherently, TDCA administration reversed hepatic cholesterol accumulation in these mice. Altogether, this work highlights the contribution of the gut microbiota to bile acid dysmetabolism and the therapeutic interest of the secondary bile acid TDCA for hepatic cholesterol homeostasis in the context of cancer cachexia. Such discovery may prove instrumental in the understanding of other metabolic diseases characterized by microbial dysbiosis. More broadly, our work demonstrates the interest and relevance of microbial activity measurements using stable isotopes, an approach currently underused in the microbiome field.
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Affiliation(s)
- Morgane M. Thibaut
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Martin Roumain
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Edwige Piron
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Justine Gillard
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Axelle Loriot
- Computational Biology and Bioinformatics Unit (CBIO), de Duve Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Audrey M. Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Julie Rodriguez
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Isabelle Massart
- Endocrinology, Diabetology and Nutrition Department, Institut de Recherches Expérimentales et Cliniques, UCLouvain, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Jean-Paul Thissen
- Endocrinology, Diabetology and Nutrition Department, Institut de Recherches Expérimentales et Cliniques, UCLouvain, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Joshua R. Huot
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Fabrizio Pin
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrea Bonetto
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nathalie M. Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Giulio G. Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Laure B. Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- Welbio Department, WEL Research Institute, Wavre, Belgium
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2
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Zhao S, Lin H, Li W, Xu X, Wu Q, Wang Z, Shi J, Chen Y, Ye L, Xi L, Chen L, Yuan M, Su J, Gao A, Jin J, Ying X, Wang X, Ye Y, Sun Y, Zhang Y, Deng X, Shen B, Gu W, Ning G, Wang W, Hong J, Wang J, Liu R. Post sleeve gastrectomy-enriched gut commensal Clostridia promotes secondary bile acid increase and weight loss. Gut Microbes 2025; 17:2462261. [PMID: 39915243 PMCID: PMC11810084 DOI: 10.1080/19490976.2025.2462261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 01/07/2025] [Accepted: 01/29/2025] [Indexed: 02/12/2025] Open
Abstract
The gut microbiome is altered after bariatric surgery and is associated with weight loss. However, the commensal bacteria involved and the underlying mechanism remain to be determined. We performed shotgun metagenomic sequencing in obese subjects before and longitudinally after sleeve gastrectomy (SG), and found a significant enrichment in microbial species in Clostridia and bile acid metabolizing genes after SG treatment. Bile acid profiling further revealed decreased primary bile acids (PBAs) and increased conjugated secondary bile acids (C-SBAs) after SG. Specifically, glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) were increased at different follow-ups after SG, and were associated with the increased abundance of Clostridia and body weight reduction. Fecal microbiome transplantation with post-SG feces increased SBA levels, and alleviated body weight gain in the recipient mice. Furthermore, both Clostridia-enriched spore-forming bacteria and GDCA supplementation increased the expression of genes responsible for lipolysis and fatty acid oxidation in adipose tissue and reduced adiposity via Takeda G-protein-coupled receptor 5 (TGR5) signaling. Our findings reveal post-SG gut microbiome and C-SBAs as contributory to SG-induced weight loss, in part via TGR5 signaling, and suggest SBA-producing gut microbes as a potential therapeutic target for obesity intervention.
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Affiliation(s)
- Shaoqian Zhao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huibin Lin
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Qihan Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Juan Shi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yufei Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingxia Ye
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liuqing Xi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lijia Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingyang Yuan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junlei Su
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aibo Gao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiabin Jin
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiayang Ying
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolin Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Yaorui Ye
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Yingkai Sun
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yifei Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaxing Deng
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baiyong Shen
- Pancreatic Disease Center, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqiong Gu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Hong
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiqiu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruixin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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3
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Xiao F, Yang M, Lv J, Li J, Guo M, Duan W, Li H, An Z, Su Z, Li A, Liu Y, Lu J, Guo H. Association between per- and polyfluoroalkyl substances with serum hepatobiliary system function biomarkers in patients with acute coronary syndrome. J Environ Sci (China) 2025; 155:773-785. [PMID: 40246507 DOI: 10.1016/j.jes.2024.06.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 06/17/2024] [Accepted: 06/19/2024] [Indexed: 04/19/2025]
Abstract
Previous studies have suggested that abnormal hepatobiliary system function may contribute to poor prognosis in patients with acute coronary syndrome (ACS) and that abnormal hepatobiliary system function may be associated with per- and polyfluoroalkyl substances (PFAS) exposure. However, there is limited evidence for this association in cardiovascular subpopulations, particularly in the ACS patients. Therefore, we performed this study to evaluate the association between plasma PFAS exposure and hepatobiliary system function biomarkers in patients with ACS. This study included 546 newly diagnosed ACS patients at the Second Hospital of Hebei Medical University, and data on 15 hepatobiliary system function biomarkers were obtained from medical records. Associations between single PFAS and hepatobiliary system function biomarkers were assessed using multiple linear regression models and restricted cubic spline model (RCS), and mixture effects were assessed using the Quantile g-computation model. The results showed that total bile acids (TBA) was negative associated with perfluorohexane sulfonic acid (PFHxS) (-7.69 %, 95 % CI: -12.15 %, -3.01 %). According to the RCS model, linear associations were found between TBA and PFHxS (P for overall = 0.003, P for non-linear = 0.234). We also have observed the association between between PFAS congeners and liver enzyme such as aspartate aminotransferase (AST) and α-l-Fucosidase (AFU), but it was not statistically significant after correction. In addition, Our results also revealed an association between prealbumin (PA) and PFAS congeners as well as mixtures. Our findings have provided a piece of epidemiological evidence on associations between PFAS congeners or mixture, and serum hepatobiliary system function biomarkers in ACS patients, which could be a basis for subsequent mechanism studies.
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Affiliation(s)
- Fang Xiao
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Ming Yang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Junli Lv
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Jing Li
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Mingmei Guo
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - WenJing Duan
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Haoran Li
- Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Ziwen An
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Zhengyi Su
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Ang Li
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Yi Liu
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Jingchao Lu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Huicai Guo
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Environment and Human Health, Shijiazhuang 050017, China; The Key Laboratory of Neural and Vascular Biology Ministry of Education, Shijiazhuang 050017, China.
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4
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Li J, Gao Q, Liu H, Liu S, Wang Y, Sun X, Zheng J, Yang H, Hu B. Integrating 16S rDNA sequencing analysis and targeted metabolomics to explore the mechanism of Xiexin Tang in treating atherosclerosis mice induced by high-fat diet. J Pharm Biomed Anal 2025; 259:116760. [PMID: 40014894 DOI: 10.1016/j.jpba.2025.116760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/01/2025]
Abstract
Xiexin Tang (XXT) is a classic Chinese medicine formula that can be used to treat Atherosclerosis (AS). This study aimed to investigate the mechanism by which XXT regulated AS lipid levels. Firstly, the mixture components of XXT were analyzed by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Then, the AS model based on Apolipoprotein E knockout (ApoE-/-) mice was established. Cytokines related to lipid metabolism and bile acid metabolism were detected by Quantitative Real-time PCR (qRT-PCR). 16S rDNA gene sequencing was performed to analyze differential bacterial populations, and the mechanism of XXT regulation of bile acids affecting lipid metabolism was further explored by targeted metabolomics. Further, antibiotic-treated mice were used to investigate the role of gut microbiota in the anti-AS effect of XXT. The results showed that XXT attenuated the lipid levels and reversed the abnormal elevation of cytokines, such as hepatic lipid metabolism and inflammatory reaction in AS mice. XXT also repaired the gut barrier damage and reversed gut microbiota disorders in AS mice. Furthermore, the metabolic levels of bile acids were reshaped by XXT. Whereas, in the absence of gut microbiota, XXT failed to attenuate lipid levels and inhibit the expression of cytokines related to inflammation and bile acid metabolism in AS mice and failed to play a role in ultimately treating AS. In conclusion, XXT could effectively inhibit the inflammatory reaction and lipid accumulation in AS mice, and this effect was closely related to its remodeling of gut microbiota to regulate bile acid metabolism.
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MESH Headings
- Animals
- Drugs, Chinese Herbal/pharmacology
- Atherosclerosis/drug therapy
- Atherosclerosis/metabolism
- Mice
- Gastrointestinal Microbiome/drug effects
- Metabolomics/methods
- Lipid Metabolism/drug effects
- Diet, High-Fat/adverse effects
- Male
- Bile Acids and Salts/metabolism
- Mice, Inbred C57BL
- Chromatography, High Pressure Liquid/methods
- Tandem Mass Spectrometry/methods
- RNA, Ribosomal, 16S/genetics
- Mice, Knockout, ApoE
- Disease Models, Animal
- DNA, Ribosomal/genetics
- Cytokines/metabolism
- Mice, Knockout
- Liver/metabolism
- Liver/drug effects
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Affiliation(s)
- Junling Li
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Qianru Gao
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hongtao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Songlin Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Yanchun Wang
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Xiongjie Sun
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Junping Zheng
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Huabing Yang
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China.
| | - Baifei Hu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education, Huangjiahu West Road 16, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Huangjiahu West Road 16, Wuhan 430065, PR China.
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5
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Lin D, Chen X, Lin X, Zhang C, Liang T, Zheng L, Xu Y, Huang L, Qiao Q, Xiong K. New insight into intestinal toxicity accelerated by aged microplastics with triclosan: Inflammation regulation by gut microbiota-bile acid axis. JOURNAL OF HAZARDOUS MATERIALS 2025; 492:138308. [PMID: 40250280 DOI: 10.1016/j.jhazmat.2025.138308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/20/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025]
Abstract
The combined toxic effects of microplastics (MPs) and their carried contaminants on organisms have been widely concerned; however, the health risks and its mechanism of "gut microbiota-host metabolism (bile acids, BA)" remain unknown. Herein, Xenopus tropicalis were exposured to aged polystyrene MPs carried triclosan (aPS+TCS) and single (a)PS-MPs & TCS, respectively. The bioaccumulation of TCS in the gut of X. tropicalis was significantly increased in aPS+TCS group, which was 89 % higher than that of PS+TCS group, causing more severe oxidative stress, inflammation and intestinal barrier disruption (leaky gut). The expressions of TNF-α, IL-6 and IL-10 in aPS+TCS group were enhanced by 276 % and 19 % and decreased by 81 %, respectively, compared to that in PS+TCS group. Moreover, co-exposure to aPS+TCS increased the number of Escherichia coli, and reduced levels of DCA and LCA (secondary BAs). Multiomics analysis further revealed that the intestinal toxicity of aPS+TCS to X. tropicalis was mainly influenced by the gut flora, BA metabolism and inflammation-related pathways. Co-exposure may exacerbate inflammation by increasing the blood levels of lipopolysaccharides and inhibiting secondary BA production, which are regulated by the gut microbiota-bile acid axis. This study provides new insights in the potential mechanisms of intestinal damage from pollutant-loaded aged MPs.
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Affiliation(s)
- Dawu Lin
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Xiangyu Chen
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Xiaojun Lin
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Chaonan Zhang
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Taojie Liang
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Li Zheng
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China; Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangzhou Key Laboratory Environmental Catalysis and Pollution Control, Institute of Environmental Health and Pollution Control, Guangzhou 510006, China.
| | - Yanbin Xu
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China.
| | - Lu Huang
- Instrumental Analysis Center, Guangdong University of Technology, Guangzhou 510006, China
| | - Qingxia Qiao
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Kairong Xiong
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
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6
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Wu D, Liu J, Guo Z, Wang L, Yao Z, Wu Q, Lu Y, Lv W. Natural bioactive compounds reprogram bile acid metabolism in MAFLD: Multi-target mechanisms and therapeutic implications. Int Immunopharmacol 2025; 157:114708. [PMID: 40306110 DOI: 10.1016/j.intimp.2025.114708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/20/2025] [Accepted: 04/20/2025] [Indexed: 05/02/2025]
Abstract
Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.
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Affiliation(s)
- Dongjie Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Jing Liu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ziwei Guo
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Liang Wang
- Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Ziang Yao
- Department of Traditional Chinese Medicine, Peking University People's Hospital, Beijing 100044, China
| | - Qingjuan Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Yanping Lu
- Department of Hepatology, Shenzhen Bao'an District Traditional Chinese Medicine Hospital, Shenzhen 518100, China.
| | - Wenliang Lv
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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7
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Guan WX, Zhuo-Lan, Luo XJ, Gao JX, Bai CX. Comparative study on the effects of high fat diet and capsicum diet on the digestive organs of guinea pigs. Sci Rep 2025; 15:17886. [PMID: 40404945 PMCID: PMC12098767 DOI: 10.1038/s41598-025-93583-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 03/07/2025] [Indexed: 05/24/2025] Open
Abstract
This study examined the different effects of high-fat and capsicum diets on the digestive organs of guinea pigs. Hartley guinea pigs (n = 24) were divided into the high-fat diet (HFD), capsicum diet (CD), and control (C) groups. Guinea pigs in the C, HFD, and CD groups received maintenance feed, high-fat, and capsicum diets, respectively. After 12 weeks of modelling, serum samples were collected for biochemical analysis. Enzyme-linked immunosorbent assay was used to quantify interleukin-1β, interleukin-6, and tumour necrosis factor-α, while haematoxylin-eosin staining was used to observe morphological changes. Blood lipid levels and inflammatory markers in the serum of guinea pigs in HFD and CD groups were significantly elevated than those in the serum of guinea pigs in the C group (P < 0.01). Inflammation and blood lipid disorders were more severe among guinea pigs in the HFD group than among those in the CD and C groups (P < 0.001). Pathological examinations revealed that high-fat and capsicum diets induce damage to the liver, stomach, gallbladder, and colon. Specifically, high-fat diets exhibited more significant effects. High-fat or capsicum diet consumption can damage the digestive organs, causing abnormal lipid metabolism; however, high-fat diets exhibit more significant effects on the digestive organs.
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Affiliation(s)
- Wen-Xiang Guan
- Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Zhuo-Lan
- Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Xiao-Jun Luo
- Hulunbuir City Chinese-Mongolian Hospital, Hulunbuir, Inner Mongolia, China.
| | - Jing-Xian Gao
- Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
| | - Chang-Xi Bai
- Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
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8
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Zhao H, Zhu D, Gao Y, Wang B. Bile Acids Modulate Hepatic Glycolipid Metabolism via the Microbiota-Gut-Liver Axis in Lambs. J Nutr 2025:S0022-3166(25)00290-1. [PMID: 40368303 DOI: 10.1016/j.tjnut.2025.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 05/05/2025] [Accepted: 05/08/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Bile acids are essential molecules that facilitate lipid emulsification and function as signaling molecules mediating host-microbiota interactions. They shape the gut microbial structure and function, playing a critical role in metabolic regulation via the gut-liver axis. OBJECTIVES This study aimed to investigate the effects of exogenous bile acids, primarily hyocholic acid (HCA), on the microbiota-gut-liver metabolism in male Tan-lambs fed a high-grain diet. METHOD Thirty six-month-old male Tan lambs (Ovis aries) were randomly allocated into either a control (CON) group or an HCA-supplemented group (n = 15 per group). The trial lasted 84 days, including a 14-day adaptation period. On day 70, six lambs from each group were randomly selected for slaughter. Rumen and ileal contents were collected for microbial profiling via 16S rRNA sequencing, and liver tissue samples were harvested for transcriptomic and metabolomic analyses. RESULTS The HCA intervention significant altered the composition and structure of ruminal and ileal bacteria. Notable increases were observed in Turicibacter (linear discriminant analysis (LDA) score = 2.48; P < 0.05) and Muribaculaceae (LDA score = 3.75; P < 0.05) in the rumen, and Eubacterium fissicatena group (LDA score = 2.50; P < 0.05) in the ileum. Key hepatic genes and metabolites targeted by HCA were identified, including ENPP3, RFK, Ifi203, LIPG, CYP1A1, CYP4A11, nordeoxycholic acid (log-fold change = 6.30, P < 0.005), α-muricholic acid (log-fold change = 5.60, P < 0.001), β-muricholic acid (log-fold change = 5.60, P < 0.001). CONCLUSIONS Exogenous bile acids regulate the microbiota-gut-liver axis, influencing hepatic glycolipid metabolism in sheep. Specifically, nordeoxycholic acid, demonstrates potential as a dietary intervention to promote metabolic homeostasis in ruminants. These findings highlight the potential of HCA and norDCA as functional feed additives or prebiotic agents for improving metabolic health in ruminants and potentially other species.
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Affiliation(s)
- Hailong Zhao
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Daiwei Zhu
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Yuyang Gao
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Bing Wang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, P. R. China.
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9
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Lee SK, Kwon JH, Jang JW, Bae SH, Yoon SK, Jung ES, Choi JY. The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome. Transplantation 2025; 109:784-793. [PMID: 39375899 DOI: 10.1097/tp.0000000000005220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4 + regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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10
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Yang S, Qiao J, Zhang M, Kwok LY, Matijašić BB, Zhang H, Zhang W. Prevention and treatment of antibiotics-associated adverse effects through the use of probiotics: A review. J Adv Res 2025; 71:209-226. [PMID: 38844120 DOI: 10.1016/j.jare.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 05/18/2024] [Accepted: 06/03/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND The human gut hosts a diverse microbial community, essential for maintaining overall health. However, antibiotics, commonly prescribed for infections, can disrupt this delicate balance, leading to antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and even neurological disorders. Recognizing this, probiotics have emerged as a promising strategy to counteract these adverse effects. AIM OF REVIEW This review aims to offer a comprehensive overview of the latest evidence concerning the utilization of probiotics in managing antibiotic-associated side effects. KEY SCIENTIFIC CONCEPTS OF REVIEW Probiotics play a crucial role in preserving gut homeostasis, regulating intestinal function and metabolism, and modulating the host immune system. These mechanisms serve to effectively alleviate antibiotic-associated adverse effects and enhance overall well-being.
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Affiliation(s)
- Shuwei Yang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Huhhot 010018, China
| | - Jiaqi Qiao
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Huhhot 010018, China
| | - Meng Zhang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Huhhot 010018, China
| | - Lai-Yu Kwok
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Huhhot 010018, China
| | | | - Heping Zhang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Huhhot 010018, China
| | - Wenyi Zhang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Huhhot 010018, China.
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11
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Luo X, Yang W, Kang Y, Ma S, Fan Y, Du J, Luo H, Wang X, Deng F. Research progress of the intestinal axis in autologous arteriovenous fistula stenosis in maintenance hemodialysis patients. J Vasc Access 2025:11297298251332047. [PMID: 40251786 DOI: 10.1177/11297298251332047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2025] Open
Abstract
The number of the patients treated with maintenance hemodialysis (HD) is increasing due to the increasing incidence of end stage renal disease (ESRD). Autologous arteriovenous fistula (AVF) is the preferable modality for long-term vascular access during HD. AVF stenosis is the main cause of AVF dysfunction in HD patients, but its mechanism has not been fully elucidated. Patients with ESRD often have various related complications due to intestinal microbiota disorders and their metabolites, and the intestinal axis reveals various metabolic disorders in patients with chronic kidney disease. This paper analyzes the correlation between intestinal axis abnormalities and AVF stenosis in patients with CKD through three axes: "gut-liver axis," "gut-brain axis," and "gut-spleen axis," to provide clinical significance for elucidating the mechanism of AVF stenosis and for the prevention and treatment of AVF stenosis.
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Affiliation(s)
- Xuyang Luo
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Sichuan Provincial People's Hospital Xinjin Hospital, Chengdu Xinjin District People's Hospital, Chengdu, China
| | - Wei Yang
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yuwei Kang
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Shijie Ma
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Fan
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jiaojiao Du
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Huan Luo
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xudong Wang
- Department of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Fei Deng
- Department of Nephrology, Sichuan Provincial People's Hospital Xinjin Hospital, Chengdu Xinjin District People's Hospital, Chengdu, China
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12
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Guilmineau C, Tremblay-Franco M, Vialaneix N, Servien R. Phoenics: a novel statistical approach for longitudinal metabolomic pathway analysis. BMC Bioinformatics 2025; 26:105. [PMID: 40240918 PMCID: PMC12001596 DOI: 10.1186/s12859-025-06118-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Metabolomics describes the metabolic profile of an organism at a given time by the concentrations of its constituent metabolites. When studied over time, metabolite concentrations can help understand the dynamical evolution of a biological process. However, metabolites are involved into sequences of chemical reactions, called metabolic pathways, related to a given biological function. Accounting for these pathways into statistical methods for metabolomic data is thus a relevant way to directly express results in terms of biological functions and to increase their interpretability. METHODS We propose a new method, phoenics, to perform differential analysis for longitudinal metabolomic data at the pathway level. In short, phoenics proceeds in two steps: First, the matrix of metabolite quantifications is transformed by a dimension reduction approach accounting for pathway information. Then, a mixed linear model is fitted on the transformed data. RESULTS This method was applied to semi-synthetic NMR data and two real NMR datasets assessing the effects of antibiotics and irritable bowel syndrome on feces. Results showed that phoenics properly controls the Type I error rate and has a better ability to detect differential metabolic pathways and to extract new impacted biological functions than alternative methods. The method is implemented in the R package phoenics available on CRAN.
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Affiliation(s)
- Camille Guilmineau
- INRAE, University of Montpellier, LBE, 102 Avenue des Etangs, 11100, Narbonne, France.
| | - Marie Tremblay-Franco
- INRAE, Université de Toulouse, ENVT, Toxalim, 31027, Toulouse, France
- Axiom Platform, MetaToul-MetaboHUB, National Infrastructure for Metabolomics and Fluxomics, 31027, Toulouse, France
| | | | - Rémi Servien
- INRAE, University of Montpellier, LBE, 102 Avenue des Etangs, 11100, Narbonne, France
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13
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Qi Y, Du S, Li W, Qiu X, Zhou F, Bai L, Zhang B, Mi Z, Qian W, Li L, Zhao X, Li Y. Sanye tablet regulates gut microbiota and bile acid metabolism to attenuate hepatic steatosis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119514. [PMID: 39971018 DOI: 10.1016/j.jep.2025.119514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 02/13/2025] [Accepted: 02/16/2025] [Indexed: 02/21/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sanye Tablet (SYT), a patent traditional Chinese prescription, is commonly used in treating type 2 diabetes mellitus and hyperlipidemia. Both clinical and animal studies suggest that SYT effectively regulates lipid metabolism. However, its mode of action on hepatic steatosis has yet to be fully elucidated. AIM OF STUDY This study investigates the lipid-regulating effects and underlying mechanism of SYT in high-fat diet (HFD)-induced hepatic steatosis mice. MATERIAL AND METHODS The inhibitory effects of SYT on developing hepatic steatosis were investigated in HFD-fed C57BL/6N mice. Biochemical markers, including total cholesterol (TC) and triglycerides (TG), were measured using specific kits. Hepatic histological alterations were determined by Hematoxylin and Eosin (H&E) and Oil Red O staining. Hepatic, fecal, and systemic bile acids (BAs) profiles were detected by UPLC-MS. mRNA and protein levels of BAs synthesis-related enzymes and critical nodes of farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15)/fibroblast growth factor receptor 4 (FGFR4) signaling were detected. Fecal microbial composition was analyzed by 16S rRNA gene sequencing and the antimicrobial activity of SYT was further evaluated in vitro. RESULTS SYT alleviated HFD-induced hepatic steatosis by decreasing TG and TC levels, relieving hepatocyte ballooning, and promoting hepatic BAs synthesis. Moreover, SYT significantly increased the levels of taurine-conjugated BAs in the liver and feces, which in turn inhibited the FXR/FGF15/FGFR4 signaling. Consequently, the hepatic BAs synthesis-related enzyme expression was promoted to reduce lipid accumulation. Notably, SYT remodeled the gut microbiota composition of HFD-fed mice, especially inhibiting the growth of bile salt hydrolase (BSH)-producing bacteria, such as Lactobacillus murinus, Lactobacillus johnsonii, and Enterococcus faecalis. CONCLUSION The findings illustrated that SYT prevented hepatic steatosis by improving hepatic lipid accumulation, which is reflected in modulating the gut-liver axis. SYT corrects BAs profile, restores perturbed FXR/FGF15/FGFR4 signaling and promotes hepatic BAs synthesis, which is associated with modulation on certain BSH-producing bacteria.
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Affiliation(s)
- Yulin Qi
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Siqi Du
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Wenwen Li
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xianzhe Qiu
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Fengjie Zhou
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Liding Bai
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Boli Zhang
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Zhuoxin Mi
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Weiqiang Qian
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lin Li
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Xin Zhao
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Yuhong Li
- Key Laboratory of Traditional Chinese Medical Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
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14
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He Y, Hu H, Liang X, Liang J, Li F, Zhou X. Gut microbes-muscle axis in muscle function and meat quality. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2885-4. [PMID: 40220074 DOI: 10.1007/s11427-024-2885-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 02/12/2025] [Indexed: 04/14/2025]
Abstract
The concept of the gut microbes-muscle axis underscores the impact of intestinal microbiota on the muscular system, an area that is increasingly coming to light. However, current interpretations and applications of this concept remain underdeveloped. In this review, we concluded and discussed factors, such as short-chain fatty acids, amino acids, vitamins, bile acids, antibiotics, cytokines, hormones, and extracellular vesicles that mediate gut microbes-muscle crosstalk and influence the gut microbes-muscle axis. Additionally, we examined how the gut microbes-muscle axis affects muscle mass, muscle strength, muscle metabolism, as well as muscle oxidative and immune status. Furthermore, we reviewed the influence of the microbes-muscle axis on muscle fiber type transition, muscle fat deposition, and meat quality. These insights illuminate the potential mechanisms by which the gut microbes-muscle axis operates in humans and animals. Thus, this review provides a theoretical foundation for future research and offers practical guidance for its application in biomedical and livestock industries.
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Affiliation(s)
- Yiwen He
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Hong Hu
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China
| | - Xuqing Liang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, 410128, China
| | - Jing Liang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fengna Li
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Xihong Zhou
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
- Hunan Provincial Key Laboratory of the Traditional Chinese Medicine Agricultural Biogenomics, Changsha Medical University, Changsha, 410219, China.
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Basu S, Običan SG, Bertaggia E, Staab H, Izquierdo MC, Gyamfi-Bannerman C, Haeusler RA. Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after UDCA treatment for intrahepatic cholestasis of pregnancy. Am J Physiol Gastrointest Liver Physiol 2025; 328:G364-G376. [PMID: 39947696 PMCID: PMC12053871 DOI: 10.1152/ajpgi.00266.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/25/2024] [Accepted: 02/03/2025] [Indexed: 02/19/2025]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor before 40 wk of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and alanine aminotransferase levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among patients with ICP, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in patients with ICP exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP.NEW & NOTEWORTHY This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.
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Affiliation(s)
- Srijani Basu
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Columbia University Digestive and Liver Disease Research Center, Columbia University, New York, New York, United States
- Department of Medicine, Columbia University, New York, New York, United States
| | - Sarah G Običan
- Department of Obstetrics and Gynecology, Columbia University, New York, New York, United States
- Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida, United States
| | - Enrico Bertaggia
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | - Hannah Staab
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
| | - M Concepcion Izquierdo
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | | | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Columbia University Digestive and Liver Disease Research Center, Columbia University, New York, New York, United States
- Department of Medicine, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
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16
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Cadena Sandoval M, Haeusler RA. Bile acid metabolism in type 2 diabetes mellitus. Nat Rev Endocrinol 2025; 21:203-213. [PMID: 39757322 PMCID: PMC12053743 DOI: 10.1038/s41574-024-01067-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 01/07/2025]
Abstract
Type 2 diabetes mellitus is a complex disorder associated with insulin resistance and hyperinsulinaemia that is insufficient to maintain normal glucose metabolism. Changes in insulin signalling and insulin levels are thought to directly explain many of the metabolic abnormalities that occur in diabetes mellitus, such as impaired glucose disposal. However, molecules that are directly affected by abnormal insulin signalling might subsequently go on to cause secondary metabolic effects that contribute to the pathology of type 2 diabetes mellitus. In the past several years, evidence has linked insulin resistance with the concentration, composition and distribution of bile acids. As bile acids are known to regulate glucose metabolism, lipid metabolism and energy balance, these findings suggest that bile acids are potential mediators of metabolic distress in type 2 diabetes mellitus. In this Review, we highlight advances in our understanding of the complex regulation of bile acids during insulin resistance, as well as how bile acids contribute to metabolic control.
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Affiliation(s)
- Marti Cadena Sandoval
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA
- Columbia Digestive and Liver Disease Research Center, Columbia University Medical Center, New York, NY, USA
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA.
- Department of Medicine, Columbia University Medical Center, New York, NY, USA.
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.
- Columbia Digestive and Liver Disease Research Center, Columbia University Medical Center, New York, NY, USA.
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17
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Liu J, Guo M, Yuan X, Fan X, Wang J, Jiao X. Gut Microbiota and Their Metabolites: The Hidden Driver of Diabetic Nephropathy? Unveiling Gut Microbe's Role in DN. J Diabetes 2025; 17:e70068. [PMID: 40189872 PMCID: PMC11973130 DOI: 10.1111/1753-0407.70068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 01/21/2025] [Accepted: 02/17/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a severe microvascular complication of diabetes with a complex pathogenesis. METHODS Recent studies were reviewed to explore the role of gut microbiota and its metabolites in DN development. RESULTS Dysbiosis of gut bacteria contributes to pathological changes such as glomerular sclerosis and renal tubule injury. Microbial metabolites are involved in DN through immune and inflammatory pathways. CONCLUSIONS Understanding the relationship between gut microbiota, its metabolites, and DN may offer potential implications for DN diagnosis, prevention, and treatment. Translating this knowledge into clinical practice presents challenges and opportunities.
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Affiliation(s)
- Jinzhou Liu
- Department of PhysiologyThe Key Laboratory of Physiology of Shanxi Province, the Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical UniversityTaiyuanChina
| | - Min Guo
- Department of PhysiologyThe Key Laboratory of Physiology of Shanxi Province, the Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical UniversityTaiyuanChina
| | - Xiaobin Yuan
- Department of UrologyFirst Hospital of Shanxi Medical UniversityTaiyuanChina
| | - Xiao Fan
- Department of UrologyFirst Hospital of Shanxi Medical UniversityTaiyuanChina
| | - Jin Wang
- Department of PhysiologyThe Key Laboratory of Physiology of Shanxi Province, the Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical UniversityTaiyuanChina
| | - Xiangying Jiao
- Department of PhysiologyThe Key Laboratory of Physiology of Shanxi Province, the Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical UniversityTaiyuanChina
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18
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Lyu Y, Hu J, Wang X, Zhang J, Li X, Cui M, Tang X, Zhou P. Lactopontin regulates gut microbiota and calcium absorption to promote bone growth in growing rats. Int J Biol Macromol 2025; 302:140557. [PMID: 39894097 DOI: 10.1016/j.ijbiomac.2025.140557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/26/2025] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
Lactopontin (LPN) is an important milk protein with the potential to improve bone health, however, the specific effects have not been determined. This study investigates the effects of LPN on early bone growth and development. 3-week-old SD rats (n = 16) were assigned to the control group and LPN group, receiving intragastric administration of deionized water and 15 mg/kg LPN for 30 days respectively. LPN supplementation increased body length, femur length and femur strength, improved femoral bone volume and microarchitecture, and upregulated the expression of osteoblast activity related mRNA (Bmp2, Smad8, Wnt10b and β-catenin) in the femur. The abundance of Parabacteroides in feces and the content of glycochenodeoxycholic acid (GCDCA) in serum were significantly elevated following LPN intervention. Additionally, the bile acid receptor TGR5 in the femur was activated in the LPN group, suggesting that LPN may regulate bone health via the microbiota-metabolites-bone axis. Furthermore, LPN promoted calcium absorption through transcellular and cellular bypass pathways, resulting in a significant increase in serum calcium content. These results indicate that LPN has potential application value in regulating bone metabolism during growth.
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Affiliation(s)
- Yipin Lyu
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Jianqiang Hu
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xinyan Wang
- International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Jie Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Xue Li
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Mengjun Cui
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xue Tang
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Peng Zhou
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
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19
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Liu Y, Wang R, Zhou J, Lyu Q, Zhao X, Yang X, Chen K, Gao Z, Li X. Myricetin alleviates high-fat diet-induced atherosclerosis in ApoE -/- mice by regulating bile acid metabolism involved in gut microbiota remodeling. Food Funct 2025; 16:2737-2749. [PMID: 40059779 DOI: 10.1039/d5fo00374a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Atherosclerosis poses a significant threat to global health. This study aimed to investigate the effects of myricetin (MYR) on high-fat diet (HFD)-induced atherosclerosis in ApoE-/- mice. Our findings demonstrated that MYR treatment significantly reduced the formation of atherosclerotic plaques, particularly at a high dose of 100 mg kg-1 day-1. Additionally, MYR markedly attenuated lipid metabolism disorders in ApoE-/- mice by decreasing body weight, improving serum lipid profiles, and reducing lipid deposition. Analysis of 16S rRNA sequencing revealed that MYR treatment enhanced the abundance of probiotic g_Lachnospiraceae_NK4A136, while it reduced that of obesity-associated genera, including Rikenellaceae_RC9_gut_group and Alistipes. Metabolomic analysis and RT-qPCR tests indicated that MYR upregulated hepatic bile acid biosynthesis, evidenced by increased total bile acid levels and enhanced expression of key enzymes CYP7A1 and CYP8B1, particularly through the classical biosynthetic pathway. Spearman's correlation analysis revealed strong associations between the regulated bile acids and these aforementioned bacteria. Therefore, our results demonstrated that MYR exerts an anti-atherosclerotic effect by modulating the gut-liver axis.
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Affiliation(s)
- Yilong Liu
- Zhejiang Key Laboratory of Horticultural Crop Quality Improvement, Zhejiang University, Hangzhou 310058, China.
| | - Ruoqi Wang
- Zhejiang Key Laboratory of Horticultural Crop Quality Improvement, Zhejiang University, Hangzhou 310058, China.
| | - Jinren Zhou
- Department of Vascular Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
| | - Qiang Lyu
- School of Pharmacy, Zhejiang Chinese Medical University, 548, Binwen Road, Hangzhou 310053, China
| | - Xiaoyong Zhao
- Zhejiang Key Laboratory of Horticultural Crop Quality Improvement, Zhejiang University, Hangzhou 310058, China.
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Shandong (Linyi) Institute of Modern Agriculture, Zhejiang University, Linyi 276000, China
| | - Kunsong Chen
- Zhejiang Key Laboratory of Horticultural Crop Quality Improvement, Zhejiang University, Hangzhou 310058, China.
| | - Zhiwei Gao
- Department of Vascular Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
| | - Xian Li
- Zhejiang Key Laboratory of Horticultural Crop Quality Improvement, Zhejiang University, Hangzhou 310058, China.
- Shandong (Linyi) Institute of Modern Agriculture, Zhejiang University, Linyi 276000, China
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20
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Jiao S, Ren Q, Chen L, Zhou Z, Cai Z, Huang W, Wang B, Chen S, Wang W, Cao Z, Yang Z, Ye Q, Zhang L, Li Z. Discovery of First-in-Class FXR and HSD17B13 Dual Modulator for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease. J Med Chem 2025; 68:6127-6148. [PMID: 39851255 DOI: 10.1021/acs.jmedchem.4c02720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by diverse metabolic and inflammatory pathways. Farnesoid X receptor (FXR) is a promising target for MASH due to its role in bile acid and lipid metabolism, while HSD17B13 regulates liver lipid droplet homeostasis. However, the existing HSD17B13 inhibitors have several druglike property challenges due to the common phenolic structure, a key pharmacophore for the HSD17B13 inhibitor. In this study, a two-round high-throughput screening was performed to identify the FXR agonist 2 as the nonphenolic HSD17B13 inhibitor. The multiparameter structural optimization led to the discovery of dual FXR/HSD17B13 modulator 6, with high target selectivity, target tissue distribution, suitable pharmacokinetic properties, and safety profiles. Moreover, even at the lower dose, compound 6 exerted a better therapeutic effect than obeticholic acid (OCA) in multiple MASH models. With attractive pharmacological activity and safety profiles, the dual FXR/HSD17B13 modulator 6 is worthy of further evaluation as a novel anti-MASH agent.
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Affiliation(s)
- Shixuan Jiao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Qiang Ren
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Lianru Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Zongtao Zhou
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
- Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Zongyu Cai
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Wanqiu Huang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Bin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Siliang Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Wenxin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Zhijun Cao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Zhongcheng Yang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Qiqing Ye
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Luyong Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
- Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
- Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
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21
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He Q, Li X, Li H, Tan A, Chi Y, Fang D, Li X, Liu Z, Shang Q, Zhu Y, Cielecka-Piontek J, Chen J. TGR5 Activation by Dietary Bioactives and Related Improvement in Mitochondrial Function for Alleviating Diabetes and Associated Complications. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:6293-6314. [PMID: 40045496 DOI: 10.1021/acs.jafc.4c10395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Takeda G protein-coupled receptor 5 (TGR5), also known as G protein-coupled bile acid receptor 1 (GPBAR1), is a cell surface receptor involved in key physiological processes, including glucose homeostasis and energy metabolism. Recent research has focused on the role of TGR5 activation in preventing or treating diabetes while also highlighting its potential impact on the progression of diabetic complications. Functional foods and edible plants have emerged as valuable sources of natural compounds that can activate TGR5, offering potential therapeutic benefits for diabetes management. Despite growing interest, studies on the activation of TGR5 by dietary bioactive compounds remain scattered. This Review aims to provide a comprehensive analysis of how dietary bioactives act as potential agents for TGR5 activation in managing diabetes and its complications. It explores the mechanisms of TGR5 activation through both direct agonistic effects and indirect pathways via modulation of the gut microbiota and bile acid metabolism.
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Affiliation(s)
- Quanrun He
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Xinhang Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Haimeng Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Aditya Tan
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Yunlin Chi
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Daozheng Fang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Xinyue Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Zhihao Liu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Qixiang Shang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Yong Zhu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
| | - Judyta Cielecka-Piontek
- Department of Pharmacognosy and Biomaterials, Poznan University of Medical Sciences, Rokietnicka 3 Str., 60-806 Poznan, Poland
| | - Jihang Chen
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Shenzhen-Hong Kong International Science and Technology Park, No. 3 Binglang Road, Futian Free Trade Zone, Futian District, Shenzhen, Guangdong 518045, P.R. China
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Rodríguez-Moro G, Cabrera-Rubio R, Selma-Royo M, Gómez-Morlote JA, Collado MC, Abril N, García-Barrera T. Modulation of the gut microbiota and the microbial-produced gut metabolites by diclofenac exposure and selenium supplementation. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2025:10.1007/s11356-025-36233-6. [PMID: 40102351 DOI: 10.1007/s11356-025-36233-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 03/03/2025] [Indexed: 03/20/2025]
Abstract
Diclofenac (DCF) exposure is of great concern due to the ecotoxicological risk linked with a decline of vulture populations in Southeast Asia, but also because it can affect the reproduction and neurotoxicity in mammals. Otherwise, selenium (Se) is an antioxidant essential element with key roles in health and with antagonistic action against pollutants, but in some cases with a synergistic effect. To investigate the potential intertwined mechanisms between DCF, Se, and gut microbiota, gut metabolomic and gut microbiota profiles were determined in mice after DCF exposure and Se supplementation. Speciation of selenoproteins in plasma was carried out by isotopic dilution analysis to quantify the levels of selenoproteins. Significant differences in the levels of 79% of the gut metabolites were determined after DCF exposure. The most significant altered pathway in DCF and DCF-Se groups is the primary bile biosynthesis, being the only pathway altered in mice exposed to DCF, while in DCF-Se, the metabolism of galactose and linoleic acid is also altered. Moreover, specific associations between specific gut microbiota and metabolites were determined in the studied mice groups suggesting intertwined mechanisms. Selenium supplementation modulated the gut metabolic and microbiota profiles affected by DCF.
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Affiliation(s)
- Gema Rodríguez-Moro
- Department of Chemistry, Faculty of Experimental Sciences, Research Center of Natural Resources, Health and the Environment (RENSMA), University of Huelva, Fuerzas Armadas Ave, 21007, Huelva, Spain
| | - Raúl Cabrera-Rubio
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Agustin Escardino 7, 46980, Paterna, Valencia, Spain
| | - Marta Selma-Royo
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Agustin Escardino 7, 46980, Paterna, Valencia, Spain
| | - José Antonio Gómez-Morlote
- Department of Chemistry, Faculty of Experimental Sciences, Research Center of Natural Resources, Health and the Environment (RENSMA), University of Huelva, Fuerzas Armadas Ave, 21007, Huelva, Spain
| | - Maria Carmen Collado
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Agustin Escardino 7, 46980, Paterna, Valencia, Spain
| | - Nieves Abril
- Department of Biochemistry and Molecular Biology, University of Córdoba, Campus de Rabanales, Edificio Severo Ochoa, 14071, Córdoba, Spain
| | - Tamara García-Barrera
- Department of Chemistry, Faculty of Experimental Sciences, Research Center of Natural Resources, Health and the Environment (RENSMA), University of Huelva, Fuerzas Armadas Ave, 21007, Huelva, Spain.
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23
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Ferrari A, Tontonoz P. Nonvesicular cholesterol transport in physiology. J Clin Invest 2025; 135:e188127. [PMID: 40091839 PMCID: PMC11910210 DOI: 10.1172/jci188127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.
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24
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Yang YJ, Zhou XC, Tian HR, Liang FX. Electroacupuncture relieves type 2 diabetes by regulating gut microbiome. World J Diabetes 2025; 16:103032. [PMID: 40093270 PMCID: PMC11885963 DOI: 10.4239/wjd.v16.i3.103032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/21/2025] Open
Abstract
Cumulative studies have shown that the composition of the gut microbiome is strongly associated with the development of type 2 diabetes mellitus (T2DM). Electroacupuncture (EA) therapy has been reported to alleviate various diseases, including T2DM, by targeting specific acupuncture points and regulating metabolic homeostasis. A recent review published in the World Journal of Diabetes detailed the role of the gut microbiome in T2DM, discussing the role of therapeutic strategies developed to alleviate T2DM and its complications based on gut microbiome in ameliorating T2DM, as well as the effects of multiple diabetes medications on gut microbiome. However, the review did not elucidate the therapeutic role of EA therapy, a common non-pharmacological intervention for T2DM. This letter complemented the effect of EA therapy on glucose metabolism by adjusting the gut microbiome composition, which reveals the underlying mechanism of glucose lowering by EA therapy and provides a scientific basis for the application of EA therapy in clinical treatment.
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Affiliation(s)
- Ya-Jing Yang
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Xu-Chang Zhou
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Hao-Ran Tian
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Feng-Xia Liang
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
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Gong X, Liu D, Liu L, Yang G, Lei Y, Li N, Chen Y, Yu H, Li X, Xiang D. Plasma bile acid profile analysis by liquid chromatography-tandem mass spectrometry and its application in healthy subjects and IBD patients. J Pharm Biomed Anal 2025; 255:116639. [PMID: 39709683 DOI: 10.1016/j.jpba.2024.116639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/03/2024] [Accepted: 12/14/2024] [Indexed: 12/24/2024]
Abstract
Bile acids (BAs), not only promote the absorption of fat-soluble nutrients and regulate the metabolism of multiple substances but also have a potential role as diagnostic and prognostic indicators in a variety of diseases such as cholestasis, hepatocellular carcinoma, and diabetes mellitus. Here, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of 50 BAs was developed and validated. Sample preparation included internal standard spiking, followed by protein precipitation, centrifugation, solvent evaporation, and reconstitution. Baseline separation of all isobaric BA species was achieved on an Ultimate XS-C18 column (5 μm, 150 mm × 4.6 mm). The method showed good linearity with high regression coefficients (>0.990) with acceptable accuracy and precision for intra-day and inter-day analyses and achieved good recovery rates for representative analytes. No apparent carryover or matrix effect was observed. The analytical method was successfully applied to the determination of the plasma BA profile in healthy subjects and patients with inflammatory bowel disease (IBD). The routine instrumentation, low sample volume, simple pretreatment, wide range of BAs, and good separation make this LC-MS/MS method suitable for use as a BA profile assay in clinical and basic research studies. This method could be poised to identify possible BA biomarkers for non-invasive early diagnosis and therapeutic evaluation of IBD.
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Affiliation(s)
- Xuepeng Gong
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lu Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guangjie Yang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yongfang Lei
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - NingHong Li
- Department of Pharmacy, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China
| | - Yufei Chen
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hengyi Yu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiping Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dong Xiang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Jia F, Liu X, Liu Y. Bile acid signaling in skeletal muscle homeostasis: from molecular mechanisms to clinical applications. Front Endocrinol (Lausanne) 2025; 16:1551100. [PMID: 40144297 PMCID: PMC11936799 DOI: 10.3389/fendo.2025.1551100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
The intricate relationship between bile acid metabolism and skeletal muscle function has emerged as a crucial area of research in metabolic health. This review synthesizes current evidence highlighting the fundamental role of bile acids as key signaling molecules in muscle homeostasis and their therapeutic potential in muscle-related disorders. Recent advances in molecular biology and metabolomics have revealed that bile acids, beyond their classical role in lipid absorption, function as essential regulators of muscle mass and function through multiple signaling pathways, particularly via the nuclear receptor FXR and membrane receptor TGR5. Clinical studies have demonstrated significant associations between altered bile acid profiles and muscle wasting conditions, while experimental evidence has elucidated the underlying mechanisms linking bile acid signaling to muscle protein synthesis, energy metabolism, and regeneration capacity. We critically examine the emerging therapeutic strategies targeting bile acid pathways, including receptor-specific agonists, microbiome modulators, and personalized interventions based on individual bile acid profiles. Additionally, we discuss novel diagnostic approaches utilizing bile acid-based biomarkers and their potential in early detection and monitoring of muscle disorders. This review also addresses current challenges in standardization and clinical translation while highlighting promising future directions in this rapidly evolving field. Understanding the bile acid-muscle axis may provide new opportunities for developing targeted therapies for age-related muscle loss and metabolic diseases.
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Affiliation(s)
- Feng Jia
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Xiangliang Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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Li S, Wang H, Li B, Lu H, Zhao J, Gao A, An Y, Yang J, Ma T. Multi-Omics Analysis Reveals the Negative Effects of High-Concentrate Diets on the Colonic Epithelium of Dumont Lambs. Animals (Basel) 2025; 15:749. [PMID: 40076032 PMCID: PMC11898968 DOI: 10.3390/ani15050749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/03/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Feeding HC diets has been found to induce metabolic dysregulation in the colon. However, the mechanisms by which changes in colonic flora and metabolites damage the colonic epithelium are poorly studied. Therefore, the present experiment used a multi-omics technique to investigate the mechanism of colonic injury induced by high-concentrate diets in lambs. Twelve male Dumont lambs were randomly split into two groups: a low-concentrate diet (LC = concentrate/forage = 30:70) group and a high-concentrate diet (HC = concentrate/forage = 70:30) group. The results showed that the HC group presented significantly increased lipopolysaccharide (LPS) concentrations in the colonic epithelium and significantly decreased serum total cholesterol (TC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels (p < 0.05), which led to cavities and inflammatory cell infiltration in the colonic epithelium. The HC group had significantly lower pH and less VFAs in colon contents, as well as a significantly increased abundance of bacteria of the genera [Eubacterium]_coprostanoligenes_group, Rikenellaceae_RC9_gut_group, Treponema, Clostridia_UCG-014, Alistipes, Ruminococcus, Christensenellaceae_R-7_group, UCG-002, Bacteroidales_RF16_group and Lachnospiraceae_AC2044_group compared to the LC diet group. These microorganisms significantly increased the level of metabolites of cholic acid, chenodeoxycholic acid, LysoPA (P-16:0/0:0), methapyrilene, and fusaric acid. A transcriptome analysis showed that cytokine-cytokine receptor interaction, glutathione metabolism, and the peroxisome signaling pathway were downregulated in the colon epithelium of the lambs fed the HC diet. Therefore, the HC diet caused epithelial inflammation and oxidative damage by affecting the interaction between the microbial flora of the colon and metabolites and the host epithelium, which eventually disrupted colon homeostasis and had a negative impact on sheep health.
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Affiliation(s)
- Shufang Li
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
| | - Hairong Wang
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
| | - Boyang Li
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
| | - Henan Lu
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
| | - Jianxin Zhao
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
| | - Aiwu Gao
- Food Science, Inner Mongolia Agricultural University, Hohhot 010018, China;
| | - Yawen An
- Veterinary Research Institute, Inner Mongolia Academy of Agricultural & Animal Husbandry Sciences, Hohhot 010018, China;
| | - Jinli Yang
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
| | - Tian Ma
- Animal Nutrition and Feed Science, Inner Mongolia Agricultural University, Hohhot 010018, China; (S.L.); (B.L.); (H.L.); (J.Z.); (J.Y.); (T.M.)
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28
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Yang S, Liu H, Liu Y. Advances in intestinal epithelium and gut microbiota interaction. Front Microbiol 2025; 16:1499202. [PMID: 40104591 PMCID: PMC11914147 DOI: 10.3389/fmicb.2025.1499202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/17/2025] [Indexed: 03/20/2025] Open
Abstract
The intestinal epithelium represents a critical interface between the host and external environment, serving as the second largest surface area in the human body after the lungs. This dynamic barrier is sustained by specialized epithelial cell types and their complex interactions with the gut microbiota. This review comprehensively examines the recent advances in understanding the bidirectional communication between intestinal epithelial cells and the microbiome. We briefly highlight the role of various intestinal epithelial cell types, such as Paneth cells, goblet cells, and enteroendocrine cells, in maintaining intestinal homeostasis and barrier function. Gut microbiota-derived metabolites, particularly short-chain fatty acids and bile acids, influence epithelial cell function and intestinal barrier integrity. Additionally, we highlight emerging evidence of the sophisticated cooperation between different epithelial cell types, with special emphasis on the interaction between tuft cells and Paneth cells in maintaining microbial balance. Understanding these complex interactions has important implications for developing targeted therapeutic strategies for various gastrointestinal disorders, including inflammatory bowel disease, metabolic disorders, and colorectal cancer.
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Affiliation(s)
- Sen Yang
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Department of Pediatrics, The Fifth Peoples Hospital of Chengdu, Chengdu, China
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China
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29
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Li X, Huang G, Khan I, Ding Z, Hsiao WLW, Liu Z. The Prebiotic Effect of Kaempferol in Regulating Bile Acid Metabolism. Food Sci Nutr 2025; 13:e70023. [PMID: 40008236 PMCID: PMC11848346 DOI: 10.1002/fsn3.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 02/27/2025] Open
Abstract
Kaempferol (Kae), as a homologous flavonoid, plays a pivotal role in human nutrition and disease treatment. This study endeavors to elucidate the in vivo metabolism of Kae and its potential to modulate the interplay between bile acids (BAs) and gut microbiota (GM). After Kae administration, we analyzed pharmacokinetics, BA levels, and drug metabolic enzymes (DMEs) amount using LC-MS/MS. Subsequently, we checked the gene and protein expression with qRT-PCR and western blot and studied the changes in GM using 16S rRNA sequencing, accompanying in-depth data analysis. Finally, molecular docking was employed to explore Kae's interaction with the Farnesoid X receptor (FXR). Kae enhances its own absorption and metabolic circulation in vivo by upregulating the UDP-Glucuronosyltransferases (UGTs) expression. Furthermore, Kae significantly suppressed the expression of cholesterol 7α-hydroxylase (CYP7A1) while concurrently elevating the sterol 27-hydroxylase (CYP27A1) expression, by activating the liver FXR, a nuclear transcription factor involved in the regulation of CYPs and UGTs enzymes. For BA analysis, Kae induced the upregulation of tauro-BAs by attenuating the activity of bile salt hydrolases (BSH), which correlated with shifts in the GM composition. Specifically, Kae increased the abundance of beneficial bacteria such as Bacteroides acidifaciens and Bifidobacterium choerinum, while reduced populations of species associated with BSH deconjugation. The study indicates that Kae may serve as a prebiotic, modulating the BA-GM interaction to confer nutritional and therapeutic advantages.
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Affiliation(s)
- Xiaoyan Li
- School of Medical Technology and Information EngineeringZhejiang Chinese Medical UniversityHangzhouZhejiangChina
- International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Guoxin Huang
- Clinical Research CenterShantou Central HospitalShantouChina
| | - Imran Khan
- Department of Biotechnology, Faculty of Chemical and Life SciencesAbdul Wali Khan University MardanMardanKhyber PakhtunkhwaPakistan
| | - Zhishan Ding
- School of Medical Technology and Information EngineeringZhejiang Chinese Medical UniversityHangzhouZhejiangChina
| | - Wen Luan Wendy Hsiao
- State Key Laboratory of Quality Research in Chinese MedicineMacau University of Science and TechnologyMacauChina
| | - Zhongqiu Liu
- International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- State Key Laboratory of Quality Research in Chinese MedicineMacau University of Science and TechnologyMacauChina
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30
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Wang J, Zhong MY, Liu YX, Yu JY, Wang YB, Zhang XJ, Sun HP. Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway. Acta Pharmacol Sin 2025; 46:662-671. [PMID: 39567750 PMCID: PMC11845675 DOI: 10.1038/s41401-024-01417-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 10/22/2024] [Indexed: 11/22/2024]
Abstract
Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800 nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.
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Affiliation(s)
- Ji Wang
- Department of Clinical Laboratory, The Second People's Hospital of Hefei / Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, China
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Meng-Yu Zhong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yun-Xia Liu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- The Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Jia-Yu Yu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yi-Bin Wang
- The Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Xue-Jiao Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
| | - Hai-Peng Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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31
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Zhang W, Wang Y, Zhang X, Zhang Y, Yu W, Tang H, Yuan WE. Polyzwitterion-branched polycholic acid nanocarriers based oral delivery insulin for long-term glucose and metabolic regulation in diabetes mellitus. J Nanobiotechnology 2025; 23:133. [PMID: 39987096 PMCID: PMC11846306 DOI: 10.1186/s12951-025-03190-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/01/2025] [Indexed: 02/24/2025] Open
Abstract
Diabetes represents a global health crisis that necessitates advancements in prevention, treatment, and management. Beyond glucose regulation, addressing weight management and associated complications is imperative. This study introduces an oral nanoparticle formulation designed to simultaneously control blood glucose, obesity, and metabolic dysfunction. These nanoparticles, based on poly (zwitterion-cholic acid), incorporate a polyzwitterion component to enhance permeation through the mucus layer and prolong drug residence. Furthermore, bile acid polymers not only regulate lipid metabolism but also ameliorate obesity-associated inflammation in adipose and liver tissues. In vivo experiments demonstrated significant hypoglycemic effects in healthy, type I diabetic, and type II diabetic mice. Notably, the nanocarriers significantly reduced body weight gain, ameliorated inflammation in adipose and liver tissues, and modulated lipid metabolism in the liver of db/db mice. Our study elucidates a comprehensive strategy for addressing glycemic control and diabetes-related complications, offering a promising approach for diabetes prevention and treatment.
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Affiliation(s)
- Wenkai Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Yue Wang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Xiangqi Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Yihui Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Wei Yu
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Haozheng Tang
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Wei-En Yuan
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China.
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32
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Guo Y, Guo W, Chen H, Sun J, Yin Y. Mechanisms of sepsis-induced acute liver injury: a comprehensive review. Front Cell Infect Microbiol 2025; 15:1504223. [PMID: 40061452 PMCID: PMC11885285 DOI: 10.3389/fcimb.2025.1504223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/31/2025] [Indexed: 05/13/2025] Open
Abstract
Sepsis is a severe, often life-threatening form of organ dysfunction that arises from an inappropriately regulated host response to infectious pathogen exposure. As the largest gland in the body, the liver serves as a regulatory hub for metabolic, immune, and detoxification activity. It is also an early sepsis target organ such that hepatic dysfunction is observed in 34-46% of patients with sepsis. The precise mechanisms that give rise to sepsis-induced liver injury, however, remain incompletely understood. Based on the research conducted to date, dysregulated systemic inflammation, microbial translocation, microcirculatory abnormalities, cell death, metabolic dysfunction, and liver inflammation may all contribute to the liver damage that can arise in the context of septicemia. This review was developed to provide an overview summarizing the potential mechanisms underlying sepsis-induced liver injury, informing the selection of potential targets for therapeutic intervention and providing a framework for the alleviation of patient symptoms and the improvement of prognostic outcomes.
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Affiliation(s)
- Yongjing Guo
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China
| | - Wanxu Guo
- Department of Neonate, The Second Hospital of Jilin University, Changchun, China
| | - Huimin Chen
- Department of Neonate, The Second Hospital of Jilin University, Changchun, China
| | - Jian Sun
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China
| | - Yongjie Yin
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China
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33
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Wang JY, Gui TT, Jiao B, Liu X, Ma XL, Wang C, Qiao J, Liu WY, Peng LJ, Ren JY, Zhu YM, Weng XQ, Wang C, Zhang QQ, Song GX, Dai YT, Wang ZY, Lv G, Gao CX, Qiao N, Zhang M, Tan Y, Liu YF, Wang SY, Hou J, Jing DH, Lyu AK, Mi JQ, Chen Z, Chen WL, Yin T, Fang H, Wang J, Chen SJ. Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2025; 122:e2423169122. [PMID: 39946534 PMCID: PMC11848409 DOI: 10.1073/pnas.2423169122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 01/03/2025] [Indexed: 02/26/2025] Open
Abstract
Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.
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Affiliation(s)
- Jun-Yu Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai200032, China
| | - Tuan-Tuan Gui
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200030, China
| | - Bo Jiao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Xuan Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Xiao-Lin Ma
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200030, China
| | - Cheng Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Jing Qiao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Wei-Yang Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Li-Jun Peng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Jia-Yi Ren
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Yong-Mei Zhu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Xiang-Qin Weng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Chao Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Qian-Qian Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Gao-Xian Song
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Yu-Ting Dai
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Zhen-Yi Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Gang Lv
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Chen-Xu Gao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Niu Qiao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Ming Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Yun Tan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Yuan-Fang Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Sheng-Yue Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Jian Hou
- Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200127, China
| | - Duo-Hui Jing
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - An-Kang Lyu
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Jian-Qing Mi
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Zhu Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Wen-Lian Chen
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai200032, China
| | - Tong Yin
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Hai Fang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Jin Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
| | - Sai-Juan Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200025, China
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Shao J, Xia Y, Wang G, Xiong Z, Yang Y, Song X, Wang Y, Ai L. The bsh1 gene of Lactobacillus plantarum AR113 ameliorates liver injury in colitis mice. NPJ Sci Food 2025; 9:22. [PMID: 39934175 DOI: 10.1038/s41538-025-00373-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/21/2025] [Indexed: 02/13/2025] Open
Abstract
The Western diet (WD) leads to hepatic lipid metabolism disorders. Previous studies have shown that the bile salt hydrolase 1 (bsh1) gene of Lactobacillus plantarum AR113 attenuates colitis under WD. In this study, we preliminarily explored how AR113 attenuates the hepatic inflammatory response in colitis mice on the WD. Our study suggests that the WD leads to abnormalities in hepatic lipid metabolism and dysbiosis of the gut microflora, and furthermore, there may be a correlation between abnormalities in lipid metabolism and hepatic inflammatory responses. AR113 significantly regulated lipid and bile acid metabolism in the liver of mice treated by WD and Dextran sulfate sodium (DSS), affected the structure of the mouse intestinal flora, and inhibited the expression of Sterol regulatory element-binding protein 1C (SREBP-1C) and P-NF-κB p65 at the protein level, thereby attenuating the hepatic injury phenotype. However, the bsh1 knockout strain did not exhibit the above function.
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Affiliation(s)
- Junlin Shao
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China
| | - Yongjun Xia
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China
| | - Guangqiang Wang
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China
| | - Zhiqiang Xiong
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China
| | - Yijin Yang
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China
| | - Xin Song
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China
| | - Yu Wang
- Department of Cardiology, Shidong Hospital affiliated to the University of Shanghai for Science and Technology, Shanghai, China.
| | - Lianzhong Ai
- University of Shanghai for Science and Technology, Shanghai Engineering Research Center of Food Microbiology, Shanghai, China.
- Department of Cardiology, Shidong Hospital affiliated to the University of Shanghai for Science and Technology, Shanghai, China.
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Gao A, Lv J, Su Y. The Inflammatory Mechanism of Parkinson's Disease: Gut Microbiota Metabolites Affect the Development of the Disease Through the Gut-Brain Axis. Brain Sci 2025; 15:159. [PMID: 40002492 PMCID: PMC11853208 DOI: 10.3390/brainsci15020159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 01/30/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Parkinson's disease is recognized as the second most prevalent neurodegenerative disorder globally, with its incidence rate projected to increase alongside ongoing population growth. However, the precise etiology of Parkinson's disease remains elusive. This article explores the inflammatory mechanisms linking gut microbiota to Parkinson's disease, emphasizing alterations in gut microbiota and their metabolites that influence the disease's progression through the bidirectional transmission of inflammatory signals along the gut-brain axis. Building on this mechanistic framework, this article further discusses research methodologies and treatment strategies focused on gut microbiota metabolites, including metabolomics detection techniques, animal model investigations, and therapeutic approaches such as dietary interventions, probiotic treatments, and fecal transplantation. Ultimately, this article aims to elucidate the relationship between gut microbiota metabolites and the inflammatory mechanisms underlying Parkinson's disease, thereby paving the way for novel avenues in the research and treatment of this condition.
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Affiliation(s)
| | | | - Yanwei Su
- Department of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (A.G.); (J.L.)
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Lyu Y, Hu J, Wang X, Zhang J, Li X, Cui M, Liu D, Tang X, Zhou P. Bovine lactopontin promotes bone development in growing rats by altering the composition of intestinal flora and bile acid metabolism. Food Funct 2025; 16:928-942. [PMID: 39806933 DOI: 10.1039/d4fo05555a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Lactopontin (LPN) is an important milk protein with the potential to improve bone health; however, its specific effects have not been determined. This study aims to investigate the effects of LPN on early bone growth and development. 3 week-old SD rats (n = 32) were assigned to the control group, whey protein concentration (WPC) group, LPN-L (low-dose LPN) group, and LPN-H (high-dose LPN) group, with intragastric administration of deionized water, 65.8 mg kg-1 WPC, and 5 and 45 mg kg-1 LPN for 30 days, respectively. LPN-H supplementation increased body length and femur length, improved femoral bone volume and microarchitecture, and upregulated osteoblast activity-related mRNA (Bmp2, Smad8, and Runx-2) expression in the femur. The content of secondary bile acid glycolithocholic acid (GLCA) in stool and serum was significantly increased after LPN-H intervention and positively correlated with the increased abundance of Parabacteroides in feces. In addition, the bile acid receptor FXR in femur was also activated in the LPN-H group, suggesting that LPN may regulate bone health through the microbiota-metabolite-bone axis. The results of this study suggest that LPN has potential application value in regulating bone metabolism during growth.
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Affiliation(s)
- Yipin Lyu
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Jianqiang Hu
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Xinyan Wang
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Jie Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
- International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xue Li
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Mengjun Cui
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Dasong Liu
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
- International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xue Tang
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Peng Zhou
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
- International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
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Liu X, Pang S, Song G, Wang Y, Fang W, Qi W. The alleviation by wheat and oat dietary fiber alone or combined of T2DM symptoms in db/ db mice. Food Funct 2025; 16:1142-1156. [PMID: 39835833 DOI: 10.1039/d4fo04037f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
The effects of wheat and oat dietary fiber (DF) alone or combined on T2DM remain unclear. In this research, db/db diabetic mice were fed with diets containing 10% insoluble wheat dietary fiber (WDF), 10% insoluble oat dietary fiber (ODF), and 10% WODF (mixture of WDF and ODF, WDF : ODF = 1 : 1) for 8 weeks. The results showed that WDF, ODF, and WODF all reduced the body weight and fasting blood glucose (FBG) and improved oral glucose tolerance in db/db mice. WDF and ODF alone further relieved insulin resistance and decreased the levels of glycated hemoglobin A1c (GHbA1c), and glycosylated serum protein (GSP). In addition, WDF and ODF alone decreased the levels of TNF-α, IL-6, and IL-1β in serum. The colon function was improved and similar changes were observed in the gut microbiota structure and abundance in all the DF groups. The change of gut microbiota mainly manifested as reducing F/B ratio at the phylum level, while at the genus level as decreasing Enterococcus, Escherichia-Shigella, Erysipelatoclostridium, and unclassified_f_Lachnospiraceae and increase of norank_f_Muribaculaceae, Bacteroides, and Alistipes. Further testing of colonic bile acids (BAs) revealed that WDF, ODF, and WODF all significantly changed the composition of BAs, mainly reducing the levels of UDCA, HDCA, and 3β-UDCA. WODF further decreased DCA and increased β-MCA, LCA-3S, and 12-KCDCA. Importantly, WODF reduced the values of 12-OH-BAs/non-12-OH-BAs. Moreover, the TGR5 level was up-regulated in both the liver and colon, and the FXR level was up-regulated in the liver while down-regulated in the colon in all the DF groups. Furthermore, for the protein level, IRS-1, p-PI3K/PI3K, and AKT were up-regulated in the liver in all the DF groups, while for the mRNA expression level, GLUT4 was up-regulated, and FOXO1, GSK3β, PEPCK, and PGC-1α were down-regulated. WDF and WODF further up-regulated the mRNA expression levels of GYS and down-regulated that of G6Pase. These results suggested that WDF, ODF, and WODF all can alleviate T2DM through the gutmicrobiota-BAs-TGR5/FXR axis and liver IRS-1/PI3K/AKT pathway in db/db mice. WDF and ODF alone are beneficial for improving glucose metabolism and inflammation indicators, while WODF helps improve BAs' profile more in the colon.
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Affiliation(s)
- Xinguo Liu
- Academy of National Food and Strategic Reserves Administration, Beijing, China.
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Shaojie Pang
- Heilongjiang Feihe Dairy Co., Ltd, C-16, 10A Jiuxianqiao Rd., Chaoyang, Beijing, China
| | - Ge Song
- Academy of National Food and Strategic Reserves Administration, Beijing, China.
| | - Yong Wang
- Academy of National Food and Strategic Reserves Administration, Beijing, China.
| | - Wei Fang
- Academy of National Food and Strategic Reserves Administration, Beijing, China.
| | - Wentao Qi
- Academy of National Food and Strategic Reserves Administration, Beijing, China.
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
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Wan YP, Li S, Li D, Huang XM, Wu JH, Jian J. Study on the molecular mechanisms of rifaximin in the treatment of non‑alcoholic steatohepatitis based on the Helicobacter‑DCA‑Fxr‑Hnf1α signalling pathway. Mol Med Rep 2025; 31:42. [PMID: 39611479 PMCID: PMC11632295 DOI: 10.3892/mmr.2024.13407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/24/2024] [Indexed: 11/30/2024] Open
Abstract
Non‑alcoholic steatohepatitis (NASH), the more progressive form of non‑alcoholic fatty liver disease, has become a major cause of cirrhosis and liver cancer. The aim of the present study was to investigate the anti‑NASH effect of the nonabsorbable antibiotic rifaximin and its specific molecular mechanisms. A methionine‑choline deficient (MCD) diet was used to induce NASH formation in mice. The mice with NASH were treated with rifaximin to observe its effects on liver fat deposition, hepatocyte inflammation and liver fibrosis. Furthermore, the intestinal microbiota of mice with NASH was analysed by 16S rRNA sequencing and terminal ileal bile acid levels were assessed using liquid chromatography‑electrospray ionization‑tandem mass spectrometry analysis. Furthermore, the correlation between the intestinal microflora and bile acid levels in the terminal ileum was investigated, and the effects of rifaximin on the intestinal Helicobacter‑deoxycholic acid (DCA)‑farnesoid X receptor (Fxr)‑hepatocyte nuclear factor 1α (Hnf1α) signalling pathway were examined. Moreover, analyses of mice after intestinal decontamination with broad‑spectrum antibiotics and of hepatocyte‑specific Hnf1α knockout (Hnf1αH‑KO) mice were used to elucidate the molecular mechanisms by which rifaximin improves NASH. Notably, treatment with rifaximin markedly ameliorated liver steatosis, hepatocyte inflammation and liver fibrosis in mice with MCD diet‑induced NASH. Rifaximin modulated the gut microbiota, especially Helicobacter hepaticus, in mice with NASH. In addition, rifaximin inhibited the intestinal Helicobacter‑DCA‑Fxr‑Hnf1α signalling pathway in mice with NASH. By contrast, rifaximin did not exert an anti‑NASH effect on decontamination‑treated mice or Hnf1αH‑KO mice. Taken together, these results indicated that rifaximin can ameliorate NASH in mice by modulating the Helicobacter‑DCA‑Fxr‑Hnf1α signalling pathway, providing a theoretical basis for the clinical treatment of patients with NASH with rifaximin.
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Affiliation(s)
- Yi-Peng Wan
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shuang Li
- Department of Teaching, Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Dan Li
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiao-Mei Huang
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jian-Hua Wu
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jie Jian
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Ma Y, Yang H, Wang X, Huang Y, Li Y, Pan G. Bile acids as signaling molecules in inflammatory bowel disease: Implications for treatment strategies. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118968. [PMID: 39427739 DOI: 10.1016/j.jep.2024.118968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 09/21/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammatory bowel disease (IBD) is a globally increasing disease. Despite continuous efforts, the clinical application of treatment drugs has not achieved satisfactory success and faces limitations such as adverse drug reactions. Numerous investigations have found that the pathogenesis of IBD is connected with disturbances in bile acid circulation and metabolism. Traditional Chinese medicine targeting bile acids (BAs) has shown significant therapeutic effects and advantages in treating inflammatory bowel disease. AIM OF THIS REVIEW IThis article reviews the role of bile acids and their receptors in IBD, as well as research progress on IBD therapeutic drugs based on bile acids. It explores bile acid metabolism and its interaction with the intestinal microbiota, summarizes clinical drugs for treating IBD including single herbal medicine, traditional herbal prescriptions, and analyzes the mechanisms of action in treating IBD. MATERIALS AND METHODS IThe electronic databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) have been utilized to retrieve relevant literature up to January 2024, using keywords "bile acid", "bile acid receptor", "inflammatory bowel disease", "intestinal microbiota" and "targeted drugs". RESULTS IImbalance in bile acid levels can lead to intestinal inflammation, while IBD can disrupt the balance of microbes, result in alterations in the bile acid pool's composition and amount. This change can damage of intestinal mucosa healing ability. Bile acids are vital for keeping the gut barrier function intact, regulating gene expression, managing metabolic equilibrium, and influencing the properties and roles of the gut's microbial community. Consequently, focusing on bile acids could offer a potential treatment strategy for IBD. CONCLUSION IIBD can induce intestinal homeostasis imbalance and changes in BA pool, leading to fluctuations in levels of relevant metabolic enzymes, transporters, and nuclear receptors. Therefore, by regulating the balance of BA and key signaling molecules of bile acids, we can treat IBD. Traditional Chinese medicine has great potential and promising prospects in treating IBD. We should focus on the characteristics and advantages of Chinese medicine, promote the development and clinical application of innovative Chinese medicine, and ultimately make Chinese medicine targeting bile acids the mainstream treatment for IBD.
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Affiliation(s)
- Yueyue Ma
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Haoze Yang
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Xiaoming Wang
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Yuhong Huang
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300250, PR China
| | - Yuhong Li
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China.
| | - Guixiang Pan
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300250, PR China.
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40
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Tao S, Wu Y, Xiao L, Huang Y, Wang H, Tang Y, Liu S, Liu Y, Ma Q, Yin Y, Dai M, Xie M, Cai J, Zhao Z, Lv Q, Zhang J, Zhang M, Wei M, Chen Y, Li M, Wang Q. Alterations in fecal bacteriome virome interplay and microbiota-derived dysfunction in patients with schizophrenia. Transl Psychiatry 2025; 15:35. [PMID: 39880843 PMCID: PMC11779829 DOI: 10.1038/s41398-025-03239-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/17/2024] [Accepted: 01/14/2025] [Indexed: 01/31/2025] Open
Abstract
Rising studies have consistently reported gut bacteriome alterations in schizophrenia (SCZ). However, little is known about the role of the gut virome on shaping the gut bacteriome in SCZ. Here in, we sequenced the fecal virome, bacteriome, and host peripheral metabolome in 49 SCZ patients and 49 health controls (HCs). We compared the gut bacterial community composition and specific abundant bacteria in SCZ patients and HCs. Specific gut viruses and host peripheral metabolites co-occurring with differential bacteria were identified using Multiple Co-inertia Analysis (MCIA). Additionally, we construct a latent serial mediation model (SMM) to investigate the effect of the gut virome on SCZ through the bacteriome and host metabolic profile. SCZ patients exhibited a decreased gut bacterial β-diversity compared to HCs, with seven differentially abundant bacteria, including Coprobacillaceae, Enterococcaceae etc. Gut viruses including Suoliviridae and Rountreeviridae, co-occur with these SCZ-related bacteria. We found that the viral-bacterial transkingdom correlations observed in HCs were dramatically lost in SCZ. The altered correlations profile observed in SCZ may impact microbiota-derived peripheral metabolites enriched in the bile acids pathway, eicosanoids pathway, and others, contributing to host immune dysfunction and inflammation. The SMM model suggested potential causal chains between gut viruses and SCZ, indicating that the effect of gut virome on SCZ is significantly mediated by bacteriome and metabolites. In conclusion, these findings provide a comprehensive perspective on the role of gut microbiota in the pathogenesis of SCZ. They reveal that patients with schizophrenia harbor an abnormal virome-bacteriome ecology, shedding light on the potential development of microbial therapeutics.
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Affiliation(s)
- Shiwan Tao
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yulu Wu
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Liling Xiao
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Yunqi Huang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Han Wang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Yiguo Tang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Siyi Liu
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Yunjia Liu
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Qianshu Ma
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Yubing Yin
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Minhan Dai
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Min Xie
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jia Cai
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zhengyang Zhao
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qiuyue Lv
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jiashuo Zhang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Mengting Zhang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Menghan Wei
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Yang Chen
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
| | - Mingli Li
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qiang Wang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China.
- Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
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41
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Wang X, Zhang B, Jiang R. Microbiome interplays in the gut-liver axis: implications for liver cancer pathogenesis and therapeutic insights. Front Cell Infect Microbiol 2025; 15:1467197. [PMID: 39936163 PMCID: PMC11810975 DOI: 10.3389/fcimb.2025.1467197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 01/07/2025] [Indexed: 02/13/2025] Open
Abstract
Globally, primary liver cancer (PLC) ranks the most fatal malignancy. Most of the patients are in advanced stage of PLC at the very time they are diagnosed with it, accounting much for its poor prognosis. With the advancement of modern medical research and care system, the main etiology of PLC more and more switches from hepatitis viruses such as HAV, HBV, HCV, HEV to other causes like metabolism-associated steatohepatitis (MASH) and metabolic-associated fatty liver disease (MAFLD). As a result, it is of great necessity to find out new ways for treatment and early diagnosis to cope with this problem. Nowadays, as the mechanism of the Gut-Liver Axis in the formation of MAFLD, MASH and PLC has been gradually elucidated. The association between gut microbiome and the formation of PLC is of great significance to take an insight into. In this review, we present the concept of Gut-Liver Axis and its function in the mutual influence between gut microbiota and PLC from several aspects in which we will focus on the structure of gut barrier and the functional influences the gut microbiota have on the immune response and metabolic changes on human liver. Furthermore, we conclude the potential association of gut microbiota constitution with the PLC. Eventually, we hope this review can offer novel instructions for early diagnosis and treatment for liver cancer.
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Affiliation(s)
- Xuran Wang
- Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Bin Zhang
- Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Runqiu Jiang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Han L, Pendleton A, Singh A, Xu R, Scott SA, Palma JA, Diebold P, Malarney KP, Brito IL, Chang PV. Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases. Cell Chem Biol 2025; 32:145-156.e9. [PMID: 38889717 PMCID: PMC11632149 DOI: 10.1016/j.chembiol.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 03/25/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024]
Abstract
The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.
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Affiliation(s)
- Lin Han
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | | | - Adarsh Singh
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Raymond Xu
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Samantha A Scott
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
| | - Jaymee A Palma
- Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Peter Diebold
- Department of Microbiology, Cornell University, Ithaca, NY 14853, USA
| | - Kien P Malarney
- Department of Microbiology, Cornell University, Ithaca, NY 14853, USA
| | - Ilana L Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Cornell Center for Immunology, Cornell University, Ithaca, NY 14853, USA; Cornell Institute of Host-Microbe Interactions and Disease, Cornell University, Ithaca, NY 14853, USA
| | - Pamela V Chang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA; Cornell Center for Immunology, Cornell University, Ithaca, NY 14853, USA; Cornell Institute of Host-Microbe Interactions and Disease, Cornell University, Ithaca, NY 14853, USA; Cornell Center for Innovative Proteomics, Cornell University, Ithaca, NY 14853, USA.
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43
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Liu Z, You C. The bile acid profile. Clin Chim Acta 2025; 565:120004. [PMID: 39419312 DOI: 10.1016/j.cca.2024.120004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/13/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.
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Affiliation(s)
- Zhenhua Liu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Chongge You
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
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44
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Song L, Hou Y, Xu D, Dai X, Luo J, Liu Y, Huang Z, Yang M, Chen J, Hu Y, Chen C, Tang Y, Rao Z, Ma J, Zheng M, Shi K, Cai C, Lu M, Tang R, Ma X, Xie C, Luo Y, Li X, Huang Z. Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress. Cell Metab 2025; 37:104-120.e9. [PMID: 39393353 DOI: 10.1016/j.cmet.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 07/31/2024] [Accepted: 09/12/2024] [Indexed: 10/13/2024]
Abstract
Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.
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Affiliation(s)
- Lintao Song
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yushu Hou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Da Xu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xijia Dai
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianya Luo
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhuobing Huang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Miaomiao Yang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jie Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yue Hu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuchu Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yuli Tang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhiheng Rao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianjia Ma
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minghua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chao Cai
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Mingqin Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yongde Luo
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Zhifeng Huang
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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Xie X, Li W, Xiong Z, Xu J, Liao T, Sun L, Xu H, Zhang M, Zhou J, Xiong W, Fu Z, Li Z, Han Q, Cui D, Anthony DC. Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice. Brain Behav Immun 2025; 123:442-455. [PMID: 39303815 DOI: 10.1016/j.bbi.2024.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 09/08/2024] [Accepted: 09/13/2024] [Indexed: 09/22/2024] Open
Abstract
As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.
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Affiliation(s)
- Xiaoxian Xie
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 201109, PR China; Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT Oxford, UK; College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Wenwen Li
- Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, PR China
| | - Ze Xiong
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Junyu Xu
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, PR China
| | - Tailin Liao
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, PR China
| | - Lei Sun
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Haoshen Xu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Mengya Zhang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Jiafeng Zhou
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Wenzheng Xiong
- Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT Oxford, UK
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, PR China
| | - Zezhi Li
- The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, PR China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, PR China.
| | - Qi Han
- Center for Brain Science Shanghai Children s Medical Center, Department of Anatomy and Physiology, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, PR China; Shanghai Center for Brain Science and Brain-inspired Technology, Shanghai 200031, PR China.
| | - Donghong Cui
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 201109, PR China.
| | - Daniel C Anthony
- Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT Oxford, UK
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Song P, Peng Z, Guo X. Gut microbial metabolites in cancer therapy. Trends Endocrinol Metab 2025; 36:55-69. [PMID: 39004537 DOI: 10.1016/j.tem.2024.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024]
Abstract
The gut microbiota plays a crucial role in maintaining homeostasis and promoting health. A growing number of studies have indicated that gut microbiota can affect cancer development, prognosis, and treatment through their metabolites. By remodeling the tumor microenvironment and regulating tumor immunity, gut microbial metabolites significantly influence the efficacy of anticancer therapies, including chemo-, radio-, and immunotherapy. Several novel therapies that target gut microbial metabolites have shown great promise in cancer models. In this review, we summarize the current research status of gut microbial metabolites in cancer, aiming to provide new directions for future tumor therapy.
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Affiliation(s)
- Panwei Song
- Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; State Key Laboratory of Molecular Oncology, Tsinghua University, Beijing 100084, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi Province 030001, China
| | - Zhi Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Xiaohuan Guo
- Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; State Key Laboratory of Molecular Oncology, Tsinghua University, Beijing 100084, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi Province 030001, China.
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Wang L, Wang Z, Zhao Y, Yang B, Huang G, Li J, Zhou X, Jiang H, Lan P, Chen Z. Gut microbiota-mediated bile acid metabolism aggravates biliary injury after liver transplantation through mitochondrial apoptosis. Int Immunopharmacol 2024; 143:113413. [PMID: 39486182 DOI: 10.1016/j.intimp.2024.113413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/30/2024] [Accepted: 10/13/2024] [Indexed: 11/04/2024]
Abstract
Ischemic-type biliary lesions (ITBL) are a major cause of graft loss and even mortality after liver transplantation (LT). The underlying cellular mechanisms for ITBL remain unclear. Gut microbiota has been found to be closely related to complications after LT. Here, using gut microbiome compositions, we found patients with ITBL had a higher abundance of bacteria associated with bile salt metabolism. These bacteria are reported to convert cholic acid (CA) into deoxycholic acid (DCA), consistent with our data that there were higher DCA concentrations and DCA/CA ratio in patients with ITBL than patients without ITBL. Using an in vitro model, human intrahepatic biliary epithelial cells (HIBEC) subjected to DCA showed a higher apoptosis rate, lower viability, and higher levels of cleaved-caspase3 than CA at the same concentration. DCA also changed the morphology of mitochondria and farnesoid X receptor (FXR) expression. Interestingly, DCA-induced apoptosis rate was significantly reduced in HIBEC when the FXR or BAX gene was knocked down, suggesting that DCA-induced apoptosis was dependent on FXR-mitochondrial pathway. Furthermore, increasing DCA/CA ratio in a bile acid-feeding mouse model resulted in cholangiocyte apoptosis and impaired liver function. The patients with ITBL also showed an increased proportion of TUNEL-positive biliary epithelial cells than those without ITBL. These suggest that changes in the gut microbiota following LT may enhance the conversion of CA to DCA, and may contribute to biliary damage via FXR-mitochondrial apoptosis pathway, providing new ideas for the early monitoring and treatment of ITBL.
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Affiliation(s)
- Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.; Department of Thyroid Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan 450004, China
| | - Zipei Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Guobin Huang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Junbo Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xi Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hongmei Jiang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Peixiang Lan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China..
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China..
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Zhang ZY, Guo XL, Liu JTY, Gu YJ, Ji XW, Zhu S, Xie JY, Guo F. Conjugated bile acids alleviate acute pancreatitis through inhibition of TGR5 and NLRP3 mediated inflammation. J Transl Med 2024; 22:1124. [PMID: 39707318 DOI: 10.1186/s12967-024-05922-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 11/27/2024] [Indexed: 12/23/2024] Open
Abstract
INTRODUCTION Severe acute pancreatitis (SAP) is a crucial gastrointestinal disease characterized by systemic inflammatory responses and persistent multiple organ failure. The role of bile acids (BAs) in diverse inflammatory diseases is increasingly recognized as crucial, but the underlying role of BA conjugation remains elusive. OBJECTIVES Our study aim to investigate the potential role of conjugated bile acids in SAP and reveal the molecular mechanisms underlying its regulatory effects. We hypothesized that taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) could protect SAP through inhibiting the activation of NLRP3 inflammasomes via the TGR5 pathway in macrophages. METHODS To test our hypothesis, we used BA-CoA: amino acid N-acyltransferase knockout (Baat-/-) mice and established SAP mouse models using caerulein- and sodium taurocholate- induced. We utilized a range of methods, including pathology sections, qRT-PCR, immunofluorescence, Western blotting, and ELISA, to identify the mechanisms of regulation. RESULTS BA-CoA: Amino acid N-acyltransferase knockout (Baat-/-) mice significantly exacerbated pancreatitis by increasing pancreatic and systemic inflammatory responses and pancreatic damage in SAP mouse models. Moreover, the serum TCDCA levels in Baat-/- mice were lower than those in wild-type (WT) mice with or without SAP, and GCDCA and TCDCA showed stronger anti-inflammatory effects than chenodeoxycholic acid (CDCA) in vitro. TCDCA treatment alleviated SAP in a Takeda G protein-coupled receptor 5 and NOD-like receptor family, pyrin domain containing 3-dependent manner in vivo. Reinforcing our conclusions from the mouse study, clinical SAP patients exhibited decreased serum content of conjugated BAs, especially GCDCA, which was inversely correlated with the severity of systemic inflammatory responses. CONCLUSION Conjugated bile acids significantly inhibit NLRP3 inflammasome activation by activating TGR5 pathway, thereby alleviating pancreatic immunopathology. The results provide new insights into the variability of clinical outcomes and paves the way for developing more effective therapeutic interventions for AP.
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Affiliation(s)
- Zi-Yi Zhang
- Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Xiu-Liu Guo
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jing-Tian-Yi Liu
- Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Yi-Jie Gu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, People's Republic of China
| | - Xing-Wei Ji
- Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Shu Zhu
- Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, People's Republic of China
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jin-Yan Xie
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, People's Republic of China.
| | - Feng Guo
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, People's Republic of China.
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Chen J, Yang H, Qin Y, Zhou X, Ma Q. Tryptophan Ameliorates Metabolic Syndrome by Inhibiting Intestinal Farnesoid X Receptor Signaling: The Role of Gut Microbiota-Bile Acid Crosstalk. RESEARCH (WASHINGTON, D.C.) 2024; 7:0515. [PMID: 39679283 PMCID: PMC11638488 DOI: 10.34133/research.0515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/23/2024] [Accepted: 10/07/2024] [Indexed: 12/17/2024]
Abstract
Background and Aims: Metabolic syndrome (MS) is a progressive metabolic disease characterized by obesity and multiple metabolic disorders. Tryptophan (Trp) is an essential amino acid, and its metabolism is linked to numerous physiological functions and diseases. However, the mechanisms by which Trp affects MS are not fully understood. Methods and Results: In this study, experiments involving a high-fat diet (HFD) and fecal microbiota transplantation (FMT) were conducted to investigate the role of Trp in regulating metabolic disorders. In a mouse model, Trp supplementation inhibited intestinal farnesoid X receptor (FXR) signaling and promoted hepatic bile acid (BA) synthesis and excretion, accompanied by elevated levels of conjugated BAs and the ratio of non-12-OH to 12-OH BAs in hepatic and fecal BA profiles. As Trp alters the gut microbiota and the abundance of bile salt hydrolase (BSH)-enriched microbes, we collected fresh feces from Trp-supplemented mice and performed FMT and sterile fecal filtrate (SFF) inoculations in HFD-treated mice. FMT and SFF not only displayed lipid-lowering properties but also inhibited intestinal FXR signaling and increased hepatic BA synthesis. This suggests that the gut microbiota play a beneficial role in improving BA metabolism through Trp. Furthermore, fexaramine (a gut-specific FXR agonist) reversed the therapeutic effects of Trp, suggesting that Trp acts through the FXR signaling pathway. Finally, validation in a finishing pig model revealed that Trp improved lipid metabolism, enlarged the hepatic BA pool, and altered numerous glycerophospholipid molecules in the hepatic lipid profile. Conclusion: Our studies suggest that Trp inhibits intestinal FXR signaling mediated by the gut microbiota-BA crosstalk, which in turn promotes hepatic BA synthesis, thereby ameliorating MS.
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Affiliation(s)
| | | | | | | | - Qingquan Ma
- College of Animal Science and Technology,
Northeast Agricultural University, Harbin 150030, China
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50
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Duan J, Li Q, Cheng Y, Zhu W, Liu H, Li F. Therapeutic potential of Parabacteroides distasonis in gastrointestinal and hepatic disease. MedComm (Beijing) 2024; 5:e70017. [PMID: 39687780 PMCID: PMC11647740 DOI: 10.1002/mco2.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/16/2024] [Accepted: 10/24/2024] [Indexed: 12/18/2024] Open
Abstract
Increasing evidences indicate that the gut microbiota is involved in the development and therapy of gastrointestinal and hepatic disease. Imbalance of gut microbiota occurs in the early stages of diseases, and maintaining the balance of the gut microbiota provides a new strategy for the treatment of diseases. It has been reported that Parabacteroides distasonis is associated with multiple diseases. As the next-generation probiotics, several studies have demonstrated its positive regulation on the gastrointestinal and hepatic disease, including inflammatory bowel disease, colorectal cancer, hepatic fibrosis, and fatty liver. The function of P. distasonis and its metabolites mainly affect host immune system, intestinal barrier function, and metabolic networks. Manipulation of P. distasonis with natural components lead to the protective effect on enterohepatic disease. In this review, the metabolic pathways regulated by P. distasonis are summarized to illustrate its active metabolites and their impact on host metabolism, the role and action mechanism in gastrointestinal and hepatic disease are discussed. More importantly, the natural components can be used to manipulate P. distasonis as treatment strategies, and the challenges and perspectives of P. distasonis in clinical applications are discussed.
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Affiliation(s)
- Jinyi Duan
- Department of Gastroenterology & HepatologyLaboratory of Hepato‐intestinal Diseases and MetabolismFrontiers Science Center for Disease‐Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
| | - Qinmei Li
- Department of Gastroenterology & HepatologyLaboratory of Hepato‐intestinal Diseases and MetabolismFrontiers Science Center for Disease‐Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
| | - Yan Cheng
- Department of Gastroenterology & HepatologyLaboratory of Hepato‐intestinal Diseases and MetabolismFrontiers Science Center for Disease‐Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
- Deparment of Pharmacy, Academician WorkstationJiangxi University of Chinese MedicineNanchangChina
| | - Weifeng Zhu
- Deparment of Pharmacy, Academician WorkstationJiangxi University of Chinese MedicineNanchangChina
| | - Hongning Liu
- Deparment of Pharmacy, Academician WorkstationJiangxi University of Chinese MedicineNanchangChina
| | - Fei Li
- Department of Gastroenterology & HepatologyLaboratory of Hepato‐intestinal Diseases and MetabolismFrontiers Science Center for Disease‐Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
- Department of Gastroenterology & Hepatology, Huaxi Joint Centre for Gastrointestinal CancerState Key Laboratory of Respiratory Health and MultimorbidityWest China HospitalSichuan UniversityChengduChina
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