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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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Masetto A, Leber T, Frömel T, Peter C, Prager K, Grimmler M. Towards routine high-throughput analysis of fecal bile acids: validation of an enzymatic cycling method for the quantification of total bile acids in human stool samples on fully automated clinical chemistry analyzers. Clin Chem Lab Med 2025; 63:1366-1375. [PMID: 39840591 DOI: 10.1515/cclm-2024-1414] [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: 12/04/2024] [Accepted: 01/13/2025] [Indexed: 01/23/2025]
Abstract
OBJECTIVES Bile acid diarrhea is a common but underdiagnosed condition. Because the gold standard test (75SeHCAT) is time-consuming and not widely available, fecal bile acid excretion is typically assessed by chromatography and mass spectrometry. Although enzymatic cycling assays are well established for the rapid and cost-effective analysis of total bile acids (TBA) in serum or plasma, their full potential has yet not been extended to stool samples in clinical routine. METHODS The performance of the 'Total bile acids 21 FS' reagent (DiaSys) was evaluated in fecal matrix according to CLSI guidelines and EU-IVD Regulations (2017/745), and compared to an established microplate-based kit (IDK®) by measuring patient stool samples (n=122). Method agreement was assessed by Passing-Bablok and Bland-Altman analysis. The quantification of eight individual BAs was assessed using HPLC-MS/MS as reference method. RESULTS The DiaSys assay showed linearity between 3.5 and 130 μmol/L, good repeatability, total precision, and reproducibility with CVs of 1.7 %, 3.5 %, and 3.0 %. Limit of blank (LoB), detection (LoD), and quantitation (LoQ) were ≤0.17, ≤0.3, and 3.5 μmol/L, respectively. No significant interference from endogenous substances was observed. The methods showed good correlation up to 140 μmol/L (r=0.988), despite differences in the quantification of individual BAs, with mean deviations of 7 % (DiaSys) and 31 % (IDK®), respectively. CONCLUSIONS The advantages of enzymatic TBA analysis on fully automated clinical chemistry platforms can be exploited for the routine analysis of stool samples. However, cycling assays may benefit from reference standards that take into account the composition of the fecal BA pool.
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Affiliation(s)
- Angelique Masetto
- Institute for Biomolecular Research, Hochschulen Fresenius gemeinnützige Trägergesellschaft mbH, University of Applied Sciences, Idstein, Germany
- 52775 DiaSys Diagnostic Systems GmbH , Holzheim, Germany
| | - Tina Leber
- 52775 DiaSys Diagnostic Systems GmbH , Holzheim, Germany
| | - Tobias Frömel
- Institute for Analytical Research, Hochschulen Fresenius gemeinnützige Trägergesellschaft mbH, University of Applied Sciences, Idstein, Germany
| | - Christoph Peter
- Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Kai Prager
- 52775 DiaSys Diagnostic Systems GmbH , Holzheim, Germany
| | - Matthias Grimmler
- Institute for Biomolecular Research, Hochschulen Fresenius gemeinnützige Trägergesellschaft mbH, University of Applied Sciences, Idstein, Germany
- 52775 DiaSys Diagnostic Systems GmbH , Holzheim, Germany
- DiaServe Laboratories GmbH, Iffeldorf, Germany
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Wu X, Yu Q, Hou Y, Zhang X, Ocholi SS, Wang L, Yan Z, Li J, Han L. Emodin-8-O-β-D-glucopyranoside alleviates cholestasis by maintaining intestinal homeostasis and regulating lipids and bile acids metabolism in mice. J Pharm Biomed Anal 2025; 258:116734. [PMID: 39933397 DOI: 10.1016/j.jpba.2025.116734] [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: 08/27/2024] [Revised: 01/12/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Cholestatic liver disease(CLD) is caused by impaired bile flow due to obstruction of the biliary tract, and long-term exposure to bile acids in the liver triggers inflammation, eventually leading to liver toxicity and liver fibrosis. Emodin-8-O-β-D-glucopyranoside(EG) is anthraquinone compound that is widely found in traditional Chinese medicine. It possessed antioxidative and anti-inflammatory activities. However, the effect of EG on cholestatic liver injury(CLI) has not been explored. In this study, Alpha-naphthyl isothiocyanate(ANIT)-induced CLI mice were used to investigate the anti-cholestasis and hepatoprotective effects of EG through serum biochemical index detection, non-targeted metabolomics, lipidomics, and intestinal flora 16S rRNA sequencing. The results suggested that EG restores homeostasis of the gut microbiome while regulating bile acids metabolism and lipid-related metabolic pathways to reduce liver damage in ANIT-induced cholestasis. This study provides a new perspective on the mechanism of EG, and help offer a more natural approach to managing liver damage.
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Affiliation(s)
- Xiaolin Wu
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Qiao Yu
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Yuzhao Hou
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Xuemei Zhang
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Simon Sani Ocholi
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Liming Wang
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Ziping Yan
- Tianjin Armed Police Corps Hospital, Tianjin 300162, China
| | - Jie Li
- Tianjin Key Laboratory of Clinical Multi-omics, Airport Economy Zone, Tianjin, China.
| | - Lifeng Han
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China.
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Lee MG, Kang MJ, Kim S, Jeong H, Kang DK, Paik HD, Park YS. Safety Assessment of Levilactobacillus brevis KU15006: A Comprehensive Analysis of its Phenotypic and Genotypic Properties. Probiotics Antimicrob Proteins 2025; 17:1117-1131. [PMID: 38430332 DOI: 10.1007/s12602-024-10237-z] [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] [Accepted: 02/27/2024] [Indexed: 03/03/2024]
Abstract
Levilactobacillus brevis KU15006, isolated from kimchi, exhibits pathogen-antagonistic and anti-diabetic activities; however, the safety of this strain has not been assessed. In the present study, L. brevis KU15006 was evaluated to elucidate its safety as a probiotic strain using phenotypic and genotypic analyses. Its safety was assessed using a minimum inhibitory concentration test comprising nine antibiotics, 26 antibiotic resistance genes, a single conjugative element, virulence gene analysis, hemolysis, cell cytotoxicity, mucin degradation, and toxic metabolite production. L. brevis KU15006 exhibited equal or lower minimum inhibitory concentration for the nine antibiotics than the cut-off value established by the European Food Safety Authority. It did not harbor antibiotic resistance and virulence genes. L. brevis KU15006 lacked β-hemolysis, mucin degradation, cytotoxicity against Caco-2 cells, gelatin liquefaction, bile salt deconjugation, and toxic metabolite production abilities. Based on the results, L. brevis KU15006, which has antagonistic and anti-diabetic effects, could be marketed as a probiotic in the future.
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Affiliation(s)
- Min-Gyu Lee
- Department of Food Science and Biotechnology, Gachon University, Seongnam, 13120, Republic of Korea
| | - Min-Joo Kang
- Department of Food Science and Biotechnology, Gachon University, Seongnam, 13120, Republic of Korea
| | - Suin Kim
- Department of Food Science and Biotechnology, Gachon University, Seongnam, 13120, Republic of Korea
| | - Huijin Jeong
- Department of Food Science and Biotechnology, Gachon University, Seongnam, 13120, Republic of Korea
| | - Dae-Kyung Kang
- Department of Animal Biotechnology, Dankook University, Cheonan, 31116, Republic of Korea
| | - Hyun-Dong Paik
- Department of Food Science and Biotechnology of Animal Resource, Konkuk University, Seoul, 05029, Republic of Korea
| | - Young-Seo Park
- Department of Food Science and Biotechnology, Gachon University, Seongnam, 13120, Republic of Korea.
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Pérez-Tierra G, Calo J, Comesaña S, Velasco C, Blanco AM, Soengas JL. Evidence for the involvement of secondary bile acids on peripheral and central regulation of feed intake in rainbow trout. Am J Physiol Endocrinol Metab 2025; 328:E787-E803. [PMID: 40257242 DOI: 10.1152/ajpendo.00072.2025] [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: 02/11/2025] [Revised: 03/16/2025] [Accepted: 04/01/2025] [Indexed: 04/22/2025]
Abstract
Recent studies suggest that secondary bile acids (SBAs) play a role in energy metabolism and feed intake regulation, but their effects in fish remain largely unknown. This study evaluates the impact of intragastric administration of the main SBAs [500 µM lithocholic acid (LCA), 1,500 µM deoxycholic acid (DCA), and their taurine conjugates: 1,000 µM T-LCA and 600 µM T-DCA] on feed intake, regulatory pathways, and bile acid-related elements in rainbow trout. Results show that all tested SBAs influenced bile acid transporters [apical sodium-dependent bile acid transporter (Asbt), Na+ taurocholate co-transporting polypeptide (Ntcp), organic solute transporter α and β (Ostα, and Ostβ)] and receptors [farnesoid X receptor like-α and β (Fxrα, Fxrβ), and Takeda G protein-coupled receptor 5 (Tgr5)], with DCA and T-DCA mainly affecting the gastrointestinal tract and LCA modulating hypothalamic pathways, suggesting a putative orexigenic role. Plasma analysis confirmed SBA absorption from the gastrointestinal tract into the bloodstream. This study provides the first evidence in fish of SBAs modulating gene and protein expression linked to appetite regulation, underscoring their role in gut-brain communication. Although all SBAs influenced fxr expression, gpbar1 remained unaffected, differing from mammals where BAs suppress appetite. Notably, despite taurine-conjugated SBAs being the most abundant in rainbow trout, only nonconjugated LCA showed significant effects. Taken together, these results provide new information on the emerging importance of SBA in feed intake regulation and bile acid mechanisms.NEW & NOTEWORTHY This study determined for the first time in teleost fish (specifically in rainbow trout): 1) the role of secondary bile acids in the regulation of feed intake and associated signaling pathways, highlighting a putative orexigenic role of lithocholic acid (LCA); 2) the response of Asbt and Ostα transporters and Tgr5 receptor in hypothalamus after LCA administration; and 3) the reabsorption of LCA, DCA, and their taurine conjugates from the gastrointestinal tract into the bloodstream.
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Affiliation(s)
- Gabriel Pérez-Tierra
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain
| | - Jessica Calo
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain
| | - Sara Comesaña
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain
| | - Cristina Velasco
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain
| | - Ayelén M Blanco
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain
| | - José L Soengas
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain
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Wang J, Gao J, Zhang Q, Lu J, Yang Y, Cai X, Dong H, Lu L. Ileal FXR Knockdown Ameliorates MASLD Progression in Rats via Modulating Bile Acid Metabolism Mediated by Gut Microbiota. J Gastroenterol Hepatol 2025. [PMID: 40411313 DOI: 10.1111/jgh.17017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/11/2025] [Accepted: 05/11/2025] [Indexed: 05/26/2025]
Abstract
BACKGROUND AND AIM Metabolic dysfunction associated steatotic liver disease (MASLD) is the predominant cause of chronic liver disease, with dysregulation of bile acid (BA) metabolism and intestinal microbiota being intricately associated with MASLD progression. In this study, we investigated the role of ileal FXR in MASLD progression and BA metabolism in portal blood. METHODS Sprague-Dawley rats were fed a typical western diet for 20 weeks, followed by local perfusion of AAV2-shNr1h4 to downregulate Nr1h4 expression in ileum tissue. To investigate the effect of ileal FXR on BA reabsorption and gut microbiota, portal blood and cecal fecal samples were collected from MASLD rats injected with AAV2-Ctrl or AAV2-shNr1h4 for metabolomics targeting BAs and 16S rRNA sequencing analysis. RESULTS Our results showed that hepatic steatosis and inflammation were alleviated, whereas the reabsorption of secondary BAs and unconjugated BAs into the portal blood was enhanced when ileal FXR was knocked down. Furthermore, knockdown of ileal FXR resulted in a significant alteration in composition of the cecal microbiota, characterized by an increasing abundance of microbes involved in secondary BA production, including Escherichia, Adlercreutzia, Eubacterium, and Clostridium. CONCLUSION These findings suggest that downregulation of ileal FXR ameliorates the progression of MASLD in rats by modulating BA metabolism mediated by the gut microbiota, indicating that ileal FXR might be a potential therapeutic target for the treatment of MASLD.
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Affiliation(s)
- Junjun Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jiaqi Gao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qingqing Zhang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jingyi Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yufei Yang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaobo Cai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Dong
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
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7
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Hillman EBM, Baumgartner M, Carson D, Amos GCA, Wazir I, Khan HA, Khan MA, Rijpkema S, Walters JRF, Wellington EMH, Arasaradnam R, Lewis SJ. Changing Gastrointestinal Transit Time Alters Microbiome Composition and Bile Acid Metabolism: A Cross-Over Study in Healthy Volunteers. Neurogastroenterol Motil 2025:e70075. [PMID: 40394972 DOI: 10.1111/nmo.70075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 03/21/2025] [Accepted: 04/30/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND The specific influence of whole gut transit time (WGTT) on microbiome dynamics and bile acid metabolism remains unclear, despite links between changes in WGTT and certain gastrointestinal disorders. Our investigation aimed to determine the impact of WGTT changes on the composition of the fecal microbiome and bile acid profile. METHODS Healthy volunteers (n = 18) received loperamide, to decrease bowel movement frequency, and senna, a laxative, each over a 6-day period, in a randomized sequence, with a minimum 16-day interval between each treatment. Stool samples were analyzed for microbiome by shotgun sequencing and bile acid composition determined with high-performance liquid chromatography coupled to tandem mass spectrometry. Sera were examined for markers of bile acid synthesis. KEY RESULTS Senna or loperamide decreased or increased WGTT, respectively. Treatment altered stool characteristics, bowel movement frequency, and stool weight. The senna-treated group had increased primary and secondary fecal bile acids; serum levels of fibroblast growth factor 19 were significantly reduced. Increasing WGTT with loperamide led to an increase in bile salt hydrolase genes, along with elevated bacterial species richness (p = 0.04). Thirty-six species exhibiting significant differences were identified, several of which have notable implications for gut health. WGTT displayed negative correlations with total primary (particularly chenodeoxycholic acid) and secondary bile acids (ursodeoxycholic acid and glycochenodeoxycholic acid). Treatment-induced changes in microbiome composition and bile acid metabolism reverted back to baseline within 16 days. CONCLUSION Whole gut transit time changes significantly affect fecal microbiome composition and function, as well as bile acid composition and synthesis in healthy subjects. This consideration is likely to have long-term implications.
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Affiliation(s)
- Evette B M Hillman
- Diagnostics, Medicines and Healthcare Products Regulatory Agency, London, UK
- School of Life Sciences, The University of Warwick, Coventry, UK
| | - Maximilian Baumgartner
- Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Danielle Carson
- Diagnostics, Medicines and Healthcare Products Regulatory Agency, London, UK
| | - Gregory C A Amos
- Diagnostics, Medicines and Healthcare Products Regulatory Agency, London, UK
| | - Imad Wazir
- Department of Gastroenterology, University Hospital Plymouth, Plymouth, UK
| | - Haider A Khan
- Department of Gastroenterology, University Hospital Plymouth, Plymouth, UK
| | - Malik A Khan
- Department of Gastroenterology, University Hospital Plymouth, Plymouth, UK
| | - Sjoerd Rijpkema
- Diagnostics, Medicines and Healthcare Products Regulatory Agency, London, UK
| | - Julian R F Walters
- Division of Digestive Diseases, Imperial College London, London, UK
- Imperial College Healthcare Trust, London, UK
| | | | - Ramesh Arasaradnam
- Department of Gastroenterology, University Hospitals Coventry & Warwickshire, Coventry, UK
- Warwick Medical School, The University of Warwick, Coventry, UK
| | - Stephen J Lewis
- Department of Gastroenterology, University Hospital Plymouth, Plymouth, UK
- Peninsula Medical School, University of Plymouth, Plymouth, UK
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8
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Zhao Q, Duan Z, Lai R, Ma P. Novel microbially transformed bile acids: Biosynthesis, structure, and function. Pharmacol Res 2025; 216:107775. [PMID: 40378940 DOI: 10.1016/j.phrs.2025.107775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/03/2025] [Accepted: 05/10/2025] [Indexed: 05/19/2025]
Abstract
The roles of gut microbiota and microbially modified bile acids in human health have become widely recognized. In the last five years, various microbially modified bile acids (e.g., proteinogenic amino-conjugated bile acids, polyamine-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acids, acylated bile acids, dicarboxylic acid-conjugated bile acids, lithocholic acid (LCA) derivatives) were identified and evaluated, which greatly enriched the mammalian bile acid pool and the bioactivity of bile acids. The structure, enzyme, function, clinical reports of these bile acids, and the bacteria to produce these bile acids were summarized in this review. These novel bile acids had various functions including immunoregulation, receptor regulator, antimicrobial activity, and microbial communities regulating effect. 70, 4, 1, 11, 19, 41, 43, 9, 10 species were observed to produce proteinogenic amino-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acids, acylated bile acids, dicarboxylic acid-conjugated bile acids, 3-oxoLCA, isoLCA, 3-oxoalloLCA, and isoalloLCA, respectively. The current review has shed new light on discovering new bile acid derivatives as drug candidates. These microbially modified bile acids may play important roles in disease such as sleeve gastrectomy, fatty liver, inflammatory bowel disease, cystic fibrosis, and type 2 diabetes, which may also participate in normal physiological processes such as growth of infants, longevity, and dietary habits.
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Affiliation(s)
- Qi Zhao
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan 650201, PR China
| | - Zilei Duan
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan 650201, PR China
| | - Ren Lai
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan 650201, PR China.
| | - Pengcheng Ma
- State Key Laboratory of Genetic Evolution and Animal Models, Kunming Insitute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
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9
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He Y, Shaoyong W, Chen Y, Li M, Gan Y, Sun L, Liu Y, Wang Y, Jin M. The functions of gut microbiota-mediated bile acid metabolism in intestinal immunity. J Adv Res 2025:S2090-1232(25)00307-8. [PMID: 40354934 DOI: 10.1016/j.jare.2025.05.015] [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: 02/14/2025] [Revised: 04/19/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation. AIM OF REVIEW This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Yanmin He
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Weike Shaoyong
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yanli Chen
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Menglin Li
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yujie Gan
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Lu Sun
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yalin Liu
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yizhen Wang
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Mingliang Jin
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China.
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10
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Richtsmeier P, Nedielkov R, Haring M, Yücel O, Elsner L, Lülf RH, Wöhlbrand L, Rabus R, Moeller H, Philipp B, Mueller FM. 7β-Hydroxysteroid dehydratase Hsh3 eliminates the 7-hydroxy group of the bile salt ursodeoxycholate during degradation by Sphingobium sp. strain Chol11 and other Sphingomonadaceae. Appl Environ Microbiol 2025:e0018525. [PMID: 40340444 DOI: 10.1128/aem.00185-25] [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] [Accepted: 04/11/2025] [Indexed: 05/10/2025] Open
Abstract
Bile salts are steroids with distinctive hydroxylation patterns that are produced and excreted by vertebrates. In contrast to common human bile salts, ursodeoxycholate (UDCA) has a 7-hydroxy group in β-configuration and is used in large amounts for the treatment of diverse gastrointestinal diseases. We isolated the 7β-hydroxysteroid dehydratase Hsh3 that is involved in UDCA degradation by Sphingobium sp. strain Chol11. Hsh3 eliminates the 7β-hydroxy group as water, leading to a double bond in the B-ring. This is similar to 7α-hydroxysteroid dehydratases in this and other strains, but Hsh3 is evolutionarily different from these. Purified Hsh3 accepted steroids with and without side chains as substrates and had minor activity with 7α-hydroxy groups. The deletion mutant strain Chol11 Δhsh3 had impacted growth with UDCA and accumulated a novel compound. The compound was identified as 3',5-dihydroxy-H-methyl-hexahydro-5-indene-1-one-propanoate, consisting of steroid rings C and D with a C3-side chain carrying the former 7β-hydroxy group, indicating that Hsh3 activity is important especially for the later stages of bile salt degradation. Hsh3 homologs were found in other sphingomonads that were also able to degrade UDCA as well as in environmental metagenomes. Thus, Hsh3 adds to the bacterial enzyme repertoire for degrading a variety of differently hydroxylated bile salts.IMPORTANCEThe bacterial degradation of different bile salts is not only important for the removal of these steroidal compounds from the environment but also harbors interesting enzymes for steroid biotechnology. The 7β-hydroxy bile salt ursodeoxycholate (UDCA) naturally occurs in high concentration in the feces of black bears and has important pharmaceutical relevance for the treatment of different liver-related diseases, for which it is administered in high and increasing amounts. Additionally, it is present in the bile salt pool of humans in trace amounts. While UDCA degradation is environmentally important, the enzyme Hsh3 modifies the hydroxy group that confers the medically relevant properties and thus might be interesting for microbiome analyses and biotechnological applications.
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Affiliation(s)
- Phil Richtsmeier
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Ruslan Nedielkov
- Institute for Chemistry, University of Potsdam, Potsdam, Germany
| | - Malte Haring
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Onur Yücel
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Lea Elsner
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Rebekka Herdis Lülf
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Lars Wöhlbrand
- General and Molecular Microbiology, Institute for Chemistry and Biology of the Marine Environment (ICBM), Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
| | - Ralf Rabus
- General and Molecular Microbiology, Institute for Chemistry and Biology of the Marine Environment (ICBM), Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
| | - Heiko Moeller
- Institute for Chemistry, University of Potsdam, Potsdam, Germany
| | - Bodo Philipp
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
- Applied Ecology and Bioresources, Fraunhofer-Institute for Molecular and Applied Ecology IME, Schmallenberg, Germany
| | - Franziska Maria Mueller
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
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11
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Xu Z, Pei Y, Wang H, Li X. Comparative analysis of gut microbiota-mediated bile acid profiles in Bufo gargarizans and Rana chensinensis tadpoles. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 55:101530. [PMID: 40373385 DOI: 10.1016/j.cbd.2025.101530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/17/2025]
Abstract
Bile acids (BAs) are cholesterol derivatives synthesized by the liver, exhibit variation between different species. Researchers have long appreciated that microbiota play the roles in the biotransformation of BAs. However, relatively few studies have been reported on microbial-mediated production and transformation of BAs in amphibians. Our focus here is principally on difference of intestinal microbial diversity and BAs profiles between two common amphibians, Bufo gargarizans (B. gargarizans) and Rana chensinensis (R. chensinensis) tadpoles, through intestinal targeted BAs metabolomics and fecal metagenomic sequencing. The results demonstrated that B. gargarizans possessed higher levels of total BAs and higher ratio of unconjugated / conjugated BAs. In addition, the relative abundance of microbiota with bile salt hydrolase (BSH) activity in B. gargarizans was significantly higher than that of R. chensinensis, which may facilitate the conversion of conjugated to unconjugated BAs. Meanwhile the higher prevalence of bile-acid-induced (BAI) gene encoding microbiota in R. chensinensis may promote the synthesis of deoxycholic acid (DCA). Furthermore, discrepancies in virulence factors (VFs) and energy metabolism were observed between the two species, which may be linked to differences in the microbiota. This study revealed substantial differences in intestinal microbes and BAs across amphibian species, emphasizing the significant impact of intestinal microbes on BAs metabolism.
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Affiliation(s)
- Zhangying Xu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Yuebin Pei
- Cotton Research Institute, Shanxi Agriculture University, Yuncheng, Shanxi 044000, China
| | - Hongyuan Wang
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Xinyi Li
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
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12
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Lian S, Lu M, Jiajing L, Zhang B, Fang Y, Wang X, Zheng M, Ni Y, Xu G, Yang Y, Jiang R. Conjugated Lithocholic Acid Activates Hepatic TGR5 to Promote Lipotoxicity and MASLD-MASH Transition by Disrupting Carnitine Biosynthesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2410602. [PMID: 40344326 DOI: 10.1002/advs.202410602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 04/22/2025] [Indexed: 05/11/2025]
Abstract
Conjugated lithocholic acid (LCA) plays a critical role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). In this process, hepatocyte inflammation-caused upregulation of its receptor, Takeda G protein-coupled receptor 5 (TGR5) is a crucial factor. Serum bile acid profiling shows an increase in conjugated LCA, which correlates with disease severity. Depletion of Gpbar1 in hepatocytes significantly protects against the progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH) that is related to conjugated LCA. In vivo and in vitro experiments indicate that TGR5 activation in hepatocytes promotes lipotoxicity-induced cell death and inflammation by suppressing de novo carnitine biosynthesis. Mechanistically, TGR5 binding to CD36 facilitates E3 ubiquitin ligase TRIM21 recruitment, leading to the degradation of BBOX1, a crucial enzyme in de novo carnitine biosynthesis. Targeting TGR5 therapeutically can restore carnitine biosynthesis, which may offer a potent strategy to prevent or reverse the transition from MASLD to MASH.
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Affiliation(s)
- Senlin Lian
- Department of Lab Medicine, The First Affiliated Hospital of Anhui Medical University. MOE Innovation Center for Basic Research in Tumor Immunotherapy, and Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, 230022, China
| | - Meixi Lu
- Medical School of Nanjing University, Nanjing, Jiangsu Province, 210993, China
| | - Luo Jiajing
- Medical School of Nanjing University, Nanjing, Jiangsu Province, 210993, China
| | - Bin Zhang
- Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing, Jiangsu Province, 210008, China
| | - Yi Fang
- Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing, Jiangsu Province, 210008, China
| | - Xuran Wang
- Medical School of Nanjing University, Nanjing, Jiangsu Province, 210993, China
| | - Minghua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
| | - Yan Ni
- The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Guifang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Yonglin Yang
- Department of Infectious Diseases, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China
| | - Runqiu Jiang
- Department of Lab Medicine, The First Affiliated Hospital of Anhui Medical University. MOE Innovation Center for Basic Research in Tumor Immunotherapy, and Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, 230022, China
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13
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Ghaffari MH, Ostendorf CS, Hemmert KJ, Schuchardt S, Koch C, Sauerwein H. Longitudinal characterization of plasma and fecal bile acids in dairy heifers from birth to first calving in response to transition milk feeding. J Dairy Sci 2025; 108:5475-5488. [PMID: 40216228 DOI: 10.3168/jds.2025-26307] [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: 01/13/2025] [Accepted: 02/27/2025] [Indexed: 05/03/2025]
Abstract
This study aimed to characterize plasma bile acid changes from birth to first calving and evaluate the effects of early transition milk (TM) feeding versus milk replacer (MR) during key stages. Fecal bile acids in TM-fed calves were also analyzed, offering insights into bile acid metabolism. Thirty female Holstein calves were fed TM or MR for the first 5 d, followed by 12 L/d MR. From d 14, calves were fed MR and starter with gradual weaning between wk 8 and 14. Blood samples were collected at 7 time points: 30 min and 12 h after birth, preweaning (wk 2, 6), weaning (wk 14), 8 mo, 13 mo, 3 wk before calving, at calving, and 3 wk after calving. Fecal samples were collected from a subset of TM-fed calves (n = 10) at birth, wk 6, wk 14, 8 mo, and calving. Samples were analyzed for bile acids using the Biocrates MxP Quant 500 kit. Cholic acid (CA) in plasma showed significant time-treatment interactions, with higher levels in TM-fed calves at weaning. Taurine- and glycine-conjugated bile acids had no treatment or time-treatment interactions, but all plasma bile acids showed significant time effects. Principal component analysis revealed that bile acid profiles at birth and after colostrum intake were tightly clustered. Plasma bile acid profiles showed greater dispersion during milk feeding and weaning, with tighter clustering observed postweaning, particularly at 13 mo, and in the transition period. Significant effects were observed for CA, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), with CA showing a notable interaction and being higher in TM-fed calves at weaning than in MR-fed calves. Bile acid levels increased toward weaning, peaked at wk 14, and decreased after weaning. Glycine-conjugated bile acids changed over time, with glycocholic acid (GCA) and glycodeoxycholic acid (GDCA) peaking at weaning, and glycochenodeoxycholic acid (GCDCA) being elevated before weaning, decreasing thereafter, and increasing again at calving. Taurine-conjugated bile acids also showed temporal changes, peaking at wk 6. The shifts in bile acid composition from birth to postcalving, with taurolithocholic acid (TLCA), GDCA, and taurocholic acid (TCA) initially dominating, CA increasing at weaning, and GDCA and DCA dominating at calving, with CA increasing again postcalving. During the transition to calving, CA decreased whereas glycine-conjugated bile acids increased relative to taurine-conjugated bile acids in plasma, irrespective of treatment. Fecal bile acid profiles in TM-fed calves clustered distinctly at birth, evolving through pre- to postweaning and calving, with increasing profile overlap over time. Most fecal bile acids, except DCA and CA, were abundant at birth but declined over time. Both DCA and CA increased postweaning, mirroring plasma trends. From wk 6 to calving, DCA was the dominant bile acid, accounting for the highest percentage of total bile acids excreted in feces. Spearman's correlation analysis was performed to assess the relationship between plasma and fecal bile acids in TN-fed calves. A significant positive correlation was observed only for GCDCA (Spearman's rank correlation coefficient [rho] = 0.35), whereas all other bile acids were not correlated. These results illustrate the complex dynamics of bile acid profiles during calf development.
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Affiliation(s)
- M H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| | - C S Ostendorf
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | - K J Hemmert
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - S Schuchardt
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | - C Koch
- Educational and Research Centre for Animal Husbandry, Hofgut Neumühle, 67728 Münchweiler an der Alsenz, Germany
| | - H Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
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14
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Jalil A, Perino A, Dong Y, Imbach J, Volet C, Vico-Oton E, Demagny H, Plantade L, Gallart-Ayala H, Ivanisevic J, Bernier-Latmani R, Hapfelmeier S, Schoonjans K. Bile acid 7α-dehydroxylating bacteria accelerate injury-induced mucosal healing in the colon. EMBO Mol Med 2025; 17:889-908. [PMID: 40065134 DOI: 10.1038/s44321-025-00202-w] [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: 08/29/2024] [Revised: 02/03/2025] [Accepted: 02/05/2025] [Indexed: 03/23/2025] Open
Abstract
Host-microbiome communication is frequently perturbed in gut pathologies due to microbiome dysbiosis, leading to altered production of bacterial metabolites. Among these, 7α-dehydroxylated bile acids are notably diminished in inflammatory bowel disease patients. Herein, we investigated whether restoration of 7α-dehydroxylated bile acids levels by Clostridium scindens, a human-derived 7α-dehydroxylating bacterium, can reestablish intestinal epithelium homeostasis following colon injury. Gnotobiotic and conventional mice were subjected to chemically-induced experimental colitis following administration of Clostridium scindens. Colonization enhanced the production of 7α-dehydroxylated bile acids and conferred prophylactic and therapeutic protection against colon injury through epithelial regeneration and specification. Computational analysis of human datasets confirmed defects in intestinal cell renewal and differentiation in ulcerative colitis patients while expression of genes involved in those pathways showed a robust positive correlation with 7α-dehydroxylated bile acid levels. Clostridium scindens administration could therefore be a promising biotherapeutic strategy to foster mucosal healing following colon injury by restoring bile acid homeostasis.
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Affiliation(s)
- Antoine Jalil
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Alessia Perino
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Yuan Dong
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Jéromine Imbach
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Colin Volet
- Environmental Microbiology Laboratory, School of Architecture, Civil and Environmental Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Eduard Vico-Oton
- Environmental Microbiology Laboratory, School of Architecture, Civil and Environmental Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Hadrien Demagny
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Lucie Plantade
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Hector Gallart-Ayala
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Rizlan Bernier-Latmani
- Environmental Microbiology Laboratory, School of Architecture, Civil and Environmental Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | | | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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15
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Tessier MEM, Shneider BL, Petrosino JF, Preidis GA. Bile acid and microbiome interactions in the developing child. J Pediatr Gastroenterol Nutr 2025; 80:832-839. [PMID: 39959949 PMCID: PMC12068970 DOI: 10.1002/jpn3.70014] [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: 04/26/2024] [Revised: 12/06/2024] [Accepted: 12/23/2024] [Indexed: 05/13/2025]
Abstract
Interactions between the gut microbiome and bile acids are complex and are linked to outcomes in pediatric liver disease by mechanisms that are incompletely understood. In adults, primary bile acids are synthesized in the liver and secreted into the intestine, where complex communities of gut microbes deconjugate, oxidize, epimerize, and 7α-dehydroxylate bile acids into a diverse array of unconjugated, secondary, allo-, iso-, and oxo-bile acids. In contrast, the infant gut microbiota contains a simple, Bifidobacterium-dominant community that transitions to a more diverse, adult-like community as additional microbes colonize the gut. This microbial succession gradually confers deconjugation, oxidation, epimerization, and 7α-dehydroxylation activities that mature the bile acid pool from a profile dominated by primary bile acids early in life to a more diverse, adult-like bile acid profile in later childhood. Altered bile acid profiles in pediatric cholestatic disorders have the potential to change the developmental trajectory of the microbiome. Conversely, alterations in the gut microbiome may re-shape the bile acid pool and hepatic bile acid metabolism. Understanding the mechanisms underlying these interactions will increase our understanding of liver pathophysiology and will motivate new therapeutic strategies for pediatric hepatic disorders. This review aims to highlight differences between the pediatric and adult intestinal microbiome and bile acid pool, and to discuss interactions between gut microbes and bile acids that are critical in early life and that may impact outcomes in infants and children with cholestatic liver disease, including biliary atresia.
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Affiliation(s)
- Mary Elizabeth M. Tessier
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/ Texas Children’s Hospital, Houston, TX, United States
| | - Benjamin L. Shneider
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/ Texas Children’s Hospital, Houston, TX, United States
| | - Joseph F. Petrosino
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States
| | - Geoffrey A Preidis
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/ Texas Children’s Hospital, Houston, TX, United States
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16
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Luangphiphat W, Jamjuree P, Chantarangkul C, Amornariyakool O, Taweechotipatr M. Protective Effects of Limosilactobacillus reuteri MSMC64 in Hyperlipidemia Rats Induced by a High-Cholesterol Diet. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10555-w. [PMID: 40310598 DOI: 10.1007/s12602-025-10555-w] [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] [Accepted: 04/21/2025] [Indexed: 05/02/2025]
Abstract
Hyperlipidemia, characterized by abnormally elevated levels of lipids such as cholesterol, is a significant risk factor for cardiovascular diseases (CVD), contributing to increased oxidative stress, inflammation, and disruption of gut immunity. Dysbiosis, or imbalance in the gut microbiome, plays a critical role in the pathogenesis of hyperlipidemia. Probiotics, as key components of the gut microbiome, have been shown to positively impact health. This study aimed to evaluate the effects of Limosilactobacillus reuteri MSMC64 on lipid profiles, blood glucose levels, hepatic steatosis, antioxidant capacity, inflammatory biomarkers, and colon barrier immunity in hyperlipidemic rats induced by a high-cholesterol diet. The results demonstrated that the administration of L. reuteri MSMC64 may improve lipid profiles and blood glucose levels, reduce hepatic steatosis and oxidative stress, and lower inflammatory biomarkers while maintaining colon barrier integrity. These findings suggest that L. reuteri MSMC64 has the potential to be developed as a probiotic supplement for mitigating risk factors associated with hyperlipidemia and CVD.
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Affiliation(s)
- Wongsakorn Luangphiphat
- Princess Srisavangavadhana Faculty of Medicine, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
- Division of Cardiology, Department of Medicine, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
| | - Praewpannarai Jamjuree
- Center of Excellence in Probiotics, Srinakharinwirot University, Bangkok, 10110, Thailand
| | | | - Onnicha Amornariyakool
- Princess Srisavangavadhana Faculty of Medicine, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
| | - Malai Taweechotipatr
- Center of Excellence in Probiotics, Srinakharinwirot University, Bangkok, 10110, Thailand.
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok, 10110, Thailand.
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17
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Ghaffari MH, Sauerwein H, Sadri H, Schuchardt S, Martín-Tereso J, Doelman JH, Daniel JB. Longitudinal characterization of the metabolome of dairy cows transitioning from one lactation to the next: Investigations in fecal samples. J Dairy Sci 2025; 108:5405-5419. [PMID: 40043758 DOI: 10.3168/jds.2025-26273] [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: 01/06/2025] [Accepted: 01/31/2025] [Indexed: 05/03/2025]
Abstract
The fecal metabolome comprises metabolites that are excreted or not absorbed by the animal. This study examined the changes in the fecal metabolome of dairy cows from the end of one lactation period, through the dry period, and into the subsequent lactation. Twelve Holstein cows (BW = 745 ± 71 kg, BCS = 3.43 ± 0.66) were housed in a tiestall barn from 7 wk before to 15 wk after parturition, with dry-off occurring approximately 6 wk before the expected calving date (mean dry-off time = 42 d). Fecal samples were taken at wk -7, -5, -1, +1, +5, +10, and +15 relative to calving. Targeted metabolomics identified a total of 93 metabolites, including AA, biogenic amines, bile acids (BA), acylcarnitines (AcylCN), and some phospholipids. Principal component analysis (PCA) revealed clear metabolic shifts that showed a clear separation between the samples from the dry period and the samples from the end, early, and middle of lactation, indicating significant changes in the metabolic profiles in the feces. The transition from the dry period (wk -5, -1 relative to calving) to lactation (wk +1, +5, +10, +15, and -7 relative to calving) is characterized by an increase in fecal AA and metabolites, such as Glu, Met, β-alanine, and methionine sulfoxide, reflecting a shift in nitrogen metabolism to support increased protein metabolism for milk production. Higher concentrations of polyamines, such as spermidine and putrescine, were observed postpartum, indicating increased cell growth and improved tissue regeneration. Elevated gamma-aminobutyric acid levels during lactation indicate increased microbial activity driven by a nutrient-rich diet. Results showed significant adjustments in BA profiles as cows transitioned into lactation. Deoxycholic acid remained the predominant BA in feces, reflecting ongoing microbial transformation, whereas glycine- and taurine-conjugated BA increased postpartum, suggesting improved enterohepatic circulation and lipid absorption. Fecal AcylCN showed dynamic shifts with elevated levels during late gestation, a decrease in the dry period, and an increase postpartum, indicating increased fatty acid oxidation to meet energy demands. Results showed that phosphatidylcholines decreased prepartum but increased after calving. This indicates shifts in lipid metabolism reflecting energy requirements in lactation and suggests that fecal lipid composition is an indicator of metabolic adaptations in dairy cows. In particular, PCA revealed considerable overlap in the fecal metabolite profiles of multiparous and primiparous cows, indicating similar metabolic profiles. This was also confirmed by volcano plots, which showed no significant differences in fecal metabolism between the 2 groups across different weeks relative to calving (wk -7, -5, -1, +1, +5, +10, and +15). Overall, these results emphasize the complex interactions between dietary factors, liver and gastrointestinal function, and the gut microbiome in shaping the fecal metabolite profile of dairy cows. These results underscore the value of this data set in advancing the application of fecal metabolome profiling to investigate metabolic changes during critical transitions in the lactation cycle of dairy cows.
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Affiliation(s)
- M H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| | - H Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - H Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 5166616471 Tabriz, Iran
| | - S Schuchardt
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | | | - J H Doelman
- Trouw Nutrition R&D, 3800 AG, Amersfoort, the Netherlands
| | - J B Daniel
- Trouw Nutrition R&D, 3800 AG, Amersfoort, the Netherlands.
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18
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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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Zhang Y, Ma R, Du X, He X, Zhang Y, Ma N, Liu H, Zhao X. Impact of bacteroides uniformis on fatty liver hemorrhagic syndrome in dawu golden phoenix laying hens: modulation of gut microbiota and arachidonic acid metabolism. Front Microbiol 2025; 16:1560887. [PMID: 40356654 PMCID: PMC12066428 DOI: 10.3389/fmicb.2025.1560887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/25/2025] [Indexed: 05/15/2025] Open
Abstract
This study explored the impact of Bacteroides uniformis (B. uniformis) on fatty liver hemorrhagic syndrome (FLHS) induced by a high-energy and low-protein (HELP) diet in laying hens, mainly focusing on hepatic lipid metabolism, gut microbiota, and arachidonic acid (AA) metabolism. A total of 120 Dawu Golden Phoenix laying hens (210-day-old) were randomly divided into four groups. The control group (CON) was fed a standard diet and received a daily gavage of PBS, while the other groups were fed with a HELP diet to induce FLHS and received a daily gavage of PBS (MOD), 1 × 109 CFU/ml B. uniformis (BUL), and 1 × 1011 CFU/ml B. uniformis (BUH) for 70 days. All hens were administered 1 ml daily by gavage. Each group had 6 replications with 5 hens per replication. The results showed that B. uniformis increased the egg production rate and feed conversion ratio and decreased body weight, liver index, and abdominal fat rate (p < 0.05). B. uniformis treatment reduced liver lipid accumulation by reducing the levels of Triglyceride (TG), Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine transaminases (ALT), and aspartate transaminases (AST) in serum and significantly elevated high-density lipoprotein cholesterol (HDL-C) (p < 0.05). The results indicated that B. uniformis altered the gut microbiota. Specifically, the abundance of Bacteroides was higher, and the relative abundances of Treponema, Helicobacter, and Spirochaetota were lower than those of the MOD group (p < 0.05). Moreover, targeted metabolomic analysis showed that supplementation of B. uniformis significantly elevated 6-keto-PGF1α and AA levels, along with significantly reduced levels of thromboxane B2 (TXB2), leukotriene D4 (LTD4), 8-isoprostaglandin F2α (8-iso-PGF2α), 12S-hydroxyeicosatetraenoic acid (12S-HETE), 15S-hydroxyeicosatetraenoic acid (15S-HETE), 9-S-hydroxy-octadecadienoic acid (9S-HODE), and 13-S-hydroxy-octadecadienoic acid (13S-HODE) (p < 0.05). In conclusion, the oral intake of B. uniformis can improve liver function, gut microbiota, and AA metabolism, thereby helping to ameliorate FLHS in Dawu Golden Phoenix laying hens.
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Affiliation(s)
- Yu Zhang
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Rongfei Ma
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Xicui Du
- Hebei Jinkun Animal Pharmaceutical Co. Ltd., Xinji, China
| | - Xin He
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Yan Zhang
- Institute of Animal Science and Veterinary Medicine, Hainan Academy of Agricultural Sciences, Haikou, China
| | - Ning Ma
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Hailong Liu
- Institute of Animal Science and Veterinary Medicine, Hainan Academy of Agricultural Sciences, Haikou, China
| | - Xinghua Zhao
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
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20
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Meessen ECE, Majait S, Ay Ü, Olde Damink SW, Romijn JA, Holst JJ, Hartmann B, Kuipers F, Nieuwdorp M, Schaap FG, Groen AK, Kemper EM, Soeters MR. Glycodeoxycholic Acid Inhibits Primary Bile Acid Synthesis With Minor Effects on Glucose and Lipid Homeostasis in Humans. J Clin Endocrinol Metab 2025; 110:1468-1477. [PMID: 38864544 PMCID: PMC12012696 DOI: 10.1210/clinem/dgae399] [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: 02/16/2024] [Revised: 05/15/2024] [Accepted: 06/07/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Bile acids play vital roles in control of lipid, glucose, and energy metabolism by activating Takeda G protein-coupled receptor 5 and Farnesoid X receptor, the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation (eg, of chenodeoxycholic acid for gallstone dissolution) has been reported to have adverse effects. STUDY DESIGN In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in 2 groups of each 10 healthy lean men, respectively. MAIN FINDINGS GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids chenodeoxycholic acid and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid, glucose, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events. CONCLUSION GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose, and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.
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Affiliation(s)
- Emma C E Meessen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centres—Location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Soumia Majait
- Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC Location AMC, 1105 AZ, Amsterdam, The Netherlands
| | - Ümran Ay
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074, Aachen, Germany
| | - Steven W Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074, Aachen, Germany
| | - Johannes A Romijn
- Department of Internal Medicine, Amsterdam University Medical Centres—Location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Folkert Kuipers
- Department of Paediatrics, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands
- European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9713 CZ, Groningen, The Netherlands
| | - Max Nieuwdorp
- Department of (Experimental) Vascular Medicine, Amsterdam University Medical Centres—Location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Frank G Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074, Aachen, Germany
| | - Albert K Groen
- Department of (Experimental) Vascular Medicine, Amsterdam University Medical Centres—Location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - E Marleen Kemper
- Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC Location AMC, 1105 AZ, Amsterdam, The Netherlands
- Department of (Experimental) Vascular Medicine, Amsterdam University Medical Centres—Location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centres—Location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
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21
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John HT, Thomas TC, Chukwuebuka EC, Ali AB, Anass R, Tefera YY, Babu B, Negrut N, Ferician A, Marian P. The Microbiota-Human Health Axis. Microorganisms 2025; 13:948. [PMID: 40284784 PMCID: PMC12029893 DOI: 10.3390/microorganisms13040948] [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: 03/16/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Trillions of microorganisms play a pivotal role in maintaining health and preventing disease in humans. Their presence influences daily life, habits, energy levels, and pathologies. The present narrative review synthesized recent studies of microbial diversity across organ systems. The composition of the microbiota regulates the intestinal barrier, modulates the immune response, influences metabolism, and produces essential compounds such as short-chain fatty acids and neurotransmitters. Dysbiosis is associated with numerous pathologies, including metabolic, autoimmune, neurodegenerative, and cardiovascular diseases. The microbiota is key to maintaining physiological balance and reducing disease risk. Therapeutic interventions, such as probiotics, prebiotics, postbiotics, and microbiome transplantation, offer promising perspectives in restoring microbial homeostasis and preventing chronic diseases.
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Affiliation(s)
- Harrie Toms John
- Department of Intensive Care, Epsom and St. Helier University Hospitals NHS Trust, Wrythe Ln, Sutton SM5 1AA, UK
| | - Treesa Clare Thomas
- Faculty of Medicine and Pharmacy, University of Oradea, Piaţa 1 Decembrie 10, 410068 Oradea, Romania; (T.C.T.); (E.C.C.); (A.B.A.); (R.A.)
| | - Ezenwa Collins Chukwuebuka
- Faculty of Medicine and Pharmacy, University of Oradea, Piaţa 1 Decembrie 10, 410068 Oradea, Romania; (T.C.T.); (E.C.C.); (A.B.A.); (R.A.)
| | - Ali Bacar Ali
- Faculty of Medicine and Pharmacy, University of Oradea, Piaţa 1 Decembrie 10, 410068 Oradea, Romania; (T.C.T.); (E.C.C.); (A.B.A.); (R.A.)
| | - Reggani Anass
- Faculty of Medicine and Pharmacy, University of Oradea, Piaţa 1 Decembrie 10, 410068 Oradea, Romania; (T.C.T.); (E.C.C.); (A.B.A.); (R.A.)
| | | | - Bency Babu
- Department of General Internal Medicine, Northampton General Hospital, NHS Trust, Northampton NN1 5BD, UK;
| | - Nicoleta Negrut
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
- Department of Psycho-Neuroscience and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Anca Ferician
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (A.F.); (P.M.)
| | - Paula Marian
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (A.F.); (P.M.)
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22
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Liu M, Ge Y, Xu E, Zhu T, Ruan H, Zheng J. The regulatory effects of epigallocatechin gallate on growth performance, systemic antioxidant status, immune response, and gut microbiota structure in geese. Poult Sci 2025; 104:105178. [PMID: 40267569 DOI: 10.1016/j.psj.2025.105178] [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: 03/18/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/25/2025] Open
Abstract
The effects of dietary supplementation with epigallocatechin-3-gallate (EGCG) on growth performance, antioxidant capacity, immune function, and gut microbiota in geese were investigated. Seventy-two healthy 35-day-old male geese were randomly divided into a control group (basal diet) or an EGCG group (basal diet + 200 mg/kg EGCG), with 36 geese per group, which was further subdivided into 6 replicates (6 geese per replicate). The experiment lasted 21 days. Geese in the EGCG group exhibited significantly higher final body weight (2.93 kg vs. 2.28 kg, P < 0.01) and average daily gain (72.38 g/d vs. 41.4 g/d, P < 0.01) along with a 42.8 % reduction in the feed conversion ratio (3.95 vs. 6.91, P < 0.01) versus the control. Liver weights in the EGCG group were significantly elevated compared to the CON group on days 14 and 21 (P < 0.05) and a strong correlation between liver weight and body weight. EGCG significantly increased catalase, glutathione peroxidase, and superoxide dismutase activities, and the total antioxidant capacity in serum and jejunum while decreasing malondialdehyde (MDA) levels (P < 0.05). Immunological analyses revealed elevated serum immunoglobulin (Ig)A, IgG, and IgM and lysozyme in the EGCG group (P < 0.05), accompanied by a decrease in the pro-inflammatory cytokines interleukin-6 and interferon-γ. Intestinal morphology demonstrated increased villus height-to-crypt depth ratios in the duodenum and ileum (P < 0.05). 16S rRNA sequencing indicated that EGCG increased the relative abundance of Akkermansia and Verrucomicrobiota (P < 0.05) in the cecal content and enriched microbial functions related to inorganic ion transport and metabolism. Correlation analysis revealed positive associations between Akkermansia and IgA, and between Firmicutes and oxidative damage markers (MDA). Overall, dietary supplementation with 200 mg/kg EGCG could improve growth performance, antioxidant capacity, immune response, and gut microbiota structure in geese, supporting its potential as a plant-based feed additive.
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Affiliation(s)
- Mengyu Liu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University,163319, Daqing, Heilongjiang, PR China
| | - Yansong Ge
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University,163319, Daqing, Heilongjiang, PR China
| | - Enshuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University,163319, Daqing, Heilongjiang, PR China
| | - Tingting Zhu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University,163319, Daqing, Heilongjiang, PR China
| | - Hongri Ruan
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University,163319, Daqing, Heilongjiang, PR China
| | - Jiasan Zheng
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University,163319, Daqing, Heilongjiang, PR China.
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23
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Ionescu VA, Diaconu CC, Gheorghe G, Mihai MM, Diaconu CC, Bostan M, Bleotu C. Gut Microbiota and Colorectal Cancer: A Balance Between Risk and Protection. Int J Mol Sci 2025; 26:3733. [PMID: 40332367 PMCID: PMC12028331 DOI: 10.3390/ijms26083733] [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: 03/21/2025] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
The gut microbiome, a complex community of microorganisms residing in the intestinal tract, plays a dual role in colorectal cancer (CRC) development, acting both as a contributing risk factor and as a protective element. This review explores the mechanisms by which gut microbiota contribute to CRC, emphasizing inflammation, oxidative stress, immune evasion, and the production of genotoxins and microbial metabolites. Fusobacterium nucleatum, Escherichia coli (pks+), and Bacteroides fragilis promote tumorigenesis by inducing chronic inflammation, generating reactive oxygen species, and producing virulence factors that damage host DNA. These microorganisms can also evade the antitumor immune response by suppressing cytotoxic T cell activity and increasing regulatory T cell populations. Additionally, microbial-derived metabolites such as secondary bile acids and trimethylamine-N-oxide (TMAO) have been linked to carcinogenic processes. Conversely, protective microbiota, including Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii, contribute to intestinal homeostasis by producing short-chain fatty acids (SCFAs) like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties. These beneficial microbes enhance gut barrier integrity, modulate immune responses, and inhibit tumor cell proliferation. Understanding the dynamic interplay between pathogenic and protective microbiota is essential for developing microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, to prevent or treat CRC. Future research should focus on identifying microbial biomarkers for early CRC detection and exploring personalized microbiome-targeted therapies. A deeper understanding of host-microbiota interactions may lead to innovative strategies for CRC management and improved patient outcomes.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Academy of Romanian Scientists, 050085 Bucharest, Romania;
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Mara-Madalina Mihai
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Department of Oncologic Dermathology, “Elias” University Emergency Hospital, 010024 Bucharest, Romania
| | - Carmen Cristina Diaconu
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
| | - Marinela Bostan
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
- Department of Immunology, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
| | - Coralia Bleotu
- Academy of Romanian Scientists, 050085 Bucharest, Romania;
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
- Research Institute of the University of Bucharest (ICUB), University of Bucharest, 060023 Bucharest, Romania
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24
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Antonini Cencicchio M, Montini F, Palmieri V, Massimino L, Lo Conte M, Finardi A, Mandelli A, Asnicar F, Pavlovic R, Drago D, Ungaro F, Andolfo A, Segata N, Martinelli V, Furlan R, Falcone M. Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity. Cell Rep Med 2025; 6:102028. [PMID: 40101713 PMCID: PMC12047456 DOI: 10.1016/j.xcrm.2025.102028] [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: 02/21/2024] [Revised: 09/25/2024] [Accepted: 02/21/2025] [Indexed: 03/20/2025]
Abstract
The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3+ regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.
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Affiliation(s)
| | - Federico Montini
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy; Clinical Neurology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Vittoria Palmieri
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy
| | - Luca Massimino
- Experimental Gastroenterology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Gastroenterology and Digestive Endoscopy Department, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Marta Lo Conte
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy
| | - Annamaria Finardi
- Clinical Neuroimmunology Unit, INSPE, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Alessandra Mandelli
- Clinical Neuroimmunology Unit, INSPE, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | | | - Radmila Pavlovic
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Denise Drago
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Federica Ungaro
- Experimental Gastroenterology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Gastroenterology and Digestive Endoscopy Department, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Annapaola Andolfo
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Nicola Segata
- Department CIBIO, University of Trento, 38123 Trento, Italy
| | | | - Roberto Furlan
- Clinical Neuroimmunology Unit, INSPE, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marika Falcone
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy.
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25
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Urbani G, Rondini E, Distrutti E, Marchianò S, Biagioli M, Fiorucci S. Phenotyping the Chemical Communications of the Intestinal Microbiota and the Host: Secondary Bile Acids as Postbiotics. Cells 2025; 14:595. [PMID: 40277921 PMCID: PMC12025480 DOI: 10.3390/cells14080595] [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: 03/04/2025] [Revised: 04/10/2025] [Accepted: 04/12/2025] [Indexed: 04/26/2025] Open
Abstract
The current definition of a postbiotic is a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health.
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Affiliation(s)
- Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
| | - Elena Rondini
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy; (E.R.); (E.D.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy; (E.R.); (E.D.)
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
| | - Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
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26
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Zhang R, Mei S, He G, Wei M, Chen L, Chen Z, Zhu M, Zhou B, Wang K, Cheng Z, Wang C, Zhu E, Chen C. Multi-omics analyses reveal fecal microbial community and metabolic alterations in finishing cattle fed probiotics-fermented distiller's grains diets. Microbiol Spectr 2025; 13:e0072124. [PMID: 40214255 PMCID: PMC12054032 DOI: 10.1128/spectrum.00721-24] [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: 03/23/2024] [Accepted: 03/13/2025] [Indexed: 05/08/2025] Open
Abstract
Distiller's grains (DG) are a potential source of animal feeds, and many studies have indicated positive regulatory roles of feeding DG diets in animal breeding. However, there is currently a dearth of research on the actions and underlying mechanisms of probiotics-fermented distiller's grains (FDG)-based diets in cattle breeding. This study aimed to assess the impact of integrating FDG into the diet of finishing cattle on their fecal microbial community and metabolites. Thirty Simmental crossbred cattle (local yellow cattle × Simmental cattle, 8.5 months old, 420.38 ± 68.11 kg) were selected and randomly divided into three dietary treatments, including the basal diet group (CON group), the FDG replacing 10% concentrate (FDG-10%) group, and the FDG replacing 20% concentrate (FDG-20%) group. 16S and ITS sequencing of fecal samples collected from each group on the 30th day of the formal feeding suggested that feeding FDG diets had little effect on the composition and diversity of fecal bacterial and fungal communities in finishing cattle. However, the relative abundance of cellulose-degrading bacteria, including the Christensenellaceae R-7 group and Ruminococcaceae family was significantly higher in both the FDG-20% vs CON comparison and the FDG-20% vs FDG-10% comparison. Besides, the FDG-10% group had a significant drop in the relative abundance of Aspergillus and a noteworthy increase in the relative abundance of Candida when compared to the CON group. Non-targeted metabolomics analysis showed that the addition of FDG modified the levels of organoheterocyclic compounds, lipids and lipid-like molecules, and benzenoids in the feces of finishing cattle and significantly enhanced the metabolic pathway of bile secretion. Further correlation analyses suggested a close association between the significantly differential fecal microbiota and metabolites. In conclusion, these results suggest that FDG supplementation has little effect on the structure and diversity of the fecal microbiota in finishing cattle, but alters intestinal metabolite profiles and influences bile secretion pathways by modulating the relative abundance of genera of fecal bacteria and fungi Christensenellaceae R-7 group, Lachnospiraceae_NK3A20_group, Mucor, and Candida. These findings provide a scientific theoretical basis for the use of FDG in animal feeds. IMPORTANCE Probiotics-fermented distiller's grains (FDG) are potential feed sources for livestock. Here, we investigated the effects of partially replacing concentrates with FDG on fecal bacterial and fungal community structure and metabolic profiles in finishing cattle. The results reveal that feeding FDG-based diets alters intestinal metabolite profiles and up-regulates bile secretion pathways through the regulation of relative abundance of certain fecal genera. These findings provide some new insights into clarifying the role and potential mechanisms of FDG diets and also offer a scientific basis for the development of FDG into functional feed resources.
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Affiliation(s)
- Rong Zhang
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Shihui Mei
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Guangxia He
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Miaozhan Wei
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Lan Chen
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Ze Chen
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Min Zhu
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Bijun Zhou
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Kaigong Wang
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Zhentao Cheng
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Chunmei Wang
- College of Animal Science, Guizhou University, Guiyang, China
| | - Erpeng Zhu
- College of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Disease Research Laboratory, Guiyang, China
| | - Chao Chen
- College of Animal Science, Guizhou University, Guiyang, China
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27
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Olivos-Caicedo KY, Fernandez-Materan FV, Daniel SL, Anantharaman K, Ridlon JM, Alves JMP. Pangenome Analysis of Clostridium scindens: A Collection of Diverse Bile Acid- and Steroid-Metabolizing Commensal Gut Bacterial Strains. Microorganisms 2025; 13:857. [PMID: 40284693 PMCID: PMC12029741 DOI: 10.3390/microorganisms13040857] [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: 01/30/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/29/2025] Open
Abstract
Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized to any significant extent. The formation of secondary bile acids is important in the etiology of cancers of the GI tract and in the prevention of Clostridioides difficile infection. We determined the presence and absence of bile acid inducible (bai) and steroid-17,20-desmolase (des) genes among C. scindens strains and the features of the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the C. scindens cultivars have an open pangenome with 12,720 orthologous gene groups and a core genome with 1630 gene families, in addition to 7051 and 4039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The pangenome profile including the MAGs also proved to be open. Our analyses reveal that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, as suggested by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.
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Affiliation(s)
- Kelly Y. Olivos-Caicedo
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
| | - Francelys V. Fernandez-Materan
- Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, IL 61801, USA;
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;
| | - Steven L. Daniel
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;
- Department of Biological Sciences, Eastern Illinois University, Charleston, IL 61920, USA
| | - Karthik Anantharaman
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA;
- Department of Data Science and AI, Indian Institute of Technology Madras, Chennai 600036, India
| | - Jason M. Ridlon
- Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, IL 61801, USA;
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - João M. P. Alves
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
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28
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Xiong S. Gut-Microbiota-Driven Lipid Metabolism: Mechanisms and Applications in Swine Production. Metabolites 2025; 15:248. [PMID: 40278377 PMCID: PMC12029090 DOI: 10.3390/metabo15040248] [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: 03/12/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 04/26/2025] Open
Abstract
Background/Objectives: The gut microbiota plays a pivotal role in host physiology through metabolite production, with lipids serving as essential biomolecules for cellular structure, metabolism, and signaling. This review aims to elucidate the interactions between gut microbiota and lipid metabolism and their implications for enhancing swine production. Methods: We systematically analyzed current literature on microbial lipid metabolism, focusing on mechanistic studies on microbiota-lipid interactions, key regulatory pathways in microbial lipid metabolism, and multi-omics evidence (metagenomic/metabolomic) from swine models. Results: This review outlines the structural and functional roles of lipids in bacterial membranes and examines the influence of gut microbiota on the metabolism of key lipid classes, including cholesterol, bile acids, choline, sphingolipids, and fatty acids. Additionally, we explore the potential applications of microbial lipid metabolism in enhancing swine production performance. Conclusions: Our analysis establishes a scientific framework for microbiota-based strategies to optimize lipid metabolism. The findings highlight potential interventions to improve livestock productivity through targeted manipulation of gut microbial communities.
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Affiliation(s)
- Shuqi Xiong
- National Key Laboratory of Pig Genetic Improvement and Germplasm Innovation, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
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29
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Yang Y, Hao C, Jiao T, Yang Z, Li H, Zhang Y, Zhang W, Doherty M, Sun C, Yang T, Li J, Wu J, Zhang M, Wang Y, Xie D, Wang T, Wang N, Huang X, Li C, Gonzalez FJ, Wei J, Xie C, Zeng C, Lei G. Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling. Science 2025; 388:eadt0548. [PMID: 40179178 DOI: 10.1126/science.adt0548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 01/27/2025] [Indexed: 04/05/2025]
Abstract
Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)-the receptor of GUDCA-alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of Clostridium bolteae, which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with C. bolteae and Food and Drug Administration-approved UDCA alleviated osteoarthritis through the gut FXR-joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota-GUDCA-intestinal FXR-GLP-1-joint pathway offers a potential strategy for osteoarthritis treatment.
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Affiliation(s)
- Yuanheng Yang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Cong Hao
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Tingying Jiao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
| | - Zidan Yang
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Bioinformatics Center, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Yuqing Zhang
- Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- The Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Weiya Zhang
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis UK, Nottingham, UK
| | - Michael Doherty
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis UK, Nottingham, UK
| | - Chuying Sun
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Tuo Yang
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Health Management Center, Xiangya Hospital, Central South University, Changsha, China
| | - Jiatian Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Wu
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Mengjiao Zhang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yilun Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Dongxing Xie
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Tingjian Wang
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Huang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Changjun Li
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jie Wei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- Bioinformatics Center, Furong Laboratory, Changsha, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chao Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Guanghua Lei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Chin WL, Lee BH, Hsu QY, Hou CY, Pai MC, Lin CW, Hsu WH. Small intestine-residing probiotics suppress neurotoxic bile acid production via extracellular vesicle-mediated inhibition of Clostridium scindens. Food Res Int 2025; 207:116049. [PMID: 40086955 DOI: 10.1016/j.foodres.2025.116049] [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: 12/17/2024] [Revised: 02/02/2025] [Accepted: 02/21/2025] [Indexed: 03/16/2025]
Abstract
Dysbiosis in gut microbiota and abnormalities in bile acids have been linked to neurodegenerative diseases. While many studies have focused on the relationship between colonic bacteria and Alzheimer's disease (AD), this study propose that alterations in the small intestine microbiota may play a more critical role. This is because the small intestine is pivotal in recycling bile acids through enterohepatic circulation. This study uses amyloid precursor protein knock-in (APPNL-G-F/NL-G-F) transgenic mice to investigate the association between intestinal microbiota and bile acid metabolism. The results showed that the accumulation of beta-amyloid (Aβ) leads to a significant decrease in Lactobacillus johnsonii and a notable increase in bacteria of the genus Clostridium in the small intestine, which are important microorganisms for producing toxic bile acids. Extracellular vesicles (EVs) involved in bacterial interactions and bacteria-host interactions are currently a focus of research. Treatment with L. johnsonii-derived EVs at concentrations of 1010 and 1012/mL) inhibited the growth of Clostridium scindens and suppressed the production of toxic secondary lithocholic acid (TLA) at non-cytotoxic concentrations (108/mL). Furthermore, the removal of small RNA from L. johnsonii-derived EVs resulted in the loss of their ability to suppress TLA production. These results suggest that the small intestine microbiota may play a more critical role than the colonic microbiota in AD. Deterioration of small intestine microbiota led to the metabolism disruption of certain secondary bile acids, which have been reported to exacerbate AD pathology. The EVs released by L. johnsonii, which is abundant in the small intestine, can suppress toxic TLA and have the potential to be developed into health-promoting probiotics.
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Affiliation(s)
- Wei-Leng Chin
- Department of Family Medicine and Community Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung 824005, Taiwan
| | - Bao-Hong Lee
- Department of Horticultural Sciences, National Chiayi University, Chiayi 600355, Taiwan
| | - Qiao-Yu Hsu
- Department of Food Safety/Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Chih-Yao Hou
- Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811213, Taiwan
| | - Ming-Chyi Pai
- Division of Behavioral Neurology, Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Chi-Wei Lin
- Department of Family Medicine and Community Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Wei-Hsuan Hsu
- Department of Food Safety/Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan.
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Xie XM, Zhang BY, Feng S, Fan ZJ, Wang GY. Activation of gut FXR improves the metabolism of bile acids, intestinal barrier, and microbiota under cholestatic condition caused by GCDCA in mice. Microbiol Spectr 2025; 13:e0315024. [PMID: 39982108 PMCID: PMC11960106 DOI: 10.1128/spectrum.03150-24] [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: 01/04/2025] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
Abnormal bile acid (BA) metabolism is involved in liver fibrosis. In a previous study, we discovered that the hydrophobic BA glycochenodeoxycholate (GCDCA) induced liver fibrosis and that GW4064, an agonist of farnesoid X receptor (FXR), alleviated liver fibrosis caused by GCDCA. However, the impacts of GCDCA on liver BAs, gut BAs, the intestinal barrier, and the gut microbiota are unclear, and obtaining this information would provide additional information into the role of GCDCA in the development of liver fibrosis. In the present study, ultra-performance liquid chromatography‒tandem mass spectrometry revealed that mice administered GCDCA by gavage had higher levels of total and primary liver BAs than those in the control group, and a significant reduction in primary liver BAs was observed in the GCDCA + GW4064 group compared with those in the GCDCA group. Compared with those in the control group, the mice administered GCDCA by gavage had greater levels of total and primary BAs in the gut, especially T-alpha-MCA and T-beta-MCA, and no significant differences in the terminal ileum were observed between the GCDCA and GCDCA + GW4064 groups. Immunohistochemistry indicated that GCDCA administration inhibited gut FXR and FGF15 expression, whereas GW4064 activated gut FXR and promoted FGF15 expression. Moreover, immunohistochemistry revealed that GCDCA administration decreased mucin2, claudin-1, occludin, and ZO-1 expression, whereas GW4064 restored their expression. 16S rDNA sequencing revealed that the alpha diversity of the microbiota did not significantly differ among the three groups, but differences in the beta diversity of the microbiota were observed among the three groups. At the phylum level, GCDCA significantly disturbed the gut microbiota, as indicated by reductions in Desulfobacterota, Bacteroidota, and Actinobacteria in the GCDCA group compared with those in the control group. However, significantly increased abundances of Proteobacteria, Cyanobacteria, and Patescibacteria were noted in the GCDCA group compared with the control group. GW4064 administration significantly improved the microbiota structure at the phylum level. The efficacy of GW4064 was also observed at the genus level. Correlation analyses revealed fewer relationships between the gut microbiota and gut BAs, whereas the gut microbiota was more closely related to liver BAs in the GCDCA and GW4064 intervention groups. Together, GCDCA induced cholestasis and disturbed BA metabolism in the gut and liver, as well as the intestinal barrier and structure of the gut microbiota. Activation of gut FXR improved intestinal barrier injury and alleviated BA metabolism dysfunction and dysbacteriosis caused by GCDCA under cholestatic conditions. IMPORTANCE Glycochenodeoxycholate (GCDCA) is a hydrophobic bile acid (BA) in humans and is highly increased in the serum and stool of liver fibrosis patients. However, the effects of GCDCA were not comprehensively investigated in the process of liver bile acid metabolism, gut microbiota, and intestinal barrier. It was reported that GCDCA can promote liver fibrosis via the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway in mice, and gut farnesoid X receptor activation alleviated the fibrosis caused by GCDCA in our previous study. Gut microbiota is also responsible for BA metabolism; meanwhile, BA metabolism may also exert an effect on the intestinal barrier. Nowadays, the comprehensive understanding of gut microbiota and intestinal barrier in relation to BA disorder was still insufficient. Current study further investigated the role of GCDCA in BA metabolism, gut microbiota, and intestinal barrier to help understand the effects of GCDCA in liver fibrosis, which may provide intervention methods for liver fibrosis caused by dysregulation of BA metabolism.
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Affiliation(s)
- Xing-Ming Xie
- Guizhou Institute of Precision Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary and Pancreatic Diseases Treatment and Bioinformatics Research, Guizhou Medical University, Guiyang, Guizhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China
| | - Bang-Yan Zhang
- Department of Respiratory and Critical Care Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
- Key Laboratory of Pulmonary Immune Diseases, National Health Commission, Guiyang, Guizhou, China
| | - Shu Feng
- Department of Medical Examination Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, USA
| | - Zi-Jun Fan
- The First Clinical School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Guo-Ying Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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Kijpaisalratana N, Phuah CL, Ament Z, Bhave VM, Garcia-Guarniz AL, Duskin J, Couch CA, Irvin MR, Kimberly WT. White matter hyperintensity severity modifies gut metabolite association with cognitive outcomes. J Prev Alzheimers Dis 2025; 12:100086. [PMID: 39939193 PMCID: PMC11969563 DOI: 10.1016/j.tjpad.2025.100086] [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: 07/23/2024] [Accepted: 11/28/2024] [Indexed: 02/14/2025]
Abstract
BACKGROUND Gut microbiome-associated metabolites and white matter hyperintensities (WMH) are independently associated with cognitive impairment. However, it is unclear if gut metabolites and WMH interact to influence dementia. OBJECTIVES To examine the association between gut microbial metabolites and cognitive outcomes and assess whether the severity of baseline WMH would impact associations between gut microbial metabolites and cognitive outcomes. DESIGN Cross-sectional design. SETTING Cohort of individuals who are clinically normal, mild cognitive impairment, or Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS A total of 578 participants with available baseline 3.0T 2D-Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) scans and baseline gut microbial metabolite measurement were included in the analysis. MEASUREMENTS Gut metabolite measurements and automated WMH volume estimations were obtained from FLAIR MRI and were used to assess the association and interaction with cognitive impairment. RESULTS Of 104 metabolites studied, glycodeoxycholic acid (GDCA) surpassed the false discovery rate and was associated the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13) score (β = 0.12, 95 % CI = 0.05-0.20, p = 0.001) and cognitive impairment determined by mini-mental status exam (MMSE) (OR = 2.11, 95 % CI = 1.41-3.15, p < 0.001). GDCA was associated with higher ADAS-Cog13 in participants with low WMH burden (β = 0.21, 95% CI = 0.10-0.32, p < 0.001) but not in participants with high WMH burden (β = 0.04, 95 % CI = -0.07 to 0.14, p = 0.48; interaction p = 0.02). CONCLUSION An elevated level of GDCA was associated with worse cognition. WMH severity modified the association between GDCA and cognitive outcomes.
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Affiliation(s)
- Naruchorn Kijpaisalratana
- Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Division of Academic Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Chia-Ling Phuah
- Departments of Neurology and Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA; Barrow Neuro Analytics Center, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Zsuzsanna Ament
- Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | | | | | - Jonathan Duskin
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Catharine A Couch
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
| | - M Ryan Irvin
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
| | - W Taylor Kimberly
- Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
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Hou S, Yu J, Li Y, Zhao D, Zhang Z. Advances in Fecal Microbiota Transplantation for Gut Dysbiosis-Related Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413197. [PMID: 40013938 PMCID: PMC11967859 DOI: 10.1002/advs.202413197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/22/2025] [Indexed: 02/28/2025]
Abstract
This article provides an overview of the advancements in the application of fecal microbiota transplantation (FMT) in treating diseases related to intestinal dysbiosis. FMT involves the transfer of healthy donor fecal microbiota into the patient's body, aiming to restore the balance of intestinal microbiota and thereby treat a variety of intestinal diseases such as recurrent Clostridioides difficile infection (rCDI), inflammatory bowel disease (IBD), constipation, short bowel syndrome (SBS), and irritable bowel syndrome (IBS). While FMT has shown high efficacy in the treatment of rCDI, further research is needed for its application in other chronic conditions. This article elaborates on the application of FMT in intestinal diseases and the mechanisms of intestinal dysbiosis, as well as discusses key factors influencing the effectiveness of FMT, including donor selection, recipient characteristics, treatment protocols, and methods for assessing microbiota. Additionally, it emphasizes the key to successful FMT. Future research should focus on optimizing the FMT process to ensure long-term safety and explore the potential application of FMT in a broader range of medical conditions.
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Affiliation(s)
- Shuna Hou
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
- Department of general surgeryThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Jiachen Yu
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Yongshuang Li
- Department of general surgeryThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Duoyi Zhao
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Zhiyu Zhang
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
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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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Bao Y, Macelline SP, Selle PH, Chrystal PV, Wang M, Liu SY, Cao A, Toghyani M. Dietary bile acid supplementation influences protein digestibility and alters plasma amino acid profiles in broiler chickens fed conventional and reduced-protein diets. Poult Sci 2025; 104:105107. [PMID: 40187008 PMCID: PMC12002919 DOI: 10.1016/j.psj.2025.105107] [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: 01/19/2025] [Revised: 03/25/2025] [Accepted: 03/29/2025] [Indexed: 04/07/2025] Open
Abstract
Reduced crude protein (CP) diets based on wheat have been shown to lower body weight (BW), increase feed conversion ratio (FCR), and elevate fat-pad deposition in broiler chickens. Bile acids facilitate lipid digestion and nutrient absorption by emulsifying fats and promoting micelle formation in the intestine. Therefore, it was hypnotized that supplementing reduced CP diets with bile acids may enhance fat utilization, improve energy efficiency, and mitigate the negative effects of low-CP diets on broiler performance and nutrient digestibility. Four dietary treatments were arranged in a 2 × 2 factorial layout, with two CP levels (standard and a 30 g/kg CP reduction), with or without 0.2 g/kg bile acids. A total of 840 off-sex male Ross 308 chicks were randomly assigned into 24 floor pens, with six replicates of 35 birds per treatment. From 0 to 42 days post-hatch, there was no interaction between dietary CP and bile acids supplementation for BW, feed intake (FI), FCR, abdominal fat pad, and nutrient digestibility (P > 0.05). As a main effect, reducing dietary CP decreased BW, FI, fat digestibility, and increased FCR and abdominal fat pad (P < 0.01). The reduced CP diet resulted in lower plasma concentrations of valine, isoleucine, arginine, histidine, phenylalanine, leucine, and tryptophan, while increasing lysine, methionine, and threonine concentrations (P < 0.01). Bile acids supplementation enhanced dry matter and protein digestibility (P < 0.05). Bile acids also showed a tendency to increase plasma methionine concentrations (P = 0.055). A significant interaction effect was observed for overall mortality, with bile acids supplementation reducing mortality in birds fed reduced CP diets (P < 0.01). These findings suggest that in reduced CP diets, the current ideal AA profile may be deficient in arginine and histidine, potentially contributing to increased fat pad weight. Elevated wheat-derived non-starch polysaccharide concentrations might lower fat digestibility in reduced CP diets. Supplementation of bile acids in these diets could mitigate endogenous taurine losses and improve overall health in broiler chickens.
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Affiliation(s)
- Yumin Bao
- Redox Pty Ltd, Minto, NSW 2566, Australia
| | - Shemil P Macelline
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia; Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia
| | - Peter H Selle
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia
| | - Peter V Chrystal
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia; Aviagen, Auckland, New Zealand
| | - Mengzhu Wang
- Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia
| | - Sonia Y Liu
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia; Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia
| | | | - Mehdi Toghyani
- Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia.
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Jiang X, Ren J, Yu G, Wu W, Chen M, Zhao Y, He C. Targeting Bile-Acid Metabolism: Nutritional and Microbial Approaches to Alleviate Ulcerative Colitis. Nutrients 2025; 17:1174. [PMID: 40218932 PMCID: PMC11990178 DOI: 10.3390/nu17071174] [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: 02/24/2025] [Revised: 03/19/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.
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Affiliation(s)
| | | | | | | | | | | | - Canxia He
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
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Baldeon AD, Holthaus TA, Khan NA, Holscher HD. Fecal Microbiota and Metabolites Predict Metabolic Health Features across Various Dietary Patterns in Adults. J Nutr 2025:S0022-3166(25)00176-2. [PMID: 40122388 DOI: 10.1016/j.tjnut.2025.03.024] [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: 12/20/2024] [Revised: 02/19/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Consuming healthful dietary patterns reduces risk of developing metabolic diseases and nourishes the intestinal microbiota. Thus, investigating the microbial underpinnings of dietary influences on metabolic health is of clinical interest. OBJECTIVES This study aimed to determine the unique contributions of fecal taxa and metabolites in predicting metabolic health markers in adults across various dietary patterns. METHODS Dietary, metabolic, and fecal microbiota and metabolome data from 118 adults (25-45 y) were used for these cross-sectional analyses. The Diet History Questionnaire II assessed adherence to the dietary approaches to stop hypertension (DASH), Mediterranean diet, Mediterranean-DASH intervention for neurocognitive delay (MIND), and the Healthy Eating Index-2020 (HEI-2020). Metabolic features included waist circumference, blood pressure, and circulating triglyceride (TG), high-density lipoprotein cholesterol, and glucose concentrations. Microbiota composition was assessed via 16S amplicon sequencing and volatile fatty acid and bile acid concentrations were measured by targeted metabolomics. Analyses of compositions with bias correction 2 (ANCOM-BC2) and correlation analyses were used to screen for microbiota features independently associated with dietary patterns and metabolic health markers. Then, hierarchical linear regression models were used to evaluate the unique contributions of select microbial features on metabolic markers beyond adherence to dietary patterns. RESULTS HEI-2020 positively associated with microbiota richness (P = 0.02). Beta diversity varied across all dietary patterns (P < 0.05). DASH diet scores, Eubacteriumxylanophilum abundance, and deoxycholic acid concentration explained the most variance in systolic (R2 = 0.32) and diastolic (R2 = 0.26) blood pressure compared with other dietary patterns and microbial features. TG concentrations were best predicted by MIND diet scores, Eeligens abundance, and isobutyrate concentrations (R2 = 0.24). CONCLUSIONS Integrating fecal taxa and metabolites alongside dietary indices improved metabolic health marker prediction. These results point to a potential role of the intestinal microbiota in underpinning physiological responses to diet and highlight potential microbial biomarkers of metabolic health.
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Affiliation(s)
- Alexis D Baldeon
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, United States
| | - Tori A Holthaus
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, United States
| | - Naiman A Khan
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, United States; Department of Health and Kinesiology, University of Illinois Urbana-Champaign, Urbana, IL, United States
| | - Hannah D Holscher
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, United States; Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL, United States.
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Beyoğlu D, Idle JR. The Microbiome and Metabolic Dysfunction-Associated Steatotic Liver Disease. Int J Mol Sci 2025; 26:2882. [PMID: 40243472 PMCID: PMC11988851 DOI: 10.3390/ijms26072882] [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: 02/17/2025] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition wherein excessive fat accumulates in the liver, leading to inflammation and potential liver damage. In this narrative review, we evaluate the tissue microbiota, how they arise and their constituent microbes, and the role of the intestinal and hepatic microbiota in MASLD. The history of bacteriophages (phages) and their occurrence in the microbiota, their part in the potential causation of MASLD, and conversely, "phage therapy" for antibiotic resistance, obesity, and MASLD, are all described. The microbiota metabolism of bile acids and dietary tryptophan and histidine is defined, together with the impacts of their individual metabolites on MASLD pathogenesis. Both periodontitis and intestinal microbiota dysbiosis may cause MASLD, and how individual microorganisms and their metabolites are involved in these processes is discussed. Novel treatment opportunities for MASLD involving the microbiota exist and include fecal microbiota transplantation, probiotics, prebiotics, synbiotics, tryptophan dietary supplements, intermittent fasting, and phages or their holins and endolysins. Although FDA is yet to approve phage therapy in clinical use, there are multiple FDA-approved clinical trials, and this may represent a new horizon for the future treatment of MASLD.
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Affiliation(s)
- Diren Beyoğlu
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA;
| | - Jeffrey R. Idle
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA;
- Department of Biomedical Research, University of Bern, 3008 Bern, Switzerland
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Zvonareva T, Courson DS, Purcell EB. Clostridioides difficile infection study models and prospectives for probing the microbe-host interface. J Bacteriol 2025; 207:e0040724. [PMID: 39912651 PMCID: PMC11925243 DOI: 10.1128/jb.00407-24] [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] [Indexed: 02/07/2025] Open
Abstract
Clostridioides difficile infection (CDI) is an urgent public health threat with a high rate of recurrence and limited treatment options. In vivo models have been indispensable in understanding CDI pathophysiology and establishing treatment protocols and continue to be essential in pre-clinal testing. More importantly, in vivo models offer the opportunity to probe the complex systemic host response to the microbe, which is impossible to recapitulate in vitro. Nonetheless, constraints related to the availability of animal models, cost, ethical considerations, and regulatory control limit their accessibility for basic research. Furthermore, physiological and habitual divergences between animal models and humans often result in poor translatability to human patients. In addition to being more accessible, in vitro CDI models offer more control over experimental parameters and allow dynamic analysis of early infection. In vitro fermentation offers models for probing microbe-microbe and microbe-microbiome interactions, while continuous multi-stage platforms allow opportunities to study C. difficile pathophysiology and treatment in context with human-derived microbiota. However, these platforms are not suitable for probing the host-pathogen interface, leaving the challenge of modeling early CDI unanswered. As a result, alternative in vitro co-culture platforms are being developed. This review evaluates the strengths and weaknesses of each approach, as well as future directions for C. difficile research.
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Affiliation(s)
- Tatiana Zvonareva
- Department of Chemistry & Biochemistry, Old Dominion University, Norfolk, Virginia, USA
| | - David S. Courson
- Department of Chemistry & Biochemistry, Old Dominion University, Norfolk, Virginia, USA
| | - Erin B. Purcell
- Department of Chemistry & Biochemistry, Old Dominion University, Norfolk, Virginia, USA
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Li C, Cheng D, Ren H, Zhang T. Unraveling the gut microbiota's role in PCOS: a new frontier in metabolic health. Front Endocrinol (Lausanne) 2025; 16:1529703. [PMID: 40171188 PMCID: PMC11958223 DOI: 10.3389/fendo.2025.1529703] [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: 11/17/2024] [Accepted: 02/27/2025] [Indexed: 04/03/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting reproductive-age women, characterized primarily by hyperandrogenism, ovulatory dysfunction, and metabolic abnormalities. In recent years, the gut microbiota has garnered widespread attention for its potential role as a key regulator of host metabolism in the pathogenesis of PCOS. Studies have shown that PCOS patients exhibit dysbiosis in their gut microbiota, characterized by reduced microbial diversity, an imbalance in the ratio of Firmicutes to Bacteroidetes, changes in the abundance of specific taxa, and abnormal levels of metabolic products. These alterations may exacerbate metabolic dysfunction in PCOS through multiple mechanisms, including influencing host energy metabolism, disrupting lipid and bile acid metabolism, and inducing chronic inflammation. Addressing gut dysbiosis through the modulation of patients' microbiomes-such the use of, prebiotics, fecal microbiota transplantation, and optimizing diet lifestyle-may offer strategies for improving metabolic abnormalities and alleviating clinical symptoms in PCOS. Additionally, the gut microbiome promises as a potential marker, aiding in the precise diagnosis and personalization of PCOS. Although our current understanding of how the gut microbiota influences PCOS is still limited, research is needed to explore the causal relationships and mechanisms involved, providing a more reliable theoretical basis for clinical. This review aims summarize the research progress on the relationship between gut microbiota and PCOS, and to suggest future directions to promote the development of prevention and treatment strategies for PCOS.
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Affiliation(s)
- Caihong Li
- Department of Assisted Reproductive Laboratory, Shenyang Jinghua Hospital, Shenyang, China
| | - Dongkai Cheng
- Department of Assisted Reproductive Laboratory, Shenyang Jinghua Hospital, Shenyang, China
| | - Haiqin Ren
- Department of Assisted Reproductive Laboratory, Shenyang Jinghua Hospital, Shenyang, China
| | - Tao Zhang
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory of Stem Cell and Regenerative Medicine, China Medical University, Shenyang, China
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Powell CE, Dohnalová L, Eisert RJ, Sun ZYJ, Seo HS, Dhe-Paganon S, Thaiss CA, Devlin AS. Gut Microbiome-Produced Bile Acid Metabolite Lengthens Circadian Period in Host Intestinal Cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.10.642513. [PMID: 40161646 PMCID: PMC11952472 DOI: 10.1101/2025.03.10.642513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Host circadian signaling, feeding, and the gut microbiome are tightly interconnected. Changes in the gut microbial community can affect the expression of core clock genes, but the specific metabolites and molecular mechanisms that mediate this relationship remain largely unknown. Here, we sought to identify gut microbial metabolites that impact circadian signaling. Through a phenotypic screen of a focused library of gut microbial metabolites, we identified a bile acid metabolite, lithocholic acid (LCA), as a circadian modulator. LCA lengthened the circadian period of core clock gene hPer2 transcription in a dose-responsive manner in human colonic cells. We found evidence that LCA modulates the casein kinase 1 δ/ε (CK1δ/ε)-protein phosphatase 1 (PP1) feedback loop and stabilizes core clock protein cryptochrome 2 (CRY2). Furthermore, we showed that LCA feeding alters circadian transcription in mouse distal ileum and colon. Taken together, our work identifies LCA as a molecular link between host circadian biology and the microbiome. Because bile acids are secreted in response to feeding, our work provides potential mechanistic insight into the molecular nature of the food-entrainable oscillator by which peripheral clocks adapt to the timing of food intake. Given the association between circadian rhythm, feeding, and metabolic disease, our insights may offer a new avenue for modulating host health.
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Zbylicki BR, Cochran S, Weiss DS, Ellermeier CD. Identification of two glycosyltransferases required for synthesis of membrane glycolipids in Clostridioides difficile. mBio 2025; 16:e0351224. [PMID: 39964170 PMCID: PMC11898633 DOI: 10.1128/mbio.03512-24] [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: 11/12/2024] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
Clostridioides difficile infections cause over 12,000 deaths and an estimated one billion dollars in healthcare costs annually in the United States. The cell membrane is an essential structure that is important for protection from the extracellular environment, signal transduction, and transport of nutrients. The polar membrane lipids of C. difficile are ~50% glycolipids, a higher percentage than most other organisms. The glycolipids of C. difficile consist of monohexosyldiradylglycerol (MHDRG) (~14%), dihexosyldiradylglycerol (DHDRG) (~15%), trihexosyldiradylglycerol (THDRG) (~5%), and a unique glycolipid aminohexosyl-hexosyldiradylglycerol (HNHDRG) (~16%). Previously, we found that HexSDF are required for the synthesis of HNHDRG. The enzymes required for the synthesis of MHDRG, DHDRG, and THDRG are not known. In this study, we identified the glycosyltransferases UgtA (CDR20291_0008), which is required for the synthesis of all glycolipids, and UgtB (CDR20291_1186), which is required for the synthesis of DHDRG and THDRG. We propose a model where UgtA synthesizes only MHDRG, HexSDF synthesize HNHDRG from MHDRG, and UgtB synthesizes DHDRG and potentially THDRG from MHDRG. We also report that glycolipids are important for critical cell functions, including sporulation, cell size and morphology, maintaining membrane fluidity, colony morphology, and resistance to some membrane-targeting antimicrobials. IMPORTANCE Clostridioides difficile infections are the leading cause of healthcare-associated diarrhea. C. difficile poses a risk to public health due to its ability to form spores and cause recurrent infections. Glycolipids make up ~50% of the polar lipids in the C. difficile membrane, a higher percentage than other common pathogens and include a unique glycolipid not present in other organisms. Here, we identify glycosyltransferases required for the synthesis of glycolipids in C. difficile and demonstrate the important role glycolipids play in C. difficile physiology.
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Affiliation(s)
- Brianne R. Zbylicki
- Department of Microbiology and Immunology, Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - Sierra Cochran
- Department of Microbiology and Immunology, Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - David S. Weiss
- Department of Microbiology and Immunology, Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
- Graduate Program in Genetics, University of Iowa, Iowa City, Iowa, USA
| | - Craig D. Ellermeier
- Department of Microbiology and Immunology, Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
- Graduate Program in Genetics, University of Iowa, Iowa City, Iowa, USA
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Tian S, Kim MS, Zhao J, Heber K, Hao F, Koslicki D, Tian S, Singh V, Patterson AD, Bisanz JE. A designed synthetic microbiota provides insight to community function in Clostridioides difficile resistance. Cell Host Microbe 2025; 33:373-387.e9. [PMID: 40037353 PMCID: PMC11911935 DOI: 10.1016/j.chom.2025.02.007] [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: 11/13/2023] [Revised: 01/19/2025] [Accepted: 02/10/2025] [Indexed: 03/06/2025]
Abstract
Clostridioides difficile, a major cause of antibiotic-associated diarrhea, is suppressed by the gut microbiome, but the precise mechanisms are not fully described. Through a meta-analysis of 12 human studies, we designed a synthetic fecal microbiota transplant (sFMT1) by reconstructing microbial networks negatively associated with C. difficile colonization. This lab-built 37-strain consortium formed a functional community suppressing C. difficile in vitro and in animal models. Using sFMT1 as a tractable model system, we find that bile acid 7α-dehydroxylation is not a determinant of sFMT1 efficacy while one strain performing Stickland fermentation-a pathway of competitive nutrient utilization-is both necessary and sufficient for the suppression of C. difficile, replicating the efficacy of a human fecal transplant in a gnotobiotic mouse model. Our data illustrate the significance of nutrient competition in suppression of C. difficile and a generalizable approach to interrogating complex community function through robust methods to leverage publicly available sequencing data.
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Affiliation(s)
- Shuchang Tian
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Min Soo Kim
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Jingcheng Zhao
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Kerim Heber
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Fuhua Hao
- One Health Microbiome Center, Huck Life Sciences Institute, The Pennsylvania State University, University Park, PA 16802, USA; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
| | - David Koslicki
- One Health Microbiome Center, Huck Life Sciences Institute, The Pennsylvania State University, University Park, PA 16802, USA; Department of Computer Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Sangshan Tian
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Vishal Singh
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Andrew D Patterson
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA; One Health Microbiome Center, Huck Life Sciences Institute, The Pennsylvania State University, University Park, PA 16802, USA; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
| | - Jordan E Bisanz
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA; One Health Microbiome Center, Huck Life Sciences Institute, The Pennsylvania State University, University Park, PA 16802, USA.
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Iliev ID, Ananthakrishnan AN, Guo CJ. Microbiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities. Nat Rev Microbiol 2025:10.1038/s41579-025-01163-0. [PMID: 40065181 DOI: 10.1038/s41579-025-01163-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 03/26/2025]
Abstract
Perturbations in the intestinal microbiome are strongly linked to the pathogenesis of inflammatory bowel disease (IBD). Bacteria, fungi and viruses all make up part of a complex multi-kingdom community colonizing the gastrointestinal tract, often referred to as the gut microbiome. They can exert various effects on the host that can contribute to an inflammatory state. Advances in screening, multiomics and experimental approaches have revealed insights into host-microbiota interactions in IBD and have identified numerous mechanisms through which the microbiota and its metabolites can exert a major influence on the gastrointestinal tract. Looking into the future, the microbiome and microbiota-associated processes will be likely to provide unparalleled opportunities for novel diagnostic, therapeutic and diet-inspired solutions for the management of IBD through harnessing rationally designed microbial communities, powerful bacterial and fungal metabolites, individually or in combination, to foster intestinal health. In this Review, we examine the current understanding of the cross-kingdom gut microbiome in IBD, focusing on bacterial and fungal components and metabolites. We examine therapeutic and diagnostic opportunities, the microbial metabolism, immunity, neuroimmunology and microbiome-inspired interventions to link mechanisms of disease and identify novel research and therapeutic opportunities for IBD.
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Affiliation(s)
- Iliyan D Iliev
- Joan and Sanford I. Weill Department of Medicine, Gastroenterology and Hepatology Division, Weill Cornell Medicine, New York, NY, USA.
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA.
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA.
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Chun-Jun Guo
- Joan and Sanford I. Weill Department of Medicine, Gastroenterology and Hepatology Division, Weill Cornell Medicine, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA
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Mignini I, Piccirilli G, Di Vincenzo F, Covello C, Pizzoferrato M, Esposto G, Galasso L, Borriello R, Gabrielli M, Ainora ME, Gasbarrini A, Zocco MA. Intestinal-Failure-Associated Liver Disease: Beyond Parenteral Nutrition. Biomolecules 2025; 15:388. [PMID: 40149924 PMCID: PMC11939910 DOI: 10.3390/biom15030388] [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: 01/30/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
Short bowel syndrome (SBS), usually resulting from massive small bowel resections or congenital defects, may lead to intestinal failure (IF), requiring intravenous fluids and parenteral nutrition to preserve patients' nutritional status. Approximately 15% to 40% of subjects with SBS and IF develop chronic hepatic damage during their life, a condition referred to as intestinal-failure-associated liver disease (IFALD), which ranges from steatosis to fibrosis or end-stage liver disease. Parenteral nutrition has been largely pointed out as the main pathogenetic factor for IFALD. However, other elements, such as inflammation, bile acid metabolism, bacterial overgrowth and gut dysbiosis also contribute to the development of liver damage and may deserve specific treatment strategies. Indeed, in our review, we aim to explore IFALD pathogenesis beyond parenteral nutrition. By critically analyzing recent literature, we seek to delve with molecular mechanisms and metabolic pathways underlying liver damage in such a complex set of patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Maria Assunta Zocco
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (I.M.); (G.P.); (F.D.V.); (C.C.); (M.P.); (G.E.); (L.G.); (R.B.); (M.G.); (M.E.A.); (A.G.)
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Xu P, Fan C, Yan M, Liu J, Zhang X. Remnant cholesterol and suicide attempts in untreated first-episode major depressive disorder. Front Psychiatry 2025; 16:1493509. [PMID: 40104336 PMCID: PMC11913861 DOI: 10.3389/fpsyt.2025.1493509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
Objective The objective of this research was to investigate the relationship between remnant cholesterol (RC) levels and suicide attempts (SA) made by Chinese patients with untreated first-episode major depressive disorder (UFE MDD). Methods This study included 1718 patients with UFE MDD. Demographic, clinical characteristics, and blood lipid parameters were collected. The 17-item Hamilton Depression Rating Scale (HAMD), the 14-item Hamilton Anxiety Rating Scale (HAMA), and the positive subscale of the Positive and Negative Syndrome Scale (PANSS) were used to assess their depression, anxiety, and psychotic symptoms, respectively. Multivariable binary logistic regression analysis was used to estimate the association between RC and the risk of SA. A two-piecewise linear regression model was used to investigate the threshold effects if non-linear associations existed. Results Univariate logistic regression analysis showed a significant positive correlation between RC and SA, but after controlling for confounding factors, the association between them was not statistically significant. After dividing the RC into quartiles, only the RC in the Q4 group was significantly positively correlated with suicide attempts (OR = 1.73, 95% CI: 1.13-2.65, P = 0.012, vs. Q1) in a fully adjusted model. Curve fitting analysis also showed a nonlinear relationship between RC and suicide attempts with an inflection point at 1.99 mmol/L in RC. On the left of the inflection point, a significant positive correlation was observed between RC and SA (OR: 1.36, 95% CI: 1.09-1.69, p=0.006). However, on the right of the inflection point, no significant correlation was found (OR: 0.79, 95% CI: 0.55-1.14, p=0.214). Conclusion This study demonstrates a non-linear association between RC levels and SA in patients with untreated first-episode major depressive disorder. When RC was less than 1.99 mmol/L, they showed a significant positive correlation.
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Affiliation(s)
- Ping Xu
- Department of Psychiatry, Nanjing Lishui District Psychiatric Hospital, Lishui, China
- Nanjing Department of Psychiatry, The Third People's Hospital of Lishui District, Lishui, China
| | - Cheng Fan
- Department of Psychiatry, Nanjing Lishui District Psychiatric Hospital, Lishui, China
- Nanjing Department of Psychiatry, The Third People's Hospital of Lishui District, Lishui, China
| | - Mingxing Yan
- Department of Psychiatry, Nanjing Lishui District Psychiatric Hospital, Lishui, China
- Nanjing Department of Psychiatry, The Third People's Hospital of Lishui District, Lishui, China
| | - Junjun Liu
- Department of Psychiatry, Nanjing Meishan Hospital, Nanjing, China
- Medical College of Soochow University, Suzhou, China
- Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Xiangyang Zhang
- Chinese Academy of Sciences (CAS) Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
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Poopan B, Kasorn A, Puttarat N, Kasemwong K, Pachekrepapol U, Taweechotipatr M. Freeze drying microencapsulation using whey protein, maltodextrin and corn powder improved survivability of probiotics during storage. Food Sci Biotechnol 2025; 34:959-970. [PMID: 39974862 PMCID: PMC11832850 DOI: 10.1007/s10068-024-01706-w] [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: 04/03/2024] [Revised: 08/11/2024] [Accepted: 09/02/2024] [Indexed: 02/21/2025] Open
Abstract
Various studies demonstrated that probiotics play important roles in maintaining the balance of microorganisms in the body. Some strains produce bile salt hydrolase enzyme (BSH), which is an indirect mechanism for lowering cholesterol. BSH-producing probiotics as a supplement might be an alternative way to help reducing cholesterol in the body. The aim of this study was to investigate the effects of different microcapsule formulations with selected vegetable powders on growth characteristics of 3 Thai probiotic strains, Lactobacillus gasseri TM1, Lacticaseibacillus rhamnosus TM7, and L. rhamnosus TM14. Probiotics were cultured in MRS broth supplemented with 5 vegetable powders. Corn powder significantly increased growth rate of probiotics from 109 to 1012 CFU/ml. Therefore, different microcapsule formulations by Maillard reaction of whey protein isolate and maltodextrin mixed with and without corn powder were studied. The results showed that probiotic microcapsules formulated with corn powder significantly effectively sustained probiotic viability under gastrointestinal and storage conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s10068-024-01706-w.
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Affiliation(s)
- Benjamaporn Poopan
- Molecular Biology Program, Faculty of Medicine, Srinakharinwirot University, 114 Sukhumvit 23, Wattana District, Bangkok, 10110 Thailand
- Center of Excellence in Probiotics, Srinakharinwirot University, 114 Sukhumvit 23, Wattana District, Bangkok, 10110 Thailand
| | - Anongnard Kasorn
- Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, 681 Samsen Road, Wachira Phayaban, Dusit District, Bangkok, 10300 Thailand
| | - Narathip Puttarat
- Center of Excellence in Probiotics, Srinakharinwirot University, 114 Sukhumvit 23, Wattana District, Bangkok, 10110 Thailand
| | - Kittiwut Kasemwong
- NANOTEC Research Unit, National Nanotechnology Center, National Science and Technology Development Agency, 130 Thailand Science Park, Paholyothin Road, Khlong Luang, Pathumthani, 12120 Thailand
| | - Ulisa Pachekrepapol
- Division of Food Science and Nutrition, Faculty of Agricultural Product Innovation and Technology, Srinakharinwirot University, 63 Village No.7, Khlong 16 Road, Ongkharak, Nakornnayok, 26120 Thailand
| | - Malai Taweechotipatr
- Center of Excellence in Probiotics, Srinakharinwirot University, 114 Sukhumvit 23, Wattana District, Bangkok, 10110 Thailand
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, 114 Sukhumvit 23, Wattana District, Bangkok, 10110 Thailand
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Yuan Q, Liu J, Wang X, Du C, Zhang Y, Lin L, Wang C, Hong Z. Deciphering the impact of dietary habits and behavioral patterns on colorectal cancer. Int J Surg 2025; 111:2603-2612. [PMID: 39869376 DOI: 10.1097/js9.0000000000002229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/02/2024] [Indexed: 01/28/2025]
Abstract
Colorectal cancer (CRC) is a malignant tumor that originates from the epithelial cells of the colon and rectum. Global epidemiological data shows that in 2020, the incidence and mortality rate of CRC ranked third and second, respectively, posing a serious threat to people's health and lives. The factors influencing CRC are numerous and can be broadly categorized as modifiable and non-modifiable based on whether they can be managed or intervened upon. Non-modifiable factors include age, gender, family history, among others. Among the modifiable factors, dietary habits and behavioral practices are the main intervention measures that people can take to prevent CRC. Numerous studies indicate that a high intake of red and processed meats, fats, as well as habits such as smoking, alcohol consumption, and prolonged sitting, increase the risk of developing CRC. Conversely, consuming ample vegetables, fruits, high dietary fiber, and engaging in moderate regular exercise may reduce the risk of CRC. This article primarily discusses the impact of dietary habits and behavioral practices on the occurrence and development of CRC, along with possible mechanisms, laying the foundation and providing direction for the prevention and control of CRC occurrence and development.
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Affiliation(s)
- Qihang Yuan
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Graduate School of Dalian Medical University, Dalian Medical University, Dalian, Liaoning, China
| | - Jiahua Liu
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Graduate School of Dalian Medical University, Dalian Medical University, Dalian, Liaoning, China
| | - Xinyu Wang
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Graduate School of Dalian Medical University, Dalian Medical University, Dalian, Liaoning, China
| | - Chunchun Du
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yao Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Lin Lin
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chengfang Wang
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zhijun Hong
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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Fiorucci S, Marchianò S, Distrutti E, Biagioli M. Bile acids and their receptors in hepatic immunity. LIVER RESEARCH (BEIJING, CHINA) 2025; 9:1-16. [PMID: 40206435 PMCID: PMC11977286 DOI: 10.1016/j.livres.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/05/2024] [Accepted: 01/23/2025] [Indexed: 04/11/2025]
Abstract
Similarly to conventional steroids, bile acids function as signaling molecules, acting on a family of membrane and nuclear receptors. The best-characterized bile acid-regulated receptors are the farnesoid X receptor, activated by primary bile acids, and the G-protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), which is activated by secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid. Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity, monocytes/macrophages, and natural killer cells. Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflammation. In recent years, however, it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity. The 3-oxoLCA and isoalloLCA, two LCA derivatives, bind receptors such as the retinoic acid receptor-related orphan receptor gamma t (RORγt) and the vitamin D receptor (VDR) that are expressed only by lymphoid cells, extending the regulatory role of bile acids to T cells, including T-helper 17 cells and type 3 innate lymphoid cells (ILC3). In this novel conceptual framework, bile acids have emerged as one of the main components of the postbiota, the waste array of chemical mediators generated by the intestinal microbiota. Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.
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Affiliation(s)
- Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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50
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Shukla A, Sharma C, Malik MZ, Singh AK, Aditya AK, Mago P, Shalimar, Ray AK. Deciphering the tripartite interaction of urbanized environment, gut microbiome and cardio-metabolic disease. JOURNAL OF ENVIRONMENTAL MANAGEMENT 2025; 377:124693. [PMID: 40022791 DOI: 10.1016/j.jenvman.2025.124693] [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: 12/02/2024] [Revised: 02/13/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025]
Abstract
The world is experiencing a sudden surge in urban population, especially in developing Asian and African countries. Consequently, the global burden of cardio-metabolic disease (CMD) is also rising owing to gut microbiome dysbiosis due to urbanization factors such as mode of birth, breastfeeding, diet, environmental pollutants, and soil exposure. Dysbiotic gut microbiome indicated by altered Firmicutes to Bacteroides ratio and loss of beneficial short-chain fatty acids-producing bacteria such as Prevotella, and Ruminococcus may disrupt host-intestinal homeostasis by altering host immune response, gut barrier integrity, and microbial metabolism through altered T-regulatory cells/T-helper cells balance, activation of pattern recognition receptors and toll-like receptors, decreased mucus production, elevated level of trimethylamine-oxide and primary bile acids. This leads to a pro-inflammatory gut characterized by increased pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-2, Interferon-ϒ and elevated levels of metabolites or metabolic endotoxemia due to leaky gut formation. These pathophysiological characteristics are associated with an increased risk of cardio-metabolic disease. This review aims to comprehensively elucidate the effect of urbanization on gut microbiome-driven cardio-metabolic disease. Additionally, it discusses targeting the gut microbiome and its associated pathways via strategies such as diet and lifestyle modulation, probiotics, prebiotics intake, etc., for the prevention and treatment of disease which can potentially be integrated into clinical and professional healthcare settings.
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Affiliation(s)
- Avaneesh Shukla
- Department of Environmental Studies, University of Delhi, New Delhi, India
| | - Chanchal Sharma
- Department of Environmental Studies, University of Delhi, New Delhi, India
| | - Md Zubbair Malik
- Department of Translational Medicine, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Alok Kumar Singh
- Department of Zoology, Ramjas College, University of Delhi, New Delhi, India
| | - Abhishek Kumar Aditya
- Department of Medicine, K.D. Medical College, Hospital and Research Center, Mathura, India
| | - Payal Mago
- Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, India; Campus of Open Learning, University of Delhi, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Ashwini Kumar Ray
- Department of Environmental Studies, University of Delhi, New Delhi, India.
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