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Zheng XQ, Wang DB, Jiang YR, Song CL. Gut microbiota and microbial metabolites for osteoporosis. Gut Microbes 2025; 17:2437247. [PMID: 39690861 DOI: 10.1080/19490976.2024.2437247] [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: 07/11/2024] [Revised: 11/13/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024] Open
Abstract
Osteoporosis is an age-related bone metabolic disease. As an essential endocrine organ, the skeletal system is intricately connected with extraosseous organs. The crosstalk between bones and other organs supports this view. In recent years, the link between the gut microecology and bone metabolism has become an important research topic, both in preclinical studies and in clinical trials. Many studies have shown that skeletal changes are accompanied by changes in the composition and structure of the gut microbiota (GM). At the same time, natural or artificial interventions targeting the GM can subsequently affect bone metabolism. Moreover, microbiome-related metabolites may have important effects on bone metabolism. We aim to review the relationships among the GM, microbial metabolites, and bone metabolism and to summarize the potential mechanisms involved and the theory of the gut‒bone axis. We also describe existing bottlenecks in laboratory studies, as well as existing challenges in clinical settings, and propose possible future research directions.
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Affiliation(s)
- Xuan-Qi Zheng
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Ding-Ben Wang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Yi-Rong Jiang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Chun-Li Song
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China
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Huang Y, Xu W, Dong W, Chen G, Sun Y, Zeng X. Anti-diabetic effect of dicaffeoylquinic acids is associated with the modulation of gut microbiota and bile acid metabolism. J Adv Res 2025; 72:17-35. [PMID: 38969095 DOI: 10.1016/j.jare.2024.06.027] [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: 03/30/2024] [Revised: 06/06/2024] [Accepted: 06/30/2024] [Indexed: 07/07/2024] Open
Abstract
INTRODUCTION The human gut microbiome plays a pivotal role in health and disease, notably through its interaction with bile acids (BAs). BAs, synthesized in the liver, undergo transformation by the gut microbiota upon excretion into the intestine, thus influencing host metabolism. However, the potential mechanisms of dicaffeoylquinic acids (DiCQAs) from Ilex kudingcha how to modulate lipid metabolism and inflammation via gut microbiota remain unclear. OBJECTIVES AND METHODS The objectives of the present study were to investigate the regulating effects of DiCQAs on diabetes and the potential mechanisms of action. Two mice models were utilized to investigate the anti-diabetic effects of DiCQAs. Additionally, analysis of gut microbiota structure and functions was conducted concurrently with the examination of DiCQAs' impact on gut microbiota carrying the bile salt hydrolase (BSH) gene, as well as on the enterohepatic circulation of BAs and related signaling pathways. RESULTS Our findings demonstrated that DiCQAs alleviated diabetic symptoms by modulating gut microbiota carrying the BSH gene. This modulation enhanced intestinal barrier integrity, increased enterohepatic circulation of conjugated BAs, and inhibited the farnesoid X receptor-fibroblast growth factor 15 (FGF15) signaling axis in the ileum. Consequently, the protein expression of hepatic FGFR4 fibroblast growth factor receptor 4 (FGFR4) decreased, accompanied by heightened BA synthesis, reduced hepatic BA stasis, and lowered levels of hepatic and plasma cholesterol. Furthermore, DiCQAs upregulated glucolipid metabolism-related proteins in the liver and muscle, including v-akt murine thymoma viral oncogene homolog (AKT)/glycogen synthase kinase 3-beta (GSK3β) and AMP-activated protein kinase (AMPK), thereby ameliorating hyperglycemia and mitigating inflammation through the down-regulation of the MAPK signaling pathway in the diabetic group. CONCLUSION Our study elucidated the anti-diabetic effects and mechanism of DiCQAs from I. kudingcha, highlighting the potential of targeting gut microbiota, particularly Acetatifactor sp011959105 and Acetatifactor muris carrying the BSH gene, as a therapeutic strategy to attenuate FXR-FGF15 signaling and ameliorate diabetes.
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Affiliation(s)
- Yujie Huang
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China; School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, China
| | - Weiqi Xu
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Wei Dong
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Guijie Chen
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Yi Sun
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Xiaoxiong Zeng
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.
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Liao W, Hu R, Ji Y, Zhong Z, Huang X, Cai T, Zhou C, Wang Y, Ye Z, Yang P. Oleic acid regulates CD4+ T cells differentiation by targeting ODC1-mediated STAT5A phosphorylation in Vogt-Koyanagi-Harada disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156660. [PMID: 40203473 DOI: 10.1016/j.phymed.2025.156660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/25/2025] [Accepted: 03/17/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Vogt-Koyanagi-Harada (VKH) is a multisystemic autoimmune disorder characterized by bilateral panuveitis frequently accompanied by neurologic manifestations. While metabolic dysregulation is increasingly recognized in the context of autoimmune diseases, the role of specific metabolites in VKH disease remains unexplored. METHODS Non-targeted and targeted metabolomics analysis, phospho-antibody array, proteome microarray, surface plasmon resonance, and molecular simulation were used to identify molecular target of OA. RESULTS We investigated metabolic profile of VKH disease and found that oleic acid (OA) was enriched in this disease. A series of functional assays showed that OA could exacerbate experimental autoimmune uveitis (EAU) in association with increased frequency of Th1 and Th17 cells and decreased proportion of Treg cells in vitro. However, the specific molecular target of OA remains elusive. Through proteome microarrays, molecular simulations and surface plasmon resonance assays, Ornithine decarboxylase 1 (ODC1) was identified as target protein of OA. OA could bind to ODC1, increase ODC1 protein expression in both a time- and concentration-dependent manner and promote subsequently putrescine production. Phospho-antibody array analysis revealed that OA inhibited phosphorylation of STAT5A (Y694) in CD4+T cells, leading to imbalance of Th1/Th17 and Treg cells and decreased transcription of IL-10. OA upregulated ODC1 protein and putrescine levels through binding to LYS-78, inhibited phosphorylation of STAT5A protein and subsequently decreased binding of STAT5A at IL-10 promoter. CONCLUSION These results reveals that OA could be a crucial metabolite for modulation of CD4+T cell differentiation and that ODC1-mediated phosphorylation and transcriptional activity of STAT5A contributes to development of VKH disease progression, highlighting ODC1 as a novel therapeutic target in VKH disease.
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Affiliation(s)
- Weiting Liao
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China
| | - Ruixue Hu
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China
| | - Yan Ji
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China
| | - Zhenyu Zhong
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China
| | - Xinyue Huang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Jinfeng Laboratory, Chongqing, China
| | - Tao Cai
- The First Affiliated Hospital of Chongqing Medical University, department of Dermatology, Chongqing, China
| | - Chunjiang Zhou
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China
| | - Yao Wang
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China
| | - Zi Ye
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China.
| | - Peizeng Yang
- Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China.
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Fan F, Chen L, Sun H, Liu J, Yang K, Gu F. Longitudinal dynamics of plasma bile acids and their associations with physiological parameters and fecal microbiome during the transition period in dairy cows. Anim Biosci 2025; 38:1194-1205. [PMID: 40045625 PMCID: PMC12061570 DOI: 10.5713/ab.24.0628] [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: 09/07/2024] [Revised: 11/07/2024] [Accepted: 12/12/2024] [Indexed: 05/09/2025] Open
Abstract
OBJECTIVE The aim of this study is to investigate the dynamic changes of plasma bile acids (BA) and their correlations with physiological parameters and fecal microbiome in transitional dairy cows. METHODS Twenty multiparous dairy cows were selected, the blood and fecal samples were collected on d -21, -7, +7, and +21 of calving. The targeted metabolome and 16s rDNA ampicon sequencing were utilized to identify BA profiles and fecal microbial composition, respectively. RESULTS A total of 32 BAs were found, comprising 9 primary BAs (PBA) and 23 secondary BAs (SBA). Majority of the PBAs (7 out to 9) and SBAs (15 out to 23) exhibited significant increases postpartum compared to prepartum levels. Notably, ursodeoxycholic acid, taurocholic acid and 7-ketodeoxycholic acid showed higher importance. Correlation analysis showed the BAs concentrations positively correlated with the concentrations of aspartate aminotransferase, total antioxidant capacity, and glutathione peroxidase, while exhibiting substantial negative correlation with triglyceride concentrations. A decline in bacterial alpha diversity in postpartum and significantly different β-diversity were observed. Furthermore, 30 distingtive genera were identified over the transition period. Among these, six and eleven biomarkers such as Alistipes and Ruminococcaceae_UCG_014 were identified at +7 d and +21 d, respectively. Furthermore, the abundances of choloylglycine hydrolase and 7-alpha-hydroxysteroid dehydrogenase which are involved in SBA biosynthesis were significantly higher postpartum as determined by PICRUSt2 analysis over the transition period. CONCLUSION The BA profile and concentrations underwent significant changes during the transition period in dairy cows and these changes are closely related to the periparturient health of the cows. Ursodeoxycholic acid and Alistipes was identified as the pivotal BA and microbial genus. Our study elucidates these metabolic processes, providing useful insights into strategies for enhancing the nutrition and well-being of perinatal dairy cows.
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Affiliation(s)
- Feixiang Fan
- College of Animal Sciences, Xinjiang Key Laboratory of Herbivorous Nutrition for Meat & Milk, Xinjiang Agricultural University, Urumqi,
China
| | - Liang Chen
- Institute of Dairy Science, College of Animal Sciences, Zhejiang University, Hangzhou,
China
| | - Huizeng Sun
- Institute of Dairy Science, College of Animal Sciences, Zhejiang University, Hangzhou,
China
| | - Jianxin Liu
- Institute of Dairy Science, College of Animal Sciences, Zhejiang University, Hangzhou,
China
| | - Kailun Yang
- College of Animal Sciences, Xinjiang Key Laboratory of Herbivorous Nutrition for Meat & Milk, Xinjiang Agricultural University, Urumqi,
China
| | - Fengfei Gu
- Institute of Dairy Science, College of Animal Sciences, Zhejiang University, Hangzhou,
China
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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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Ni C, Wang L, Bai Y, Huang F, Shi H, Wu H, Wu X, Huang J. Taurochenodeoxycholic acid activates autophagy and suppresses inflammatory responses in microglia of MPTP-induced Parkinson's disease mice via AMPK/mTOR, AKT/NFκB and Pink1/Parkin signaling pathways mediated by Takeda G protein-coupled receptor 5. Free Radic Biol Med 2025; 235:347-363. [PMID: 40324640 DOI: 10.1016/j.freeradbiomed.2025.04.053] [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: 02/11/2025] [Revised: 04/18/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration and necrosis of dopaminergic neurons in the substantia nigra and decreased dopamine secretion in the striatum. Bile acids are important components of animal bile. In recent years, a variety of hydrophilic bile acids have been reported to have ameliorative effects in neurodegenerative diseases. Taurochenodeoxycholic acid (TCDCA) is one of the components of bile acids. However, whether TCDCA can treat PD and its specific mechanism is unclear. In this study, 1-methyl-4-phenylpyridine (MPTP)-induced PD model mice were established to investigate the effects of TCDCA on PD model mice and the impact of microglia-mediated neuroinflammation. Concurrently, in vitro cell experiments utilized the lipopolysaccharide (LPS)-induced BV-2 microglial inflammation model to further investigate the effect and mechanism of TCDCA in inhibiting neuroinflammation. TCDCA effectively improved dyskinesia, attenuated dopaminergic neuronal damage in the substantia nigra and striatum, and inhibited α-Synuclein (α-Syn) expression in the substantia nigra of PD mice. TCDCA significantly inhibited microglia and astrocyte activation in the substantia nigra of PD mice, and decreased the messenger ribonucleic acid (mRNA) and protein expressions of inflammatory factors. In addition, TCDCA was found to inhibit nitric oxide release and reactive oxygen species production in LPS-stimulated BV2 microglia. Furthermore, TCDCA suppressed the production of inflammatory factors, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α), both in vivo and in vitro. Meanwhile, TCDCA significantly promoted Takeda G protein-coupled receptor 5 (TGR5) protein expression and inhibited the phosphorylation of serine/threonine kinase B (AKT), nuclear factor κB (NFκB) and inhibitor of NFκB (IκBα). TCDCA promoted autophagy in vivo and in vitro by increasing adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation, inhibiting mammalian target of rapamycin (mTOR) phosphorylation, increasing LC3II/LC3I and Beclin1 expression, and decreasing P62 expression. Furthermore, TCDCA demonstrated mitochondrial protection by enhancing the expression of PTEN induced putative kinase 1 (Pink1) and Parkin. However, knockdown of TGR5 expression partially counteracted the inhibitory effect of TCDCA on LPS-treated BV-2 cells. Our results manifested that TCDCA activated autophagy and inhibited microglia-mediated neuroinflammation in experimental PD models probably through regulation of AKT/NFκB, AMPK/mTOR and Pink1/Parkin signaling pathways via activation of TGR5.
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Affiliation(s)
- Chenyang Ni
- Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Lupeng Wang
- Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Yuyan Bai
- Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fei Huang
- Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xiaojun Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Jin Huang
- Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Zhou C, Zhang P, Ming Y. Characteristics of Intestinal Flora in Patients With Schistosoma japonicum Infection Undergoing Splenectomy. Parasite Immunol 2025; 47:e70008. [PMID: 40317954 PMCID: PMC12046944 DOI: 10.1111/pim.70008] [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: 08/17/2024] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 05/07/2025]
Abstract
Schistosomiasis japonica is a parasitic disease that seriously endangers human health. Patients with advanced Schistosoma japonicum infection often suffer from cirrhosis and portal hypertension. Splenectomy has been widely used in the treatment of these patients. Previous studies have confirmed that S. japonicum infection is closely related to the gut microbiota, but the impact of splenectomy on the gut microbiota of patients with advanced S. japonicum infection remains unclear. This study used 16sRNA sequencing technology to compare the differences in intestinal flora between patients with advanced S. japonicum infection who underwent splenectomy and non-surgical patients. We focused on the changes in the species composition, diversity and functions of the intestinal flora. Our study shows that dysbiosis of the gut microbiome occurred in patients with advanced S. japonicum infection, including changes in abundance and diversity and the disorder of biological function. The intestinal flora structure, diversity and function of patients who underwent splenectomy were significantly changed compared with those who did not undergo surgery.
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Affiliation(s)
- Chen Zhou
- Transplantation Center, Engineering and Technology Research Center for Transplantation Medicine of National Health ComissionThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Pengpeng Zhang
- Transplantation Center, Engineering and Technology Research Center for Transplantation Medicine of National Health ComissionThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Yingzi Ming
- Transplantation Center, Engineering and Technology Research Center for Transplantation Medicine of National Health ComissionThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
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Lin X, Xia L, Zhou Y, Xie J, Tuo Q, Lin L, Liao D. Crosstalk Between Bile Acids and Intestinal Epithelium: Multidimensional Roles of Farnesoid X Receptor and Takeda G Protein Receptor 5. Int J Mol Sci 2025; 26:4240. [PMID: 40362481 PMCID: PMC12072030 DOI: 10.3390/ijms26094240] [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: 03/16/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders.
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Affiliation(s)
| | | | | | | | | | | | - Duanfang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; (X.L.); (L.X.); (Y.Z.); (J.X.); (Q.T.); (L.L.)
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He L, Li X, Jiang S, Ou Y, Wang S, Shi N, Yang Z, Yuan JL, Silverman G, Niu H. The influence of the gut microbiota on B cells in autoimmune diseases. Mol Med 2025; 31:149. [PMID: 40264032 PMCID: PMC12016346 DOI: 10.1186/s10020-025-01195-5] [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: 11/07/2023] [Accepted: 04/01/2025] [Indexed: 04/24/2025] Open
Abstract
Mounting evidence shows that gut microbiota communities and the human immune system coexist and influence each other, and there are a number of reports of a correlation between specific changes in gut microbiota and the occurrence of autoimmune diseases. B lymphocytes play a central role in the regulation of both gut microbiota communities and in autoimmune diseases. Here, we summarize evidence of the influence of gut microbiota-B cell pathways on autoimmune diseases and how B cells regulate microorganisms, which provides mechanistic insights with relevance for identification of potential therapeutic targets and related fields.
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Affiliation(s)
- Lun He
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xin Li
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Shan Jiang
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Yanhua Ou
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Shanshan Wang
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Na Shi
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhongshan Yang
- Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China
| | - Jia-Li Yuan
- Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
| | - Gregg Silverman
- Division of Rheumatology, New York University School of Medicine, New York, NY, 10016, USA.
| | - Haitao Niu
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
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10
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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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11
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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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12
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Fu Y, Guzior DV, Okros M, Bridges C, Rosset SL, González CT, Martin C, Karunarathne H, Watson VE, Quinn RA. Balance between bile acid conjugation and hydrolysis activity can alter outcomes of gut inflammation. Nat Commun 2025; 16:3434. [PMID: 40210868 PMCID: PMC11985902 DOI: 10.1038/s41467-025-58649-x] [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: 09/06/2024] [Accepted: 03/27/2025] [Indexed: 04/12/2025] Open
Abstract
Conjugated bile acids (BAs) are multi-functional detergents in the gastrointestinal (GI) tract produced by the liver enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) and by the microbiome from the acyltransferase activity of bile salt hydrolase (BSH). Humans with inflammatory bowel disease (IBD) have an enrichment in both host and microbially conjugated BAs (MCBAs), but their impacts on GI inflammation are not well understood. We investigated the role of host-conjugated BAs in a mouse model of colitis using a BAAT knockout background. Baat-/- KO mice have severe phenotypes in the colitis model that were rescued by supplementation with taurocholate (TCA). Gene expression and histology showed that this rescue was due to an improved epithelial barrier integrity and goblet cell function. However, metabolomics also showed that TCA supplementation resulted in extensive metabolism to secondary BAs. We therefore investigated the BSH activity of diverse gut bacteria on a panel of conjugated BAs and found broad hydrolytic capacity depending on the bacterium and the amino acid conjugate. The complexity of this microbial BA hydrolysis led to the exploration of bsh genes in metagenomic data from human IBD patients. Certain bsh sequences were enriched in people with Crohn's disease particularly that from Ruminococcus gnavus. This study shows that both host and microbially conjugated BAs may provide benefits to those with IBD, but this is dictated by a delicate balance between BA conjugation/deconjugation based on the bsh genes present.
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Affiliation(s)
- Yousi Fu
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Douglas V Guzior
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
- Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA
| | - Maxwell Okros
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Christopher Bridges
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Sabrina L Rosset
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Cely T González
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Christian Martin
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
- Mass Spectrometry and Metabolomics Core, Michigan State University, East Lansing, MI, USA
| | - Hansani Karunarathne
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Victoria E Watson
- Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Robert A Quinn
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
- Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA.
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13
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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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14
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Xiao W, Chen Q, Liu C, Yu Y, Liu T, Jin Y, Ma H, Chen S, Jiang C. Gut microbiota in cancer: From molecular mechanisms to precision medicine applications. IMETA 2025; 4:e70017. [PMID: 40236776 PMCID: PMC11995170 DOI: 10.1002/imt2.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/01/2025] [Accepted: 03/05/2025] [Indexed: 04/17/2025]
Abstract
The gut microbiota-cancer interaction functions through multi-level biological mechanisms, forming the basis for both diagnostic and therapeutic applications. Current technical and biological challenges drive the field toward precision medicine approaches, aiming to integrate multi-dimensional data for optimized, personalized cancer treatments.
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Affiliation(s)
- Weihua Xiao
- Department of Pathology, Beilun Branch of the First Affiliated Hospital, College of MedicineZhejiang UniversityNingboChina
| | - Qiong Chen
- MOE Key Laboratory of Biosystems Homeostasis & Protection, and Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Chunjiao Liu
- Department of Pathology, Beilun Branch of the First Affiliated Hospital, College of MedicineZhejiang UniversityNingboChina
| | - Yueer Yu
- Department of Tea Research InstituteZhejiang UniversityHangzhouChina
| | - Tianliang Liu
- HaploX BiotechnologyShenzhenChina
- LifeX Institute, School of Medical TechnologyGannan Medical UniversityGanzhouChina
| | - Yang Jin
- Institute for Cancer Genetics and InformaticsOslo University HospitalOsloNorway
| | - Haifen Ma
- Department of Pathology, Beilun Branch of the First Affiliated Hospital, College of MedicineZhejiang UniversityNingboChina
| | - Shifu Chen
- HaploX BiotechnologyShenzhenChina
- LifeX Institute, School of Medical TechnologyGannan Medical UniversityGanzhouChina
| | - Chao Jiang
- MOE Key Laboratory of Biosystems Homeostasis & Protection, and Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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15
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Feng X, Wang H, Zhong Z, Tan S, Liao W, Yang P. Palmitic acid exacerbates experimental autoimmune uveitis by activating T helper 17 cells via regulating STING signaling. Exp Eye Res 2025; 253:110283. [PMID: 39956351 DOI: 10.1016/j.exer.2025.110283] [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: 10/18/2024] [Revised: 01/05/2025] [Accepted: 02/11/2025] [Indexed: 02/18/2025]
Abstract
Recent studies found that palmitic acid (PA), the most abundant fatty acid in human body, was increased in uveitis patients. However, its exact effect on uveitis has not been clarified. In this study, experimental autoimmune uveitis (EAU), an animal model of human uveitis, was successfully induced with interphotoreceptor retinoid-binding protein (IRBP) 651-670 and pertussis toxin. The immunized mice were treated with daily intragastric PA or vehicle from day 1-14. The results showed that PA could aggravate EAU activities and increase the proportion of T helper (Th) 17 cells as well as mRNA expression level of Il17a. There were no significant changes in Th1/Treg cell responses between these two groups. In vitro experiments showed that PA treatment could promote IRBP-specific Th17 cell response in association with increased proportion of Th17 cells as well as up-regulated expression of IL-17A. Proteomics showed an increased expression of stimulator of interferon genes protein (STING) in PA-treated mice as compared to vehicle-treated mice. H-151, a potent antagonist of STING, attenuated the activities of EAU and Th17 cell responses induced by PA. Moreover, NF-κB/IL-6 signaling pathway was found to be downregulated after H-151 treatment. Collectively, PA could exacerbate EAU severity possibly through the activation of Th17 cells mediated by up-regulating STING.
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Affiliation(s)
- Xiaojie Feng
- Ophthalmology medical center, The First Affiliate Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Diseases and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Hongmiao Wang
- Ophthalmology medical center, The First Affiliate Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Diseases and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Zhenyu Zhong
- Ophthalmology medical center, The First Affiliate Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Diseases and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Shiyao Tan
- Ophthalmology medical center, The First Affiliate Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Diseases and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Weiting Liao
- Ophthalmology medical center, The First Affiliate Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Diseases and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Peizeng Yang
- Ophthalmology medical center, The First Affiliate Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Diseases and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China.
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16
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He S, Song L, Xiao Y, Huang Y, Ren Z. Genomic, Probiotic, and Functional Properties of Bacteroides dorei RX2020 Isolated from Gut Microbiota. Nutrients 2025; 17:1066. [PMID: 40292459 PMCID: PMC11944543 DOI: 10.3390/nu17061066] [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: 02/27/2025] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND/OBJECTIVES Gut microbiota is essential for maintaining host immune homeostasis and has been confirmed to be closely related to some intestinal and extraintestinal diseases. Bacteroides, as the dominant bacterial genus in the human gut, has attracted great attention due to its excellent metabolic activity, but there are few studies on Bacteroides dorei species. In our previous study, a gut commensal strain, Bacteroides dorei RX2020 (B. dorei), was isolated from healthy human feces and exhibited superior flavonoid metabolic activity, prompting further analysis of its uncharacterized genomic features, probiotic potential, safety, and immunomodulatory activity. RESULTS The results showed that B. dorei exhibited intrinsic probiotic functionalities with preserved genomic and phenotypic stability, demonstrated safety profiles in murine models through in vivo assessments, and conferred antagonistic activity against enteric foodborne pathogens via competitive exclusion. The strain also demonstrated abundant metabolic activity and was involved in the metabolism of tryptophan and bile acids (BAs). Moreover, B. dorei can promote the production of IFNβ by dendritic cells (DCs) to inhibit the replication of influenza virus in epithelial cells, which may be achieved by regulating host metabolism. CONCLUSIONS This study reveals the potential of B. dorei as next-generation probiotics (NGPs), contributing to a broader understanding and application of these novel probiotics in health and disease management.
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Affiliation(s)
| | | | | | | | - Zhihong Ren
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China; (S.H.)
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17
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Ladakis DC, Harrison KL, Smith MD, Solem K, Gadani S, Jank L, Hwang S, Farhadi F, Dewey BE, Fitzgerald KC, Sotirchos ES, Saidha S, Calabresi PA, Bhargava P. Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease. MED 2025; 6:100522. [PMID: 39447576 PMCID: PMC11911100 DOI: 10.1016/j.medj.2024.09.011] [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: 03/18/2024] [Revised: 07/31/2024] [Accepted: 09/25/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. METHODS Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters. FINDINGS In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p = 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups. CONCLUSIONS Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration. FUNDING National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.
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Affiliation(s)
- Dimitrios C Ladakis
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Kimystian L Harrison
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Matthew D Smith
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Krista Solem
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Sachin Gadani
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Larissa Jank
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Soonmyung Hwang
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Farzaneh Farhadi
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Blake E Dewey
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Kathryn C Fitzgerald
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Elias S Sotirchos
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Shiv Saidha
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Peter A Calabresi
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA
| | - Pavan Bhargava
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205, USA.
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18
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Liu Y, Li F, Wang J, Yang R. Exploring effects of gut microbiota on tertiary lymphoid structure formation for tumor immunotherapy. Front Immunol 2025; 15:1518779. [PMID: 40124706 PMCID: PMC11925796 DOI: 10.3389/fimmu.2024.1518779] [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: 10/28/2024] [Accepted: 12/20/2024] [Indexed: 03/25/2025] Open
Abstract
Anti-tumor immunity, including innate and adaptive immunity is critical in inhibiting tumorigenesis and development of tumor. The adaptive immunity needs specific lymph organs such as tertiary lymphoid structures (TLSs), which are highly correlated with improved survival outcomes in many cancers. In recent years, with increasing attention on the TLS in tumor microenvironment, TLSs have emerged as a novel target for anti-tumor therapy. Excitingly, studies have shown the contribution of TLSs to the adaptive immune responses. However, it is unclear how TLSs to form and how to more effectively defense against tumor through TLS formation. Recent studies have shown that the inflammation plays a critical role in TLS formation. Interestingly, studies have also found that gut microbiota can regulate the occurrence and development of inflammation. Therefore, we here summarize the potential effects of gut microbiota- mediated inflammation or immunosuppression on the TLS formation in tumor environments. Meanwhile, this review also explores how to manipulate mature TLS formation through regulating gut microbiota/metabolites or gut microbiota associated signal pathways for anti-tumor immunity, which potentially lead to a next-generation cancer immunotherapy.
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Affiliation(s)
- Yuqing Liu
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Fan Li
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Juanjuan Wang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Rongcun Yang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
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19
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Li Z, Deng L, Cheng M, Ye X, Yang N, Fan Z, Sun L. Emerging role of bile acids in colorectal liver metastasis: From molecular mechanism to clinical significance (Review). Int J Oncol 2025; 66:24. [PMID: 39981904 PMCID: PMC11844338 DOI: 10.3892/ijo.2025.5730] [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: 10/25/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Liver metastasis is the leading cause of colorectal cancer (CRC)‑related mortality. Microbiota dysbiosis serves a role in the pathogenesis of colorectal liver metastases. Bile acids (BAs), cholesterol metabolites synthesized by intestinal bacteria, contribute to the metastatic cascade of CRC, encompassing colorectal invasion, migration, angiogenesis, anoikis resistance and the establishment of a hepatic pre‑metastatic niche. BAs impact inflammation and modulate the immune landscape within the tumor microenvironment by activating signaling pathways, which are used by tumor cells to facilitate metastasis. Given the widespread distribution of BA‑activated receptors in both tumor and immune cells, strategies aimed at restoring BA homeostasis and blocking metastasis‑associated signaling are of importance in cancer therapy. The present study summarizes the specific role of BAs in each step of colorectal liver metastasis, elucidating the association between BA and CRC progression to highlight the potential of BAs as predictive biomarkers for colorectal liver metastasis and their therapeutic potential in developing novel treatment strategies.
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Affiliation(s)
- Zhaoyu Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Lingjun Deng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Mengting Cheng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Xiandong Ye
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Nanyan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
| | - Li Sun
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
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20
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Chen J, Malhi KK, Li X, Xu X, Kang J, Zhao B, Xu Y, Li X, Li J. Metasilicate-based alkaline mineral water improves the growth performance of weaned piglets by maintaining gut-liver axis homeostasis through microbiota-mediated secondary bile acid pathway. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2025; 20:95-109. [PMID: 39949730 PMCID: PMC11821399 DOI: 10.1016/j.aninu.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 08/31/2024] [Accepted: 09/19/2024] [Indexed: 02/16/2025]
Abstract
Weaning stress causes substantial economic loss in the swine industry. Moreover, weaning-induced intestinal barrier damage and dysfunction of the gut-liver axis are associated with reduced growth performance in piglets. Metasilicate-based alkaline mineral water (AMW) has shown potential therapeutic effects on gastrointestinal disorders; however, the mechanisms involved and their overall effects on the gut-liver axis have not been explored. Here, sodium metasilicate (SMS) was used to prepare metasilicate-based AMW (basal water + 500 mg/L SMS). A total of 240 newly weaned piglets were allocated to the Control and SMS groups (6 replicate pens per group and 20 piglets per pen) for a 15-day trial period. Histopathological evaluations were conducted using hematoxylin and eosin staining. To analyze the composition of the gut microbiota, 16S rRNA PacBio SMRT Gene Full-Length Sequencing was performed. Western blotting and immunofluorescence were employed to assess protein expression levels. Our results indicated that metasilicate-based AMW effectively alleviated weaning-induced colonic or liver morphological injury and inflammatory response, as well as liver cholesterol metabolism disorders. Further analysis showed that metasilicate-based AMW promoted deoxycholic acid (DCA) biosynthesis by increasing the abundance of Lactobacillus_delbrueckii in the colon (P < 0.001). This consequently improved weaning-induced colon and liver injury and dysfunction through the DCA-secondary bile acid (SBA) receptors (SBAR)-nuclear factor-kappaB (NF-κB)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) pathways. Growth performance parameters, including final body weight (P = 0.034) and average daily gain (P < 0.001), in the SMS group were significantly higher than those in the Control group. Therefore, metasilicate-based AMW maintains gut-liver axis homeostasis by regulating the microbiota-mediated SBA-SBAR pathway in piglets under weaning stress. Our research provides a new strategy for mitigating stress-induced gut-liver axis dysfunction in weaned piglets.
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Affiliation(s)
- Jian Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Kanwar K. Malhi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Xiaowei Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Xiangwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Jianxun Kang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Bichen Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Yaru Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
| | - Xuenan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jinlong Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030 China
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
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21
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Faas MM, Smink AM. Shaping immunity: the influence of the maternal gut bacteria on fetal immune development. Semin Immunopathol 2025; 47:13. [PMID: 39891756 PMCID: PMC11787218 DOI: 10.1007/s00281-025-01039-8] [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: 06/06/2024] [Accepted: 01/13/2025] [Indexed: 02/03/2025]
Abstract
The development of the fetal immune response is a highly complex process. In the present review, we describe the development of the fetal immune response and the role of the maternal gut bacteria in this process. In contrast to the previous belief that the fetal immune response is inert, it is now thought that the fetal immune response is uniquely tolerant to maternal and allo-antigens, but able to respond to infectious agents, such as bacteria. This is accomplished by the development of T cells toward regulatory T cells rather than toward effector T cells, but also by the presence of functional innate immune cells, such as monocytes and NK cells. Moreover, in fetuses there is different programming of CD8 + T cells and memory T cells toward innate immune cells rather than to adaptive immune cells. The maternal gut bacteria are important in shaping the fetal immune response by producing bacterial products and metabolites that pass the placenta into the fetus and influence development of the fetal immune response. Insight into how and when these products affect the fetal immune response may open new treatment options with pre- or probiotics to affect the maternal gut bacteria and therewith the fetal immune response.
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Affiliation(s)
- Marijke M Faas
- Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands.
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands
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22
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Stagg J, Gutkind JS. Targeting G Protein-Coupled Receptors in Immuno-Oncological Therapies. Annu Rev Pharmacol Toxicol 2025; 65:315-331. [PMID: 39270681 DOI: 10.1146/annurev-pharmtox-061724-080852] [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] [Indexed: 09/15/2024]
Abstract
The advent of cancer immunotherapy based on PD-1 and CTLA-4 immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many cancers do not respond to ICB, highlighting the urgent need for additional approaches to achieve durable cancer remission. The large family of G protein-coupled receptors (GPCRs) is the target of more than 30% of all approved drugs, but GPCRs have been underexploited in cancer immunotherapy. In this review, we discuss the central role of GPCRs in immune cell migration and function and describe how single-cell transcriptomic studies are illuminating the complexity of the human tumor immune GPCRome. These receptors include multiple GPCRs expressed in CD8 T cells that are activated by inflammatory mediators, protons, neurotransmitters, and metabolites that accumulate in the tumor microenvironment, thereby promoting T cell dysfunction. We also discuss new opportunities to target GPCRs as a multimodal approach to enhance the response to ICB for a myriad of human malignancies.
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Affiliation(s)
- John Stagg
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada;
| | - J Silvio Gutkind
- Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California, USA;
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23
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Xia L, Li C, Zhao J, Sun Q, Mao X. Rebalancing immune homeostasis in combating disease: The impact of medicine food homology plants and gut microbiome. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156150. [PMID: 39740376 DOI: 10.1016/j.phymed.2024.156150] [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: 05/31/2024] [Revised: 09/27/2024] [Accepted: 10/10/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Gut microbiota plays an important role in multiple human physiological processes and an imbalance in it, including the species, abundance, and metabolites can lead to diseases. These enteric microorganisms modulate immune homeostasis by presenting a myriad of antigenic determinants and microbial metabolites. Medicinal and food homologous (MFH) plants, edible herbal materials for both medicine and food, are important parts of Traditional Chinese Medicine (TCM). MFH plants have drawn much attention due to their strong biological activity and low toxicity. However, the interplay of MFH and gut microbiota in rebalancing the immune homeostasis in combating diseases needs systematic illumination. PURPOSE The review discusses the interaction between MFH and gut microbiota, including the effect of MFH on the major group of gut microbiota and the metabolic effect of gut microbiota on MFH. Moreover, how gut microbiota influences the immune system in terms of innate and adaptive immunity is addressed. Finally, the immunoregulatory mechanisms of MFH in regulation of host pathophysiology via gut microbiota are summarized. METHODS Literature was searched, analyzed, and collected using databases, including PubMed, Web of Science, and Google Scholar using relevant keywords. The obtained articles were screened and summarized by the research content of MFH and gut microbiota in immune regulation. RESULTS The review demonstrates the interaction between MFH and gut microbiota in disease prevention and treatment. Not only do the intestinal microorganisms and intestinal mucosa constitute an important immune barrier of the human body, but also lymphoid tissue and diffused immune cells within the mucosa participate in the response of innate immunity and adaptive immunity. MFH modulates immune regulation by affecting intestinal flora, helps maintain the balance of the immune system and interfere with the occurrence and development of a broad category of diseases. CONCLUSION Being absorbed from the gastrointestinal tract, MFH can have profound effects on gut microbiota. In turn, the gut microbiota also actively participate in the bioconversion of complex constituents from MFH, which could further influence their physiological and pharmacological properties. The review deepens the understanding of the relationship among MFH, gut microbiota, immune system, and human diseases and further promotes the progression of additional relevant research.
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Affiliation(s)
- Lu Xia
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Chuangen Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Jia Zhao
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Quancai Sun
- Department of Health, Nutrition, and Food sciences, Florida State University, Tallahassee, USA
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
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24
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Darmanto AG, Yen TL, Jan JS, Linh TTD, Taliyan R, Yang CH, Sheu JR. Beyond metabolic messengers: Bile acids and TGR5 as pharmacotherapeutic intervention for psychiatric disorders. Pharmacol Res 2025; 211:107564. [PMID: 39733841 DOI: 10.1016/j.phrs.2024.107564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.
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Affiliation(s)
- Arief Gunawan Darmanto
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; School of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia
| | - Ting-Lin Yen
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Department of Medical Research, Cathay General Hospital, Taipei 22174, Taiwan, ROC
| | - Jing-Shiun Jan
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC
| | - Tran Thanh Duy Linh
- Family Medicine Training Center, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Viet Nam
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Chih-Hao Yang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Joen-Rong Sheu
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
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25
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Richardson H, Yoon G, Moussa G, Kumar A, Harvey P. Ocular Manifestations of IBD: Pathophysiology, Epidemiology, and Iatrogenic Associations of Emerging Treatment Strategies. Biomedicines 2024; 12:2856. [PMID: 39767762 PMCID: PMC11673599 DOI: 10.3390/biomedicines12122856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/10/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a complex, multisystemic disease and is associated with ocular pathology in 4-12% of patients. In general, ocular disease affects Crohn's patients more frequently than those with ulcerative colitis. Episcleritis and uveitis are the most common presentations, with episcleritis often correlating with IBD flares, whereas uveitis presents independently of IBD activity and, in some cases, may even alert clinicians to a new diagnosis of IBD. Corneal EIMs encompass a range of pathologies, such as the common and benign keratoconjunctivitis sicca (dry eye disease), which nevertheless causes significant patient discomfort, and the rarer condition of peripheral ulcerative keratitis, which warrants urgent review due to the risk of corneal perforation. Alongside EIMs, clinicians should also be aware of the iatrogenic consequences to the eye following treatment of IBD. Corticosteroids may cause cataracts, glaucoma, and-indirectly via hyperglycaemia-diabetic retinopathy. Methotrexate is irritating to ocular tissues and may cause conjunctivitis and blepharitis. Biologic medications, such as anti-TNFα agents, overlap in their use as treatment of both IBD and uveitis, and yet in some patients may also increase the risk of acute uveitis flares, as well as opportunistic, sight-threatening infections. With integrated care between gastroenterology and ophthalmology, patient outcomes can be improved by facilitating earlier detection and management of ocular disease. This narrative review summarises the ocular extraintestinal manifestations of IBD, including pathophysiology, epidemiology, and current treatment strategies.
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Affiliation(s)
- Holly Richardson
- Department of Undergraduate Medical Education, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | - Giho Yoon
- Department of Undergraduate Medical Education, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | - George Moussa
- Manchester Royal Eye Hospital, Manchester M13 9WL, UK;
| | - Aditi Kumar
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK;
| | - Philip Harvey
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK;
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26
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Zhang B, Wang J, Chen X, Xue T, Xin J, Liu Y, Wang X, Li X. Laminaria japonica Polysaccharide Regulates Fatty Hepatosis Through Bile Acids and Gut Microbiota in Diabetes Rat. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2024; 26:1165-1178. [PMID: 39207652 DOI: 10.1007/s10126-024-10365-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024]
Abstract
In this study, we examined the effect of Laminaria japonica polysaccharide (fucoidan) on the regulation of lipid metabolism. A rat model of diabetes mellitus (DM) was established by a high-sugar and high-fat diet combined with streptozotocin. Changes in the rats' body weight and blood glucose level during the experiment were recorded. Before the end of the experiment, an automatic biochemical analyzer was used to detect the fasting blood glucose (FBG), lipid content in serum, and insulin content, and calculate the insulin resistance index. Oil red O staining was used to detect lipid deposition in the liver. H&E staining, Masson staining, and PASM staining were used to observe the pathological structural changes in the liver. 16 s RNA sequencing and targeted metabolomics were used to detect intestinal microbiota and bile acid content. The results showed that fucoidan was able to inhibit weight loss in the DM rats and reduce the content of triglycerides (TG), cholesterol (TC), and low-density lipoprotein (LDL-C) in serum. Oil red O staining showed a decrease in liver fat accumulation after fucoidan treatment. 16 s RNA sequencing demonstrated that fucoidan increased the abundance of Bacteroidia, Campylobacteria, Clostridia, Gammaproteobacteria, Negativicutes, and Verrucomicrobi. Fucoidan also increased the secretion of secondary bile acids (Nor-DCA, TLCA, β-UDCA) and alleviated lipid metabolism disorders. The expression of α-SMA was inhibited by fucoidan, whereas the expression of FXR and TGR5 was promoted. Fucoidan shows good activity in regulating lipid metabolism by regulating the expression of FXR and TGR5 and acting on the intestinal flora-bile acid axis.
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Affiliation(s)
- Bo Zhang
- Linyi University, Linyi, Shandong, China
| | - Jiacai Wang
- Linyi University, Linyi, Shandong, China
- Guizhou University, Guiyang, Guizhou, China
| | | | - Tao Xue
- Linyi University, Linyi, Shandong, China
| | - Jie Xin
- Linyi University, Linyi, Shandong, China
| | | | - Xiao Wang
- Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong, China
| | - Xinpeng Li
- Linyi University, Linyi, Shandong, China.
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27
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Urtecho G, Moody T, Huang Y, Sheth RU, Richardson M, Descamps HC, Kaufman A, Lekan O, Zhang Z, Velez-Cortes F, Qu Y, Cohen L, Ricaurte D, Gibson TE, Gerber GK, Thaiss CA, Wang HH. Spatiotemporal dynamics during niche remodeling by super-colonizing microbiota in the mammalian gut. Cell Syst 2024; 15:1002-1017.e4. [PMID: 39541983 PMCID: PMC12066173 DOI: 10.1016/j.cels.2024.10.007] [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: 10/31/2023] [Revised: 01/29/2024] [Accepted: 10/21/2024] [Indexed: 11/17/2024]
Abstract
While fecal microbiota transplantation (FMT) has been shown to be effective in reversing gut dysbiosis, we lack an understanding of the fundamental processes underlying microbial engraftment in the mammalian gut. Here, we explored a murine gut colonization model leveraging natural inter-individual variations in gut microbiomes to elucidate the spatiotemporal dynamics of FMT. We identified a natural "super-donor" consortium that robustly engrafts into diverse recipients and resists reciprocal colonization. Temporal profiling of the gut microbiome showed an ordered succession of rapid engraftment by early colonizers within 72 h, followed by a slower emergence of late colonizers over 15-30 days. Moreover, engraftment was localized to distinct compartments of the gastrointestinal tract in a species-specific manner. Spatial metagenomic characterization suggested engraftment was mediated by simultaneous transfer of spatially co-localizing species from the super-donor consortia. These results offer a mechanism of super-donor colonization by which nutritional niches are expanded in a spatiotemporally dependent manner. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Guillaume Urtecho
- Department of Systems Biology, Columbia University, New York, NY, USA
| | - Thomas Moody
- Department of Systems Biology, Columbia University, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
| | - Yiming Huang
- Department of Systems Biology, Columbia University, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
| | - Ravi U Sheth
- Department of Systems Biology, Columbia University, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
| | - Miles Richardson
- Department of Systems Biology, Columbia University, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
| | - Hélène C Descamps
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew Kaufman
- Department of Systems Biology, Columbia University, New York, NY, USA
| | - Opeyemi Lekan
- Department of Systems Biology, Columbia University, New York, NY, USA; Columbia College, Columbia University, New York, NY 10027, USA
| | - Zetian Zhang
- Department of Systems Biology, Columbia University, New York, NY, USA; Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Florencia Velez-Cortes
- Department of Systems Biology, Columbia University, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
| | - Yiming Qu
- Department of Systems Biology, Columbia University, New York, NY, USA
| | - Lucas Cohen
- Department of Systems Biology, Columbia University, New York, NY, USA
| | - Deirdre Ricaurte
- Department of Systems Biology, Columbia University, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
| | - Travis E Gibson
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA, USA; Computer Science and AI Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Georg K Gerber
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; MIT-Harvard Health Sciences and Technology, Cambridge, MA, USA
| | - Christoph A Thaiss
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Harris H Wang
- Department of Systems Biology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; Columbia University Digestive and Liver Disease Research Center, New York, NY 10032, USA.
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28
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Liu P, Jin M, Hu P, Sun W, Tang Y, Wu J, Zhang D, Yang L, He H, Xu X. Gut microbiota and bile acids: Metabolic interactions and impacts on diabetic kidney disease. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100315. [PMID: 39726973 PMCID: PMC11670419 DOI: 10.1016/j.crmicr.2024.100315] [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] [Indexed: 12/28/2024] Open
Abstract
The intestinal microbiota comprises approximately 1013-1014 species of bacteria and plays a crucial role in host metabolism by facilitating various chemical reactions. Secondary bile acids (BAs) are key metabolites produced by gut microbiota.Initially synthesized by the liver, BA undergoes structural modifications through the activity of various intestinal microbiota enzymes, including eukaryotic, bacterial, and archaeal enzymes. These modified BA then activate specific receptors that regulate multiple metabolic pathways in the host, such as lipid and glucose metabolism, energy balance, inflammatory response, and cell proliferation and death. Recent attention has been given to intestinal flora disorders in diabetic kidney disease (DKD), where activation of BA receptors has shown promise in alleviating diabetic kidney damage by modulating renal lipid metabolism and mitochondrial production. Imbalances in the intestinal flora can influence the progression of DKD through the regulation of bile acid and its receptor pathways. This review aims to propose a mechanism involving the gut-BA-diabetes and nephropathy axes with the goal of optimizing new strategies for treating DKD.
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Affiliation(s)
| | | | - Ping Hu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Weiqian Sun
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Yuyan Tang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Jiajun Wu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Dongliang Zhang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Licai Yang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Haidong He
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Xudong Xu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
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29
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Zhuang T, Wang X, Wang Z, Gu L, Yue D, Wang Z, Li X, Yang L, Huang W, Ding L. Biological functions and pharmacological behaviors of bile acids in metabolic diseases. J Adv Res 2024:S2090-1232(24)00495-8. [PMID: 39522690 DOI: 10.1016/j.jare.2024.11.003] [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: 07/17/2024] [Revised: 11/02/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Bile acids, synthesized endogenously from cholesterol, play a central role in metabolic regulation within the enterohepatic circulatory system. Traditionally known as emulsifying agents that facilitate the intestinal absorption of vitamins and lipids, recent research reveals their function as multifaceted signal modulators involved in various physiological processes. These molecules are now recognized as key regulators of chronic metabolic diseases and immune dysfunction. Despite progress in understanding their roles, their structural diversity and the specific functions of individual bile acids remain underexplored. AIM OF REVIEW This study categorizes the bile acids based on their chemical structures and their roles as signaling molecules in physiological processes. It consolidates current knowledge and provides a comprehensive overview of the current research. The review also includes natural and semisynthetic variants that have demonstrated potential in regulating metabolic processes in animal models or clinical contexts. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acids circulate primarily within the enterohepatic circulation, where they help maintain a healthy digestive system. Disruptions in their balance are linked to metabolic disorders, hepatobiliary diseases and intestinal inflammation. Through receptor-mediated pathways, bile acids influence the progression of metabolic diseases by regulating glucose and lipid metabolism, immune function, and energy expenditure. This review aims to provide a comprehensive, systematic foundation to for understanding their physiological roles and supporting future therapeutic developments for metabolic and inflammatory diseases.
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Affiliation(s)
- Tongxi Zhuang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China; Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Zixuan Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Lihua Gu
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Dawei Yue
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Xiaohua Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200163, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| | - Wendong Huang
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
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Kong FS, Huang P, Chen JH, Ma Y. The Novel Insight of Gut Microbiota from Mouse Model to Clinical Patients and the Role of NF-κB Pathway in Polycystic Ovary Syndrome. Reprod Sci 2024; 31:3323-3333. [PMID: 38653859 DOI: 10.1007/s43032-024-01562-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Abstract
Polycystic Ovary Syndrome (PCOS) is a metabolic disorder characterized by hyperandrogenism and related symptoms in women of reproductive age. Emerging evidence suggests that chronic low-grade inflammation plays a significant role in the development of PCOS. The gut microbiota, a complex bacterial ecosystem, has been extensively studied for various diseases, including PCOS, while the underlying mechanisms are not fully understood. This review comprehensively summarizes the changes in gut microbiota and metabolites observed in PCOS and their potential association with the condition. Additionally, we discuss the role of abnormal nuclear factor κB signaling in the pathogenesis of PCOS. These findings offer valuable insights into the mechanisms of PCOS and may pave the way for the development of control and therapeutic strategies for this condition in clinical practice. By bridging the gap between mouse models and clinical patients, this review contributes to a better understanding of the interplay between gut microbiota and inflammation in PCOS, thus paving new ways for future investigations and interventions.
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Affiliation(s)
- Fan-Sheng Kong
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Panwang Huang
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology of Guangdong Academy of Science, Jiangnan University, Wuxi, Jiangsu, China.
- Jiangnan University Brain Institute, Wuxi, Jiangsu, China.
| | - Yaping Ma
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China.
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
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31
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Lee MH, Nuccio SP, Mohanty I, Hagey LR, Dorrestein PC, Chu H, Raffatellu M. How bile acids and the microbiota interact to shape host immunity. Nat Rev Immunol 2024; 24:798-809. [PMID: 39009868 DOI: 10.1038/s41577-024-01057-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 07/17/2024]
Abstract
Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.
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Affiliation(s)
- Michael H Lee
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Sean-Paul Nuccio
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
- Collaborative Mass Spectrometry Innovation Center, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | - Hiutung Chu
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA.
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Francis EC, Hunt KJ, Grobman WA, Skupski DW, Mani A, Hinkle SN. Maternal Obesity and Differences in Child Urine Metabolome. Metabolites 2024; 14:574. [PMID: 39590810 PMCID: PMC11596954 DOI: 10.3390/metabo14110574] [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: 09/10/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 11/28/2024] Open
Abstract
Background/objective: Approximately one-third of pregnant individuals in the U.S. are affected by obesity, which can adversely impact the in utero environment and offspring. This study aimed to investigate the differences in urine metabolomics between children exposed and unexposed to maternal obesity. Methods: In a study nested within a larger pregnancy cohort of women-offspring pairs, we measured untargeted metabolomics using liquid chromatography-mass spectrometry in urine samples from 68 children at 4-8 years of age. We compared metabolite levels between offspring exposed to maternal obesity (body mass index [BMI] ≥ 30.0 kg/m2) vs. unexposed (maternal BMI 18.5-24.9 kg/m2) and matched them on covariates, using two-sample t-tests, with additional sensitivity analyses based on children's BMI. This study reports statistically significant results (p ≤ 0.05) and potentially noteworthy findings (fold change > 1 or 0.05 < p < 0.15), considering compounds' involvement in common pathways or similar biochemical families. Results: The mean (SD) maternal age at study enrollment was 28.0 (6.3) years, the mean child age was 6.6 (0.8) years, 56% of children were male, and 38% of children had a BMI in the overweight/obese range (BMI ≥ 85th percentile). Children exposed to maternal obesity had lower levels of 5-hydroxyindole sulfate and 7-hydroxyindole sulfate and higher levels of secondary bile acids. Phenylacetic acid derivatives were lower in offspring exposed to obesity and in offspring who had a current BMI in the overweight/obese range. Exposure to maternal obesity was associated with lower levels of androgenic steroid dehydroepiandrosterone sulfate (DHEA-S). Conclusions: In this preliminary study, children exposed to maternal obesity in utero had differences in microbiome-related metabolites in urine suggestive of altered microbial catabolism of tryptophan and acetylated peptides. Some of these differences were partially attributable to the offspring's current BMI status. This study highlights the potential of urine metabolomics to identify biomarkers and pathways impacted by in utero exposure to maternal obesity.
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Affiliation(s)
- Ellen C. Francis
- Department of Biostatistics & Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, USA;
| | - Kelly J. Hunt
- Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA;
| | - William A. Grobman
- Department of Obstetrics and Gynecology, Brown University Medical School, Providence, RI 02903, USA;
| | - Daniel W. Skupski
- Weill Cornell Medicine, New York Presbyterian Queens, Flushing, NY 11355, USA;
| | - Ashika Mani
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Stefanie N. Hinkle
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Liu C, Fu L, Wang Y, Yang W. Influence of the gut microbiota on immune cell interactions and cancer treatment. J Transl Med 2024; 22:939. [PMID: 39407240 PMCID: PMC11476117 DOI: 10.1186/s12967-024-05709-3] [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: 07/16/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
The tumour microenvironment represents a novel frontier in oncological research. Over the past decade, accumulating evidence has underscored the importance of the tumour microenvironment (TME), including tumour cells, stromal cells, immune cells, and various secreted factors, which collectively influence tumour growth, invasion, and responses to therapeutic agents. Immune cells within the TME are now widely acknowledged to play pivotal roles in tumour development and treatment. While some perspectives have posited that immune cells within the TME facilitate tumour progression and confer resistance to therapeutic interventions, contrasting conclusions also exist. Affirmative and negative conclusions appear to be context dependent, and a unified consensus has yet to be reached. The burgeoning body of research on the relationship between the gut microbiota and tumours in recent years has led to a growing understanding. Most studies have indicated that specific components of the gut microbiota, such as unique bacterial communities or specific secretory factors, play diverse roles in regulating immune cells within the TME, thereby influencing the prognosis and outcomes of cancer treatments. A detailed understanding of these factors could provide novel insights into the TME and cancer therapy. In this study, we aimed to synthesise information on the interactions between the gut microbiota and immune cells within the TME, providing an in-depth exploration of the potential guiding implications for future cancer therapies.
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Affiliation(s)
- Chunxiao Liu
- Department of Gastroenterological Surgery, Hengqin Hospital, First Affiliated Hospital of Guangzhou Medical University, No. 118 Baoxing Road, Hengqin, Guangdong, 519031, China
| | - Lingfeng Fu
- Department of Gastroenterological Surgery, Hengqin Hospital, First Affiliated Hospital of Guangzhou Medical University, No. 118 Baoxing Road, Hengqin, Guangdong, 519031, China
| | - Yuxin Wang
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, No. 1838, North Guangzhou Avenue, Guangzhou, Guangdong, 510515, China.
- Central Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Weijun Yang
- Department of Gastroenterological Surgery, Hengqin Hospital, First Affiliated Hospital of Guangzhou Medical University, No. 118 Baoxing Road, Hengqin, Guangdong, 519031, China.
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Li W, He S, Tan J, Li N, Zhao C, Wang X, Zhang Z, Liu J, Huang J, Li X, Zhou Q, Hu K, Yang P, Hou S. Transcription factor EGR2 alleviates autoimmune uveitis via activation of GDF15 to modulate the retinal microglial phenotype. Proc Natl Acad Sci U S A 2024; 121:e2316161121. [PMID: 39298490 PMCID: PMC11441539 DOI: 10.1073/pnas.2316161121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 07/29/2024] [Indexed: 09/21/2024] Open
Abstract
Uveitis is a vision-threatening disease primarily driven by a dysregulated immune response, with retinal microglia playing a pivotal role in its progression. Although the transcription factor EGR2 is known to be closely associated with uveitis, including Vogt-Koyanagi-Harada disease and Behcet's disease, and is essential for maintaining the dynamic homeostasis of autoimmunity, its exact role in uveitis remains unclear. In this study, diminished EGR2 expression was observed in both retinal microglia from experimental autoimmune uveitis (EAU) mice and inflammation-induced human microglia cell line (HMC3). We constructed a mice model with conditional knockout of EGR2 in microglia and found that EGR2 deficiency resulted in increased intraocular inflammation. Meanwhile, EGR2 overexpression downregulated the expression of inflammatory cytokines as well as cell migration and proliferation in HMC3 cells. Next, RNA sequencing and ChIP-PCR results indicated that EGR2 directly bound to its downstream target growth differentiation factor 15 (GDF15) and further regulated GDF15 transcription. Furthermore, intravitreal injection of GDF15 recombinant protein was shown to ameliorate EAU progression in vivo. Meanwhile, knockdown of GDF15 reversed the phenotype of EGR2 overexpression-induced microglial inflammation in vitro. In summary, this study highlighted the protective role of the transcription factor EGR2 in AU by modulating the microglial phenotype. GFD15 was identified as a downstream target of EGR2, providing a unique target for uveitis treatment.
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Affiliation(s)
- Wanqian Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Siyuan He
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Jun Tan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Na Li
- Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China
| | - Chenyang Zhao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Xiaotang Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Zhi Zhang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Jiangyi Liu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Jiaxing Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Xingran Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Qian Zhou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Ke Hu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, China
| | - Shengping Hou
- Department of Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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Grant ET, Parrish A, Boudaud M, Hunewald O, Hirayama A, Ollert M, Fukuda S, Desai MS. Dietary fibers boost gut microbiota-produced B vitamin pool and alter host immune landscape. MICROBIOME 2024; 12:179. [PMID: 39307855 PMCID: PMC11418204 DOI: 10.1186/s40168-024-01898-7] [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: 07/27/2023] [Accepted: 07/31/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Dietary fibers can alter microbial metabolic output in support of healthy immune function; however, the impact of distinct fiber sources and immunomodulatory effects beyond short-chain fatty acid production are underexplored. In an effort to discern the effects of diverse fibers on host immunity, we employed five distinct rodent diets with varying fiber content and source in specific-pathogen-free, gnotobiotic (containing a 14-member synthetic human gut microbiota), and germ-free mice. RESULTS Broad-scale metabolomics analysis of cecal contents revealed that fiber deprivation consistently reduced the concentrations of microbiota-produced B vitamins. This phenomenon was not always explained by reduced biosynthesis, rather, metatranscriptomic analyses pointed toward increased microbial usage of certain B vitamins under fiber-free conditions, ultimately resulting in a net reduction of host-available B vitamins. Broad immunophenotyping indicated that the local gut effector immune populations and activated T cells accumulate in a microbiota-dependent manner. Supplementation with the prebiotic inulin recovered the availability of microbially produced B vitamins and restored immune homeostasis. CONCLUSIONS Our findings highlight the potential to use defined fiber polysaccharides to boost microbiota-derived B vitamin availability in an animal model and to regulate local innate and adaptive immune populations of the host. Video abstract.
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Affiliation(s)
- Erica T Grant
- Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-Sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, 4365, Esch-Sur-Alzette, Luxembourg
| | - Amy Parrish
- Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-Sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, 4365, Esch-Sur-Alzette, Luxembourg
| | - Marie Boudaud
- Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-Sur-Alzette, Luxembourg
| | - Oliver Hunewald
- Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-Sur-Alzette, Luxembourg
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Yamagata, 997-0052, Japan
| | - Markus Ollert
- Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-Sur-Alzette, Luxembourg
- Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, 5000, Odense, Denmark
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Yamagata, 997-0052, Japan
- Transborder Medical Research Center, University of Tsukuba, Ibaraki, 305-8575, Japan
- Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kanagawa, 210-0821, Japan
| | - Mahesh S Desai
- Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-Sur-Alzette, Luxembourg.
- Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, 5000, Odense, Denmark.
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Zitvogel L, Fidelle M, Kroemer G. Long-distance microbial mechanisms impacting cancer immunosurveillance. Immunity 2024; 57:2013-2029. [PMID: 39151425 DOI: 10.1016/j.immuni.2024.07.020] [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: 05/30/2024] [Revised: 07/13/2024] [Accepted: 07/21/2024] [Indexed: 08/19/2024]
Abstract
The intestinal microbiota determines immune responses against extraintestinal antigens, including tumor-associated antigens. Indeed, depletion or gross perturbation of the microbiota undermines the efficacy of cancer immunotherapy, thereby compromising the clinical outcome of cancer patients. In this review, we discuss the long-distance effects of the gut microbiota and the mechanisms governing antitumor immunity, such as the translocation of intestinal microbes into tumors, migration of leukocyte populations from the gut to the rest of the body, including tumors, as well as immunomodulatory microbial products and metabolites. The relationship between these pathways is incompletely understood, in particular the significance of the tumor microbiota with respect to the identification of host and/or microbial products that regulate the egress of bacteria and immunocytes toward tumor beds.
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Affiliation(s)
- Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR 1015, ClinicObiome, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Université Paris-Saclay, Ile-de-France, France; Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France.
| | - Marine Fidelle
- Gustave Roussy Cancer Campus, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR 1015, ClinicObiome, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Université Paris-Saclay, Ile-de-France, France
| | - Guido Kroemer
- Gustave Roussy Cancer Campus, Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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Saki N, Hadi H, Keikhaei B, Mirzaei A, Purrahman D. Gut microbiome composition and dysbiosis in immune thrombocytopenia: A review of literature. Blood Rev 2024; 67:101219. [PMID: 38862311 DOI: 10.1016/j.blre.2024.101219] [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: 02/16/2024] [Revised: 04/14/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by excessive reticuloendothelial platelet destruction and inadequate compensatory platelet production. However, the pathogenesis of ITP is relatively complex, and its exact mechanisms and etiology have not been definitively established. The gut microbiome, namely a diverse community of symbiotic microorganisms residing in the gastrointestinal system, affects health through involvement in human metabolism, immune modulation, and maintaining physiological balance. Emerging evidence reveals that the gut microbiome composition differs in patients with ITP compared to healthy individuals, which is related with platelet count, disease duration, and response to treatment. These findings suggest that the microbiome and metabolome profiles of individuals could unveil a new pathway for aiding diagnosis, predicting prognosis, assessing treatment response, and formulating personalized therapeutic approaches for ITP. However, due to controversial reports, definitive conclusions cannot be drawn, and further investigations are needed.
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Affiliation(s)
- Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hakimeh Hadi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Bijan Keikhaei
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Arezoo Mirzaei
- Department of Bacteriology and Virology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Daryush Purrahman
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Jia H, Dong N. Effects of bile acid metabolism on intestinal health of livestock and poultry. J Anim Physiol Anim Nutr (Berl) 2024; 108:1258-1269. [PMID: 38649786 DOI: 10.1111/jpn.13969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 01/27/2024] [Accepted: 04/08/2024] [Indexed: 04/25/2024]
Abstract
Bile acids are synthesised in the liver and are essential amphiphilic steroids for maintaining the balance of cholesterol and energy metabolism in livestock and poultry. They can be used as novel feed additives to promote fat utilisation in the diet and the absorption of fat-soluble substances in the feed to improve livestock performance and enhance carcass quality. With the development of understanding of intestinal health, the balance of bile acid metabolism is closely related to the composition and growth of livestock intestinal microbiota, inflammatory response, and metabolic diseases. This paper systematically reviews the effects of bile acid metabolism on gut health and gut microbiology in livestock. In addition, our paper summarised the role of bile acid metabolism in performance and disease control.
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Affiliation(s)
- Hongpeng Jia
- The Laboratory of Molecular Nutrition and Immunity, Institute of Animal Nutrition, Northeast Agricultural University, Harbin, China
| | - Na Dong
- The Laboratory of Molecular Nutrition and Immunity, Institute of Animal Nutrition, Northeast Agricultural University, Harbin, China
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40
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Li W, Chen H, Tang J. Interplay between Bile Acids and Intestinal Microbiota: Regulatory Mechanisms and Therapeutic Potential for Infections. Pathogens 2024; 13:702. [PMID: 39204302 PMCID: PMC11356816 DOI: 10.3390/pathogens13080702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/30/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Bile acids (BAs) play a crucial role in the human body's defense against infections caused by bacteria, fungi, and viruses. BAs counteract infections not only through interactions with intestinal bacteria exhibiting bile salt hydrolase (BSH) activity but they also directly combat infections. Building upon our research group's previous discoveries highlighting the role of BAs in combating infections, we have initiated an in-depth investigation into the interactions between BAs and intestinal microbiota. Leveraging the existing literature, we offer a comprehensive analysis of the relationships between BAs and 16 key microbiota. This investigation encompasses bacteria (e.g., Clostridioides difficile (C. difficile), Staphylococcus aureus (S. aureus), Escherichia coli, Enterococcus, Pseudomonas aeruginosa, Mycobacterium tuberculosis (M. tuberculosis), Bacteroides, Clostridium scindens (C. scindens), Streptococcus thermophilus, Clostridium butyricum (C. butyricum), and lactic acid bacteria), fungi (e.g., Candida albicans (C. albicans) and Saccharomyces boulardii), and viruses (e.g., coronavirus SARS-CoV-2, influenza virus, and norovirus). Our research found that Bacteroides, C. scindens, Streptococcus thermophilus, Saccharomyces boulardii, C. butyricum, and lactic acid bacteria can regulate the metabolism and function of BSHs and 7α-dehydroxylase. BSHs and 7α-dehydroxylase play crucial roles in the conversion of primary bile acid (PBA) to secondary bile acid (SBA). It is important to note that PBAs generally promote infections, while SBAs often exhibit distinct anti-infection roles. In the antimicrobial action of BAs, SBAs demonstrate antagonistic properties against a wide range of microbiota, with the exception of norovirus. Given the intricate interplay between BAs and intestinal microbiota, and their regulatory effects on infections, we assert that BAs hold significant potential as a novel approach for preventing and treating microbial infections.
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Affiliation(s)
| | - Hui Chen
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Fudan University, 128 Ruili Road, Shanghai 200240, China;
| | - Jianguo Tang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Fudan University, 128 Ruili Road, Shanghai 200240, China;
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Luo Z, Zhou W, Xie T, Xu W, Shi C, Xiao Z, Si Y, Ma Y, Ren Q, Di L, Shan J. The role of botanical triterpenoids and steroids in bile acid metabolism, transport, and signaling: Pharmacological and toxicological implications. Acta Pharm Sin B 2024; 14:3385-3415. [PMID: 39220868 PMCID: PMC11365449 DOI: 10.1016/j.apsb.2024.04.027] [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: 12/22/2023] [Revised: 03/28/2024] [Accepted: 04/22/2024] [Indexed: 09/04/2024] Open
Abstract
Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.
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Affiliation(s)
- Zichen Luo
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Zhou
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Tong Xie
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Weichen Xu
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Chen Shi
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zihan Xiao
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Si
- Jiangsu CM Clinical Medicine Innovation Center for Obstetrics, Gynecology, and Reproduction, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, China
| | - Yan Ma
- National Institute of Biological Sciences, Beijing 102206, China
| | - Qingling Ren
- Jiangsu CM Clinical Medicine Innovation Center for Obstetrics, Gynecology, and Reproduction, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, China
| | - Liuqing Di
- Jiangsu Engineering Research Center for Efficient Delivery System of TCM, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jinjun Shan
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Mohanty I, Allaband C, Mannochio-Russo H, El Abiead Y, Hagey LR, Knight R, Dorrestein PC. The changing metabolic landscape of bile acids - keys to metabolism and immune regulation. Nat Rev Gastroenterol Hepatol 2024; 21:493-516. [PMID: 38575682 DOI: 10.1038/s41575-024-00914-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/14/2024] [Indexed: 04/06/2024]
Abstract
Bile acids regulate nutrient absorption and mitochondrial function, they establish and maintain gut microbial community composition and mediate inflammation, and they serve as signalling molecules that regulate appetite and energy homeostasis. The observation that there are hundreds of bile acids, especially many amidated bile acids, necessitates a revision of many of the classical descriptions of bile acids and bile acid enzyme functions. For example, bile salt hydrolases also have transferase activity. There are now hundreds of known modifications to bile acids and thousands of bile acid-associated genes, especially when including the microbiome, distributed throughout the human body (for example, there are >2,400 bile salt hydrolases alone). The fact that so much of our genetic and small-molecule repertoire, in both amount and diversity, is dedicated to bile acid function highlights the centrality of bile acids as key regulators of metabolism and immune homeostasis, which is, in large part, communicated via the gut microbiome.
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Affiliation(s)
- Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Celeste Allaband
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Helena Mannochio-Russo
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Yasin El Abiead
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California San Diego, San Diego, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
- Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
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Xie X, Huang C. Role of the gut-muscle axis in mitochondrial function of ageing muscle under different exercise modes. Ageing Res Rev 2024; 98:102316. [PMID: 38703951 DOI: 10.1016/j.arr.2024.102316] [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: 12/21/2023] [Revised: 03/29/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
The fundamental role of the gut microbiota through the gut-muscle axis in skeletal muscle ageing is increasingly recognised. Metabolites derived from the intestinal microbiota are essential in maintaining skeletal muscle function and metabolism. The energy produced by mitochondria and moderate levels of reactive oxygen species can contribute to this process. Metabolites can effectively target the mitochondria, slowing the progression of muscle ageing and potentially representing a marker of ageing-related skeletal muscle loss. Moreover, mitochondria can contribute to the immune response, gut microbiota biodiversity, and maintenance of the intestinal barrier function. However, the causal relationship between mitochondrial function and gut microbiota crosstalk remains poorly understood. In addition to elucidating the regulatory pathways of the gut-muscle axis during the ageing process, we focused on the potential role of the "exercise-gut-muscle axis", which represents a pathway under stimulation from different exercise modes to induce mitochondrial adaptations, skeletal muscle metabolism and maintain intestinal barrier function and biodiversity stability. Meanwhile, different exercise modes can induce mitochondrial adaptations and skeletal muscle metabolism and maintain intestinal barrier function and biodiversity. Resistance exercise may promote mitochondrial adaptation, increase the cross-sectional area of skeletal muscle and muscle hypertrophy, and promote muscle fibre and motor unit recruitment. Whereas endurance exercise promotes mitochondrial biogenesis, aerobic capacity, and energy utilisation, activating oxidative metabolism-related pathways to improve skeletal muscle metabolism and function. This review describes the effects of different exercise modes through the gut-muscle axis and how they act through mitochondria in ageing to define the current state of the field and issues requiring resolution.
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Affiliation(s)
- Xiaoting Xie
- Department of Sports Science, Zhejiang University, Hangzhou, China; Laboratory for Digital Sports and Health, College of Education, Zhejiang University, Hangzhou, China
| | - Cong Huang
- Department of Sports Science, Zhejiang University, Hangzhou, China; Laboratory for Digital Sports and Health, College of Education, Zhejiang University, Hangzhou, China; Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Japan.
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44
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Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [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: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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Li C, Wang L, Xie W, Chen E, Chen Y, Li H, Can D, Lei A, Wang Y, Zhang J. TGR5 deficiency in excitatory neurons ameliorates Alzheimer's pathology by regulating APP processing. SCIENCE ADVANCES 2024; 10:eado1855. [PMID: 38941459 PMCID: PMC11212731 DOI: 10.1126/sciadv.ado1855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 05/23/2024] [Indexed: 06/30/2024]
Abstract
Bile acids (BAs) metabolism has a significant impact on the pathogenesis of Alzheimer's disease (AD). We found that deoxycholic acid (DCA) increased in brains of AD mice at an early stage. The enhanced production of DCA induces the up-regulation of the bile acid receptor Takeda G protein-coupled receptor (TGR5), which is also specifically increased in neurons of AD mouse brains at an early stage. The accumulation of exogenous DCA impairs cognitive function in wild-type mice, but not in TGR5 knockout mice. This suggests that TGR5 is the primary receptor mediating these effects of DCA. Furthermore, excitatory neuron-specific knockout of TGR5 ameliorates Aβ pathology and cognition impairments in AD mice. The underlying mechanism linking TGR5 and AD pathology relies on the downstream effectors of TGR5 and the APP production, which is succinctly concluded as a "p-STAT3-APH1-γ-secretase" signaling pathway. Our studies identified the critical role of TGR5 in the pathological development of AD.
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Affiliation(s)
- Chenli Li
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Liangjie Wang
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Wenting Xie
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Erqu Chen
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Yanbing Chen
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Huifang Li
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Dan Can
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Aiyu Lei
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Yue Wang
- Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Jie Zhang
- Institute of Neuroscience, Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China
- Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China
- Institute of Neuroscience, Fujian Medical University, Fuzhou, Fujian, 350122, China
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, College of Basic Medicine, Hebei Medical University, Shijiazhuang, China
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Ronen D, Rokach Y, Abedat S, Qadan A, Daana S, Amir O, Asleh R. Human Gut Microbiota in Cardiovascular Disease. Compr Physiol 2024; 14:5449-5490. [PMID: 39109979 DOI: 10.1002/cphy.c230012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N -oxide (TMAO), short-chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449-5490, 2024.
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Affiliation(s)
- Daniel Ronen
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yair Rokach
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Suzan Abedat
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abed Qadan
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Samar Daana
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Offer Amir
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rabea Asleh
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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Nanaware PP, Khan ZN, Clement CC, Shetty M, Mota I, Seltzer ES, Dzieciatkowska M, Gamboni F, D'Alessandro A, Ng C, Nagayama M, Lichti CF, Soni RK, Jacob B Geri, Matei I, Lyden D, Longman R, Lu TT, Wan X, Unanue ER, Stern LJ, Santambrogio L. Role of the afferent lymph as an immunological conduit to analyze tissue antigenic and inflammatory load. Cell Rep 2024; 43:114311. [PMID: 38848214 PMCID: PMC11233987 DOI: 10.1016/j.celrep.2024.114311] [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: 10/16/2023] [Revised: 04/03/2024] [Accepted: 05/16/2024] [Indexed: 06/09/2024] Open
Abstract
The lymphatic fluid is the conduit by which part of the tissue "omics" is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the lymph inflammatory and damage-associated molecular pattern signatures, microbiome-derived by-products, and immunomodulatory molecules, including metabolites of the gut-brain axis, mapped in the afferent mesenteric lymph. Our data point to the relevance of the lymphatic fluid to probe the tissue-specific antigenic and inflammatory load transported to the draining lymph node for immunosurveillance.
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Affiliation(s)
- Padma P Nanaware
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Zohaib N Khan
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Cristina C Clement
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Madhur Shetty
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ines Mota
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ethan S Seltzer
- Pediatric Rheumatology and Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York NY 100021, USA
| | - Monika Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Fabia Gamboni
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Charles Ng
- Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY 10065, USA
| | - Manabu Nagayama
- Division of Gastroenterology and Hepatology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY 10065, USA
| | - Cheryl F Lichti
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
| | - Rajesh K Soni
- Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York 10032, NY, USA
| | - Jacob B Geri
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY 10065, USA
| | - Irina Matei
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA
| | - David Lyden
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA
| | - Randy Longman
- Division of Gastroenterology and Hepatology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY 10065, USA
| | - Theresa T Lu
- Pediatric Rheumatology and Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York NY 100021, USA
| | - Xiaoxiao Wan
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
| | - Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
| | - Lawrence J Stern
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Laura Santambrogio
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY 10065, USA.
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Rana S, Canfield JR, Ward CS, Sprague JE. Bile acids and the gut microbiome are involved in the hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA). Sci Rep 2024; 14:14485. [PMID: 38914648 PMCID: PMC11196659 DOI: 10.1038/s41598-024-65433-2] [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: 02/02/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024] Open
Abstract
Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.
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Affiliation(s)
- Srishti Rana
- Department of Biological Sciences, Bowling Green State University, Bowling Green, OH, 43403, USA
| | - Jeremy R Canfield
- The Ohio Attorney General's Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, 43403, USA
| | - Christopher S Ward
- Department of Biological Sciences, Bowling Green State University, Bowling Green, OH, 43403, USA
| | - Jon E Sprague
- The Ohio Attorney General's Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, 43403, USA.
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Sun C, Chao Y, Xu H, Yang X, Pei L, Xu G, Wang F, Fan X, Tang L, Xie C, Su Y, Wang X. Combined analysis of metabolomics and 16S rRNA sequencing for ankylosing spondylitis patients before and after secukinumab therapy. Int J Rheum Dis 2024; 27:e15218. [PMID: 38923187 DOI: 10.1111/1756-185x.15218] [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: 01/02/2024] [Revised: 04/28/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024]
Abstract
OBJECTIVE Alterations in gut microbiota have been implicated in the pathogenesis of ankylosing spondylitis (AS), but the underlying mechanisms remain elusive. This study aims to investigate changes in gut microbiota and metabolites in individuals with AS before and after treatment with secukinumab, to identify the biological characteristics specific to AS patients and investigate the potential biomarkers, for optimizing therapeutic strategies more effectively. METHODS Fecal microbiome data were collected from 30 AS patients before and after secukinumab therapy and compared with data from 40 healthy controls (HC). Additionally, we analyzed the metabolic profile of both groups from plasma. RESULTS Findings indicated that the treatment-induced changes in the composition of several crucial bacterial groups, including Megamonas, Prevotella_9, Faecalibacterium, Roseburia, Bacteroides, and Agathobacter. Post-treatment, these groups exhibited a distribution more akin to that of the healthy populations compared with their pretreatment status. We identified three gut microbial taxa, namely Prevotellaceae_bacterium_Marseille_P2831, Prevotella_buccae, and Elusimicrobiota, as potential biomarkers for diagnosing individuals at a higher risk of developing AS and assessing disease outcomes. Plasma metabolomics analysis revealed 479 distinct metabolites and highlighted three disrupted metabolic pathways. Integration of microbiome and metabolomics datasets demonstrated a significant degree of correlation, underscoring the impact of the microbiome on metabolic activity. CONCLUSION Secukinumab can restore the balance of the gut microbiome and metabolites in AS patients, rendering them more similar to those found in the healthy population. The analysis of microbiome and metabolomics data have unveiled some candidate biomarkers capable of evaluating treatment efficacy.
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Affiliation(s)
- Chao Sun
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, Bengbu, China
| | - Yuyan Chao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Haojie Xu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Xinmeng Yang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, Bengbu, China
| | - Lijia Pei
- Department of Orthopedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Guixia Xu
- Department of Dermatology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Fei Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, China
| | - Xiaoyun Fan
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, Bengbu, China
| | - Lin Tang
- Biomarker Technologies Corporation, Beijing, China
| | - Changhao Xie
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, Bengbu, China
| | - Yin Su
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Xin Wang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, Bengbu, China
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Wu Y, Fan H, Feng Y, Yang J, Cen X, Li W. Unveiling the gut microbiota and metabolite profiles in guinea pigs with form deprivation myopia through 16S rRNA gene sequencing and untargeted metabolomics. Heliyon 2024; 10:e30491. [PMID: 38756593 PMCID: PMC11096930 DOI: 10.1016/j.heliyon.2024.e30491] [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: 02/02/2024] [Revised: 04/26/2024] [Accepted: 04/28/2024] [Indexed: 05/18/2024] Open
Abstract
Aim The aim of this study was to confirm the presence of the form deprivation myopia (FDM) guinea pig eye-gut axis and investigate the relationship between serum vasoactive intestinal peptide (VIP), lipopolysaccharides (LPS), specific gut microbiota and their metabolites. Method 20 specific-pathogen-free (SPF) guinea pigs were divided into the FDM and the control(Con) group. Following model induction, serum levels of VIP and LPS were quantified. A combination of 16S ribosomal ribosomal Ribonucleic Acid (rRNA) gene sequencing, non-targeted metabolomics and bioinformatics analysis were employed to identify disparities in gut microbiota and metabolites between the two groups of guinea pigs. Result Compared to the control group, FDM guinea pigs exhibited a significant trend towards myopia, along with significantly elevated concentrations of LPS and VIP (p < 0.0001). Furthermore, Ruminococcus_albus emerged as the predominant bacterial community enriched in FDM (p < 0.05), and demonstrated positive correlations with 10 metabolites, including l-Glutamic acid, Additionally, Ruminococcus_albus exhibited positive correlations with VIP and LPS levels (p < 0.05). Conclusion The findings suggest that the Ruminococcus_Albus and glutamate metabolic pathways play a significant role in myopia development, leading to concurrent alterations in serum VIP and LPS levels in FDM guinea pigs. This underscores the potential of specific gut microbiota and their metabolites as pivotal biomarkers involved in the pathogenesis of myopia.
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Affiliation(s)
- Yajun Wu
- Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, 410000, China
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, 200235, China
- Shanghai Aier Eye Institute, Shanghai, 200235, China
| | - Hua Fan
- Shanxi Aier Eye Hospital, Taiyuan, Shanxi, 030000, China
| | - Yuliang Feng
- Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, 410000, China
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, 200235, China
- Shanghai Aier Eye Institute, Shanghai, 200235, China
| | - Jiasong Yang
- Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, 410000, China
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, 200235, China
- Shanghai Aier Eye Institute, Shanghai, 200235, China
| | - Xiaobo Cen
- WestChina-Frontier PharmaTech Co., Ltd, Chengdu, Sichuan, 610000, China
| | - Wensheng Li
- Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, 410000, China
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, 200235, China
- Shanghai Aier Eye Institute, Shanghai, 200235, China
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