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Shu JZ, Huang YH, He XH, Liu FY, Liang QQ, Yong XT, Xie YF. Gut microbiota differences, metabolite changes, and disease intervention during metabolic - dysfunction - related fatty liver progression. World J Hepatol 2025; 17:103854. [PMID: 40177201 PMCID: PMC11959672 DOI: 10.4254/wjh.v17.i3.103854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/17/2025] [Accepted: 02/12/2025] [Indexed: 03/26/2025] Open
Abstract
In the current era, metabolic dysfunction-associated steatotic liver disease (MASLD) has gradually developed into a major type of chronic liver disease that is widespread globally. Numerous studies have shown that the gut microbiota plays a crucial and indispensable role in the progression of MASLD. Currently, the gut microbiota has become one of the important entry points for the research of this disease. Therefore, the aim of this review is to elaborate on the further associations between the gut microbiota and MASLD, including the changes and differences in the microbiota between the healthy liver and the diseased liver. Meanwhile, considering that metabolic dysfunction-associated fatty liver and metabolic dysfunction-associated steatohepatitis are abnormal pathological states in the development of the disease and that the liver exhibits different degrees of fibrosis (such as mild fibrosis and severe fibrosis) during the disease progression, we also conduct a comparison of the microbiota in these states and use them as markers of disease progression. It reveals the changes in the production and action mechanisms of short-chain fatty acids and bile acids brought about by changes in the gut microbiota, and the impact of lipopolysaccharide from Gram-negative bacteria on the disease. In addition, the regulation of the gut microbiota in disease and the production and inhibition of related disease factors by the use of probiotics (including new-generation probiotics) will be explored, which will help to monitor the disease progression of patients with different gut microbiota compositions in the future and carry out personalized targeted therapies for the gut microbiota. This will achieve important progress in preventing and combating this disease.
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Affiliation(s)
- Jian-Zhong Shu
- Department of Encephalopathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400015, China
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
- College of Integrated Traditional Chinese and Western Medicine, Chongqing University of Traditional Chinese Medicine, Chongqing 402760, China
| | - Yu-Han Huang
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Xiao-Hong He
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Feng-Ying Liu
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Qian-Qian Liang
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Xue-Tong Yong
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Yong-Fang Xie
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
- Institute of Bioinformatics, Chongqing University of Posts and Telecommunications, Chongqing 400065, China.
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Li Z, Zheng Y, Zhang M, Wu K, Zhang L, Yao Y, Zheng C. Gut microbiota-derived metabolites associate with circulating immune cell subsets in unexplained recurrent spontaneous abortion. Heliyon 2024; 10:e24571. [PMID: 38312612 PMCID: PMC10835175 DOI: 10.1016/j.heliyon.2024.e24571] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/18/2023] [Accepted: 01/10/2024] [Indexed: 02/06/2024] Open
Abstract
Currently, the precise causes of over 40 % of recurrent spontaneous abortion (RSA) cases cannot be identified, leading to the term "unexplained RSA" (URSA). Through an exploration of the gut microbiota, metabolites, and immune cell subsets in URSA, this study establishes a link between gut microbiota-derived metabolites and immune cells. The results indicate reduced diversity in the gut microbiota of URSA. Targeted metabolomic analyses reveal decreased levels of gut microbiota-derived deoxycholic acid (DCA), glycolithocholic acid (GLCA), acetate, propionate, and butyrate in URSA. Furthermore, elevated frequencies of Th1, Th17, and plasma B cells, along with decreased frequencies of Tregs and Bregs, are observed in the peripheral blood of URSA. The results demonstrate correlations between the levels of gut microbiota-derived bile acids and short-chain fatty acids and the frequencies of various immune cell subsets in circulation. Collectively, this study uncovers an association between gut microbiota-derived metabolites and circulating immune cell subsets in URSA.
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Affiliation(s)
- Zhi Li
- Department of Gynaecology and Obstetrics, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
| | - Yongquan Zheng
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
| | - Meng Zhang
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
| | - Kaiqi Wu
- Department of Clinical Laboratory, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
| | - Long Zhang
- Department of Clinical Laboratory, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
| | - Yao Yao
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, China
| | - Caihong Zheng
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou, 310006, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, China
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3
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Farnesoid X receptor activation by the novel agonist TC-100 (3α, 7α, 11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid) preserves the intestinal barrier integrity and promotes intestinal microbial reshaping in a mouse model of obstructed bile acid flow. Biomed Pharmacother 2022; 153:113380. [PMID: 36076475 DOI: 10.1016/j.biopha.2022.113380] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/21/2022] [Accepted: 07/06/2022] [Indexed: 12/12/2022] Open
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Gadaleta RM, Cariello M, Crudele L, Moschetta A. Bile Salt Hydrolase-Competent Probiotics in the Management of IBD: Unlocking the "Bile Acid Code". Nutrients 2022; 14:3212. [PMID: 35956388 PMCID: PMC9370712 DOI: 10.3390/nu14153212] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 01/18/2023] Open
Abstract
Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient.
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Affiliation(s)
- Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Lucilla Crudele
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
- INBB National Instituto for Biostructure and Biosystems, Viale delle Medaglie d’Oro 305, 00136 Rome, Italy
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5
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Koh E, Hwang IY, Lee HL, De Sotto R, Lee JWJ, Lee YS, March JC, Chang MW. Engineering probiotics to inhibit Clostridioides difficile infection by dynamic regulation of intestinal metabolism. Nat Commun 2022; 13:3834. [PMID: 35787625 PMCID: PMC9253155 DOI: 10.1038/s41467-022-31334-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Clostridioides difficile infection (CDI) results in significant morbidity and mortality in hospitalised patients. The pathogenesis of CDI is intrinsically related to the ability of C. difficile to shuffle between active vegetative cells and dormant endospores through the processes of germination and sporulation. Here, we hypothesise that dysregulation of microbiome-mediated bile salt metabolism contributes to CDI and that its alleviation can limit the pathogenesis of CDI. We engineer a genetic circuit harbouring a genetically encoded sensor, amplifier and actuator in probiotics to restore intestinal bile salt metabolism in response to antibiotic-induced microbiome dysbiosis. We demonstrate that the engineered probiotics limited the germination of endospores and the growth of vegetative cells of C. difficile in vitro and further significantly reduced CDI in model mice, as evidenced by a 100% survival rate and improved clinical outcomes. Our work presents an antimicrobial strategy that harnesses the host-pathogen microenvironment as the intervention target to limit the pathogenesis of infection. Clostridioides difficile infection (CDI) results in significant morbidity and mortality in hospitalised patients. Here the authors engineer probiotics to restore intestinal bile salt metabolism in response to antibiotic-induced microbiome dysbiosis significantly inhibit Clostridioides difficile infection in model mice, presenting a microbiome-based antimicrobial strategy
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Affiliation(s)
- Elvin Koh
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - In Young Hwang
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hui Ling Lee
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ryan De Sotto
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jonathan Wei Jie Lee
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yung Seng Lee
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John C March
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | - Matthew Wook Chang
- NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore. .,Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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6
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Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022; 30:289-300. [PMID: 35271802 PMCID: PMC8923532 DOI: 10.1016/j.chom.2022.02.004] [Citation(s) in RCA: 405] [Impact Index Per Article: 135.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are heterogeneous intestinal diseases that threaten the health of an increasing number of individuals as their lifestyles become westernized. New insights have been discovered with the development of various omics techniques, revealing that gut-microbiota-derived metabolites play important roles in maintaining intestinal homeostasis and modulating the progression of intestinal diseases from both metabolic and immunological perspectives. Clinical metagenomic and metabolomic studies have revealed links between microbial bile acid (BA) metabolism and IBD and CRC progression. Several BA-derived metabolites were recently been demonstrated to play a role in intestinal immunity, providing fresh insights into how BAs affect the course of IBD and CRC. In this review, we discuss recent studies on the involvement of gut microbiota-derived BAs in intestinal immunity, inflammation, and tumorigenesis along with human omics data to provide prospective insights into future prevention and treatment of IBD and CRC.
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Affiliation(s)
- Jie Cai
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Lulu Sun
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
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7
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Manipulating the Microbiome: An Alternative Treatment for Bile Acid Diarrhoea. MICROBIOLOGY RESEARCH 2021. [DOI: 10.3390/microbiolres12020023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Bile acid diarrhoea (BAD) is a widespread gastrointestinal disease that is often misdiagnosed as irritable bowel syndrome and is estimated to affect 1% of the United Kingdom (UK) population alone. BAD is associated with excessive bile acid synthesis secondary to a gastrointestinal or idiopathic disorder (also known as primary BAD). Current licensed treatment in the UK has undesirable effects and has been the same since BAD was first discovered in the 1960s. Bacteria are essential in transforming primary bile acids into secondary bile acids. The profile of an individual’s bile acid pool is central in bile acid homeostasis as bile acids regulate their own synthesis. Therefore, microbiome dysbiosis incurred through changes in diet, stress levels and the introduction of antibiotics may contribute to or be the cause of primary BAD. This literature review focuses on primary BAD, providing an overview of bile acid metabolism, the role of the human gut microbiome in BAD and the potential options for therapeutic intervention in primary BAD through manipulation of the microbiome.
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8
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Microbial Hydroxysteroid Dehydrogenases: From Alpha to Omega. Microorganisms 2021; 9:microorganisms9030469. [PMID: 33668351 PMCID: PMC7996314 DOI: 10.3390/microorganisms9030469] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/08/2021] [Accepted: 02/18/2021] [Indexed: 12/23/2022] Open
Abstract
Bile acids (BAs) and glucocorticoids are steroid hormones derived from cholesterol that are important signaling molecules in humans and other vertebrates. Hydroxysteroid dehydrogenases (HSDHs) are encoded both by the host and by their resident gut microbiota, and they reversibly convert steroid hydroxyl groups to keto groups. Pairs of HSDHs can reversibly epimerize steroids from α-hydroxy conformations to β-hydroxy, or β-hydroxy to ω-hydroxy in the case of ω-muricholic acid. These reactions often result in products with drastically different physicochemical properties than their precursors, which can result in steroids being activators or inhibitors of host receptors, can affect solubility in fecal water, and can modulate toxicity. Microbial HSDHs modulate sterols associated with diseases such as colorectal cancer, liver cancer, prostate cancer, and polycystic ovary syndrome. Although the role of microbial HSDHs is not yet fully elucidated, they may have therapeutic potential as steroid pool modulators or druggable targets in the future. In this review, we explore metabolism of BAs and glucocorticoids with a focus on biotransformation by microbial HSDHs.
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Garcia-Gonzalez N, Battista N, Prete R, Corsetti A. Health-Promoting Role of Lactiplantibacillus plantarum Isolated from Fermented Foods. Microorganisms 2021; 9:349. [PMID: 33578806 PMCID: PMC7916596 DOI: 10.3390/microorganisms9020349] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/01/2021] [Accepted: 02/05/2021] [Indexed: 12/12/2022] Open
Abstract
Fermentation processes have been used for centuries for food production and preservation. Besides the contribution of fermentation to food quality, recently, scientific interest in the beneficial nature of fermented foods as a reservoir of probiotic candidates is increasing. Fermented food microbes are gaining attention for their health-promoting potential and for being genetically related to human probiotic bacteria. Among them, Lactiplantibacillus (Lpb.) plantarum strains, with a long history in the food industry as starter cultures in the production of a wide variety of fermented foods, are being investigated for their beneficial properties which are similar to those of probiotic strains, and they are also applied in clinical interventions. Food-associated Lpb. plantarum showed a good adaptation and adhesion ability in the gastro-intestinal tract and the potential to affect host health through various beneficial activities, e.g., antimicrobial, antioxidative, antigenotoxic, anti-inflammatory and immunomodulatory, in several in vitro and in vivo studies. This review provides an overview of fermented-associated Lpb. plantarum health benefits with evidence from clinical studies. Probiotic criteria that fermented-associated microbes need to fulfil are also reported.
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Affiliation(s)
| | | | - Roberta Prete
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, 64100 Teramo, Italy; (N.G.-G.); (N.B.); (A.C.)
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Tian Y, Gui W, Koo I, Smith PB, Allman EL, Nichols RG, Rimal B, Cai J, Liu Q, Patterson AD. The microbiome modulating activity of bile acids. Gut Microbes 2020; 11:979-996. [PMID: 32138583 PMCID: PMC7524280 DOI: 10.1080/19490976.2020.1732268] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Bile acids are potent antibacterial compounds and play an important role in shaping the microbial ecology of the gut. Here, we combined flow cytometry, growth rate measurements (OD600), and NMR- and mass spectrometry-based metabolomics to systematically profile the impact of bile acids on the microbiome using in vitro and in vivo models. This study confirmed that (1) unconjugated bile acids possess more potent antibacterial activity than conjugated bile acids; (2) Gram-positive bacteria are more sensitive to bile acids than Gram-negative bacteria; (3) some probiotic bacteria such as Lactobacillus and Bifidobacterium and 7α-dehydroxylating bacteria such as Clostridium scindens show bile acid resistance that is associated with activation of glycolysis. Moreover, we demonstrated that (4) as one of most hydrophobic bile acids, lithocholic acid (LCA) shows reduced toxicity to bacteria in the cecal microbiome in both in vivo and in vitro models; (5) bile acids directly and rapidly affect bacterial global metabolism including membrane damage, disrupted amino acid, nucleotide, and carbohydrate metabolism; and (6) in vivo, short-term exposure to bile acids significantly affected host metabolism via alterations of the bacterial community structure. This study systematically profiled interactions between bile acids and gut bacteria providing validation of previous observation and new insights into the interaction of bile acids with the microbiome and mechanisms related to bile acid tolerance.
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Affiliation(s)
- Yuan Tian
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA,CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, P. R. China
| | - Wei Gui
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Imhoi Koo
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Philip B. Smith
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Erik L. Allman
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Robert G. Nichols
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Qing Liu
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Andrew D. Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA,CONTACT Andrew D. Patterson 322 Life Science Bldg, University Park16802
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Prete R, Long SL, Gallardo AL, Gahan CG, Corsetti A, Joyce SA. Beneficial bile acid metabolism from Lactobacillus plantarum of food origin. Sci Rep 2020; 10:1165. [PMID: 31980710 PMCID: PMC6981223 DOI: 10.1038/s41598-020-58069-5] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 01/10/2020] [Indexed: 02/07/2023] Open
Abstract
Bile acid (BA) signatures are altered in many disease states. BA metabolism is an important microbial function to assist gut colonization and persistence, as well as microbial survival during gastro intestinal (GI) transit and it is an important criteria for potential probiotic bacteria. Microbes that express bile salt hydrolase (BSH), gateway BA modifying enzymes, are considered to have an advantage in the gut. This property is reported as selectively limited to gut-associated microbes. Food-associated microbes have the potential to confer health benefits to the human consumer. Here, we report that food associated Lactobacillus plantarum strains are capable of BA metabolism, they can withstand BA associated stress and propagate, a recognised important characteristic for GIT survival. Furthermore, we report that these food associated Lactobacillus plantarum strains have the selective ability to alter BA signatures in favour of receptor activation that would be beneficial to humans. Indeed, all of the strains examined showed a clear preference to alter human glycol-conjugated BAs, although clear strain-dependent modifications were also evident. This study demonstrates that BA metabolism by food-borne non-pathogenic bacteria is beneficial to both microbe and man and it identifies an evolutionary-conserved characteristic, previously considered unique to gut residents, among food-associated non-pathogenic isolates.
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Affiliation(s)
- Roberta Prete
- University of Teramo, Faculty of Bioscience and Technology for Food, Agriculture and Environment, 64100, Via Balzarini 1, Teramo, Italy
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Sarah Louise Long
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Alvaro Lopez Gallardo
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Cormac G Gahan
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Pharmacy, University College Cork, Cork, Ireland
- School of Microbiology, University College Cork, Cork, Ireland
| | - Aldo Corsetti
- University of Teramo, Faculty of Bioscience and Technology for Food, Agriculture and Environment, 64100, Via Balzarini 1, Teramo, Italy
| | - Susan A Joyce
- APC Microbiome Ireland, University College Cork, Cork, Ireland.
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
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12
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Schenck LP, Beck PL, MacDonald JA. Gastrointestinal dysbiosis and the use of fecal microbial transplantation in Clostridium difficile infection. World J Gastrointest Pathophysiol 2015; 6:169-180. [PMID: 26600975 PMCID: PMC4644881 DOI: 10.4291/wjgp.v6.i4.169] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/28/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The impact of antibiotics on the human gut microbiota is a significant concern. Antibiotic-associated diarrhea has been on the rise for the past few decades with the increasing usage of antibiotics. Clostridium difficile infections (CDI) have become one of the most prominent types of infectious diarrheal disease, with dramatically increased incidence in both the hospital and community setting worldwide. Studies show that variability in the innate host response may in part impact upon CDI severity in patients. That being said, CDI is a disease that shows the most prominent links to alterations to the gut microbiota, in both cause and treatment. With recurrence rates still relatively high, it is important to explore alternative therapies to CDI. Fecal microbiota transplantation (FMT) and other types of bacteriotherapy have become exciting avenues of treatment for CDI. Recent clinical trials have generated excitement for the use of FMT as a therapeutic option for CDI; however, the exact components of the human gut microbiota needed for protection against CDI have remained elusive. Additional investigations on the effects of antibiotics on the human gut microbiota and subsequent CDI will help reduce the socioeconomic burden of CDI and potentially lead to new therapeutic modalities.
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Lambert JM, Bongers RS, de Vos WM, Kleerebezem M. Functional analysis of four bile salt hydrolase and penicillin acylase family members in Lactobacillus plantarum WCFS1. Appl Environ Microbiol 2008; 74:4719-26. [PMID: 18539794 PMCID: PMC2519332 DOI: 10.1128/aem.00137-08] [Citation(s) in RCA: 162] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Accepted: 04/16/2008] [Indexed: 12/18/2022] Open
Abstract
Bile salts play an important role in the digestion of lipids in vertebrates and are synthesized and conjugated to either glycine or taurine in the liver. Following secretion of bile salts into the small intestine, intestinal microbes are capable of deconjugating the glycine or taurine from the bile salts, using an enzyme called bile salt hydrolase (Bsh). Intestinal lactobacilli are regarded as major contributors to bile salt hydrolysis in vivo. Since the bile salt-hydrolyzing strain Lactobacillus plantarum WCFS1 was predicted to carry four bsh genes (bsh1, bsh2, bsh3, and bsh4), the functionality of these bsh genes was explored using Lactococcus lactis heterologous overexpression and multiple bsh deletion strains. Thus, Bsh1 was shown to be responsible for the majority of Bsh activity in L. plantarum WCFS1. In addition, bsh1 of L. plantarum WCFS1 was shown to be involved in conferring tolerance to specific bile salts (i.e., glycocholic acid). Northern blot analysis established that bsh1, bsh2, bsh3, and bsh4 are all expressed in L. plantarum WCFS1 during the exponential growth phase. Following biodiversity analysis, bsh1 appeared to be the only bsh homologue that was variable among L. plantarum strains; furthermore, the presence of bsh1 correlated with the presence of Bsh activity, suggesting that Bsh1 is commonly responsible for Bsh activity in L. plantarum strains. The fact that bsh2, bsh3, and bsh4 genes appeared to be conserved among L. plantarum strains suggests an important role of these genes in the physiology and lifestyle of the species L. plantarum. Analysis of these additional bsh-like genes in L. plantarum WCFS1 suggests that they might encode penicillin acylase rather than Bsh activity, indicating their implication in the conversion of substrates other than bile acids in the natural habitat.
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Affiliation(s)
- Jolanda M Lambert
- TI Food & Nutrition, P.O. Box 557, 6700 AN Wageningen, The Netherlands
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Martin FPJ, Wang Y, Sprenger N, Yap IKS, Lundstedt T, Lek P, Rezzi S, Ramadan Z, van Bladeren P, Fay LB, Kochhar S, Lindon JC, Holmes E, Nicholson JK. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol Syst Biol 2008; 4:157. [PMID: 18197175 PMCID: PMC2238715 DOI: 10.1038/msb4100190] [Citation(s) in RCA: 301] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Accepted: 10/17/2007] [Indexed: 01/12/2023] Open
Abstract
The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics.
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Affiliation(s)
- Francois-Pierre J Martin
- Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK
- Nestlé Research Center, Lausanne, Switzerland
| | - Yulan Wang
- Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK
| | | | - Ivan K S Yap
- Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK
| | - Torbjörn Lundstedt
- AcurePharmaAB, Uppsala, Sweden
- Department of Medicinal Chemistry, BMC, Uppsala University, Uppsala, Sweden
| | - Per Lek
- AcurePharmaAB, Uppsala, Sweden
| | - Serge Rezzi
- Nestlé Research Center, Lausanne, Switzerland
| | | | | | | | | | - John C Lindon
- Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK
| | - Elaine Holmes
- Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK
| | - Jeremy K Nicholson
- Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK
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15
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Abstract
Secondary bile acids, produced solely by intestinal bacteria, can accumulate to high levels in the enterohepatic circulation of some individuals and may contribute to the pathogenesis of colon cancer, gallstones, and other gastrointestinal (GI) diseases. Bile salt hydrolysis and hydroxy group dehydrogenation reactions are carried out by a broad spectrum of intestinal anaerobic bacteria, whereas bile acid 7-dehydroxylation appears restricted to a limited number of intestinal anaerobes representing a small fraction of the total colonic flora. Microbial enzymes modifying bile salts differ between species with respect to pH optima, enzyme kinetics, substrate specificity, cellular location, and possibly physiological function. Crystallization, site-directed mutagenesis, and comparisons of protein secondary structure have provided insight into the mechanisms of several bile acid-biotransforming enzymatic reactions. Molecular cloning of genes encoding bile salt-modifying enzymes has facilitated the understanding of the genetic organization of these pathways and is a means of developing probes for the detection of bile salt-modifying bacteria. The potential exists for altering the bile acid pool by targeting key enzymes in the 7alpha/beta-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.
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Affiliation(s)
- Jason M Ridlon
- Department of Microbiology/Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA
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16
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Begley M, Gahan CGM, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev 2005; 29:625-51. [PMID: 16102595 DOI: 10.1016/j.femsre.2004.09.003] [Citation(s) in RCA: 1214] [Impact Index Per Article: 60.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2004] [Revised: 08/30/2004] [Accepted: 09/14/2004] [Indexed: 02/07/2023] Open
Abstract
Commensal and pathogenic microorganisms must resist the deleterious actions of bile in order to survive in the human gastrointestinal tract. Herein we review the current knowledge on the mechanisms by which Gram-positive and Gram-negative bacteria contend with bile stress. We describe the antimicrobial actions of bile, assess the variations in bile tolerance between bacterial genera and examine the interplay between bile stress and other stresses. The molecular mechanisms underlying bile tolerance are investigated and the relationship between bile and virulence is examined. Finally, the potential benefits of bile research are briefly discussed.
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Affiliation(s)
- Máire Begley
- Department of Microbiology and Alimentary Pharmabiotic Centre, University College Cork, Ireland
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17
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Knarreborg A, Engberg RM, Jensen SK, Jensen BB. Quantitative determination of bile salt hydrolase activity in bacteria isolated from the small intestine of chickens. Appl Environ Microbiol 2002; 68:6425-8. [PMID: 12450872 PMCID: PMC134412 DOI: 10.1128/aem.68.12.6425-6428.2002] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
A quantitative assay based on high-performance liquid chromatography analysis of bile salts and bacterial protein determination was established for investigating bile salt hydrolase (BSH) activity in bacteria isolated from the small intestine of chickens. Bacteria were isolated using various media and were subsequently grouped according to cell morphology, fermentation profile, and 16S ribosomal DNA sequence. Representative isolates from each bacterial group were assayed for BSH activity. The isolates differed in BSH activity with respect to the state of growth and preculturing with and without taurochenodeoxycholate. The highest levels of BSH activity were found with Enterococcus faecium and Clostridium perfringens.
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Affiliation(s)
- Ane Knarreborg
- Danish Institute of Agricultural Sciences, Department of Animal Nutrition and Physiology, Research Centre Foulum, DK-8830 Tjele, Denmark.
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18
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Dean M, Cervellati C, Casanova E, Squerzanti M, Lanzara V, Medici A, Polverino De Laureto P, Bergamini CM. Characterization of cholylglycine hydrolase from a bile-adapted strain of Xanthomonas maltophilia and its application for quantitative hydrolysis of conjugated bile salts. Appl Environ Microbiol 2002; 68:3126-8. [PMID: 12039776 PMCID: PMC123940 DOI: 10.1128/aem.68.6.3126-3128.2002] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purified bile salt hydrolase from bile-adapted Xanthomonas maltophilia displays Michaelis-Menten kinetics on cholylglycine and cholyltaurine and hydrolyzes bile salts also in crude bovine bile. The protein is a dimer and is resistant to proteinases and to heating at 55 to 60 degrees C for up to 60 min, in agreement with calorimetric data.
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Affiliation(s)
- Mariangela Dean
- Department of Biochemistry and Molecular Biology, University of Ferrara, 44100 Ferrara, Italy
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19
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Elkins CA, Moser SA, Savage DC. Genes encoding bile salt hydrolases and conjugated bile salt transporters in Lactobacillus johnsonii 100-100 and other Lactobacillus species. MICROBIOLOGY (READING, ENGLAND) 2001; 147:3403-12. [PMID: 11739773 DOI: 10.1099/00221287-147-12-3403] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Lactobacillus johnsonii strain 100-100 expresses two antigenically distinct conjugated bile salt hydrolases (BSH), alpha and beta, that combine to form native homo- and heterotrimers. This paper reports characterization of loci within the genome that encode this capacity. A locus that encodes BSH beta (cbsH beta), a partial (cbsT1) and a complete conjugated bile salt transporter (cbsT2) was identified previously. DNA sequence analysis at this locus was extended and revealed a complete ORF for cbsT1 and no other ORFs in tandem. The three genes, cbsT1, cbsT2 and cbsH beta, probably constitute an operon; a putative promoter was identified upstream of cbsT1. A second locus that expresses BSH activity in strain 100-100 was identified. Sequence analysis of the clone predicted a 978 nt ORF that did not share tandem organization with other ORFs, was similar in sequence to other BSH genes, and matched, in predicted protein sequence, the first 25 amino acids of BSH alpha. A phenotypic screen for BSH activity and a genetic screen for the cbsH beta locus were performed on 50 Lactobacillus isolates from humans or dairy products. Nearly all of the isolates that were positive for cbsH beta were from human sources. Variability in the BSH phenotype and cbsH beta genotype was identified in isolates of the same species. DNA sequence was obtained and analysed from the cbsH beta locus of one human isolate, L. acidophilus strain KS-13. This organism has cbsT1, cbsT2 and cbs beta genes that are 84, 87 and 85% identical in DNA sequence to those of strain 100-100. DNA sequence identity to strain 100-100 ends in regions flanking this locus. The findings of this study suggest that BSH genes have been acquired horizontally and that BSH activity is important at some level for lactobacilli to colonize the lower gastrointestinal tract.
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Affiliation(s)
- C A Elkins
- Department of Microbiology, M409 Walters Life Sciences Bldg, University of Tennessee, Knoxville, TN 37996-0845, USA
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20
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Tanaka H, Doesburg K, Iwasaki T, Mierau I. Screening of lactic acid bacteria for bile salt hydrolase activity. J Dairy Sci 1999; 82:2530-5. [PMID: 10629797 DOI: 10.3168/jds.s0022-0302(99)75506-2] [Citation(s) in RCA: 190] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bile salt hydrolysis is an important metabolic reaction in the bile salt metabolism of mammals. This reaction has a facilitating effect for bile salt excretion but can also be involved in various illnesses. In recent years interest has increased to use bile salt hydrolysis to influence the cholesterol metabolism of humans and farm animals. To understand the distribution and range of bile salt hydrolase activity in lactic acid bacteria, we screened more than 300 strains of the genera Bifidobacterium and Lactobacillus and the species Lactococcus lactis, Leuconostoc mesenteroides, and Streptococcus thermophilus. Results obtained for 273 strains showed that bile salt hydrolase activity is common in Bifidobacterium and Lactobacillus but absent in L. lactis, Leu. mesenteroides, and S. thermophilus. Nearly all bifidobacteria species and strains have bile salt hydrolase activity, whereas this activity can only be found in selected species of lactobacilli. A strong correlation can be observed between the habitat of a genus or species and the presence of bile salt hydrolase activity. Most often bile salt hydrolase activity is found in strains that have been isolated from the intestines or from feces from mammals--an environment rich in conjugated and unconjugated bile acids. Strains and species from other habitats like milk or vegetables--environments from which bile salts are absent--do normally not have bile salt hydrolase activity. In two independent assays, we established that bile salt hydrolase activity in bifidobacteria is, in general, much higher than in lactobacilli.
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Affiliation(s)
- H Tanaka
- Snow Brand European Research Laboratories b.v., Groningen, The Netherlands
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21
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Arndt H, Kullmann F, Schölmerich J, Palitzsch KD. Acute and chronic effects of different bile acids on indomethacin-induced intestinal inflammation. Inflammation 1997; 21:553-67. [PMID: 9429904 DOI: 10.1023/a:1027390920570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The role of bile acids in the pathogenesis of bowel inflammation is unknown. The objective of this study was to determine whether urso- (UDC), cheno- (CDC), and taurochenodeoxycholic acid (TCDC) exert a pro- or antiinflammatory action in the acute and chronic phase of the indomethacin model of a long lasting ileitis in rats. Short-term and long-term inflammatory responses (48 h and 10 days, respectively) after two subcutaneous indomethacin (Indo) injections were elicited in rat small bowel and mesentery. To distinguish between common and model-specific effects bile acids were tested also in another model of acute inflammation induced by mesenteric superfusion with leukotriene B4(LTB4). The number of adherent and emigrated leukocytes, leukocyte rolling velocity, and venular wall shear rate were monitored in normal and inflamed postcapillary venules, and fecal pH of ileal contents which has been shown to correlate with degree of inflammation was measured, 6.5- and 2.3-fold increases in leukocyte adherence and comparable increments in leukocyte emigration were observed 48 h and ten days after indomethacin treatment, respectively. UDC, CDC, and TCDC (10 mg/kg) given daily from Indo administration until the experiment attenuated the leukocyte adherence and emigration responses elicited by indomethacin in short- and long-term inflammation. This effect was accompanied by a significant increase of fecal pH which had been lowered by indomethacin. None of the bile acids reduced the LTB4-induced increases in adherence and emigration. Oral administration of UDC, CDC, and TCDC reduces leukocyte adhesion and emigration in acute and chronic stages of Indo-induced inflammation. This could be due to the alkalizing effect of these bile acids on fecal pH which has been shown to correlate with a decrease of leukocyte-endothelial cell interactions but--according to the missing effectiveness in another model of intestinal inflammation--not to specific influences on leukocyte-endothelial cell adhesion.
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Affiliation(s)
- H Arndt
- Department of Internal Medicine I, University of Regensburg, Germany
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