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Sharma B, Agriantonis G, Twelker K, Ebelle D, Kiernan S, Siddiqui M, Soni A, Cheerasarn S, Simon W, Jiang W, Cardona A, Chapelet J, Agathis AZ, Gamboa A, Dave J, Mestre J, Bhatia ND, Shaefee Z, Whittington J. Gut Microbiota Serves as a Crucial Independent Biomarker in Inflammatory Bowel Disease (IBD). Int J Mol Sci 2025; 26:2503. [PMID: 40141145 PMCID: PMC11942158 DOI: 10.3390/ijms26062503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), is a complex intestinal disorder influenced by genetic, environmental, and microbial factors. Recent evidence highlights the gut microbiota as a pivotal biomarker and modulator in IBD pathogenesis. Dysbiosis, characterized by reduced microbial diversity and altered composition, is a hallmark of IBD. A consistent decrease in anti-inflammatory bacteria, such as Faecalibacterium prausnitzii, and an increase in pro-inflammatory species, including Escherichia coli, have been observed. Metabolomic studies reveal decreased short-chain fatty acids (SCFAs) and secondary bile acids, critical for gut homeostasis, alongside elevated pro-inflammatory metabolites. The gut microbiota interacts with host immune pathways, influencing morphogens, glycosylation, and podoplanin (PDPN) expression. The disruption of glycosylation impairs mucosal barriers, while aberrant PDPN activity exacerbates inflammation. Additionally, microbial alterations contribute to oxidative stress, further destabilizing intestinal barriers. These molecular and cellular disruptions underscore the role of the microbiome in IBD pathophysiology. Emerging therapeutic strategies, including probiotics, prebiotics, and dietary interventions, aim to restore microbial balance and mitigate inflammation. Advanced studies on microbiota-targeted therapies reveal their potential to reduce disease severity and improve patient outcomes. Nevertheless, further research is needed to elucidate the bidirectional interactions between the gut microbiome and host immune responses and to translate these insights into clinical applications. This review consolidates current findings on the gut microbiota's role in IBD, emphasizing its diagnostic and therapeutic implications, and advocates for the continued exploration of microbiome-based interventions to combat this debilitating disease.
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Affiliation(s)
- Bharti Sharma
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - George Agriantonis
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Kate Twelker
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Danielle Ebelle
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Samantha Kiernan
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
| | - Maham Siddiqui
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Aditi Soni
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Sittha Cheerasarn
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
| | - Whenzdjyny Simon
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Winston Jiang
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Angie Cardona
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
| | - Jessica Chapelet
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Alexandra Z. Agathis
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Alejandro Gamboa
- Department of Medicine, Medical University of the Americas, Devens, MA 01434, USA;
| | - Jasmine Dave
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Juan Mestre
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Navin D. Bhatia
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Zahra Shaefee
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Jennifer Whittington
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
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Lu D, Ma X, Tao K, Lei H. Advancements in the Pathogenesis, Diagnosis, and Therapeutic Implications of Intestinal Bacteria. Curr Issues Mol Biol 2025; 47:106. [PMID: 39996827 PMCID: PMC11853859 DOI: 10.3390/cimb47020106] [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: 12/31/2024] [Revised: 01/28/2025] [Accepted: 02/06/2025] [Indexed: 02/26/2025] Open
Abstract
Intestinal bacteria form one of the most complex microbial communities in the human body, playing a crucial role in maintaining host health and contributing to the development of various diseases. Here, we provide a comprehensive overview of the composition and function of intestinal bacteria, the factors affecting their homeostasis, and their association and mechanisms with a range of diseases (e.g., inflammatory bowel diseases, colorectal cancer, metabolic diseases). Additionally, their advanced potential in disease diagnosis and treatment is highlighted. Therapies, such as chemotherapy, radiotherapy, and immunotherapy, are significantly impacted by intestinal bacteria, with research indicating that bacteria can enhance chemoimmunotherapy efficiency by affecting T cell recruitment and immune cell infiltration. Fecal microbiota transplantation has emerged as a promising option for treating recurrent Clostridium difficile infections and certain metabolic and neurological disorders. Gut bacteria-related serum metabolites serve as non-invasive indicators for diagnosing CRC, while fecal immunochemical tests offer promising applications in CRC screening. Future research is needed to better understand the causal relationships between intestinal bacteria and diseases, develop more precise diagnostic tools, and evaluate the effectiveness and safety of microbiome-targeted therapies in clinical treatment. This study provides deeper insights into the role of intestinal bacteria in human health and disease, providing a scientific basis for innovative therapeutic strategies that have the potential to transform the landscape of healthcare.
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Affiliation(s)
| | | | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (D.L.); (X.M.)
| | - Hongwei Lei
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (D.L.); (X.M.)
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Ma Y, Yang H, Wang X, Huang Y, Li Y, Pan G. Bile acids as signaling molecules in inflammatory bowel disease: Implications for treatment strategies. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118968. [PMID: 39427739 DOI: 10.1016/j.jep.2024.118968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 09/21/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammatory bowel disease (IBD) is a globally increasing disease. Despite continuous efforts, the clinical application of treatment drugs has not achieved satisfactory success and faces limitations such as adverse drug reactions. Numerous investigations have found that the pathogenesis of IBD is connected with disturbances in bile acid circulation and metabolism. Traditional Chinese medicine targeting bile acids (BAs) has shown significant therapeutic effects and advantages in treating inflammatory bowel disease. AIM OF THIS REVIEW IThis article reviews the role of bile acids and their receptors in IBD, as well as research progress on IBD therapeutic drugs based on bile acids. It explores bile acid metabolism and its interaction with the intestinal microbiota, summarizes clinical drugs for treating IBD including single herbal medicine, traditional herbal prescriptions, and analyzes the mechanisms of action in treating IBD. MATERIALS AND METHODS IThe electronic databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) have been utilized to retrieve relevant literature up to January 2024, using keywords "bile acid", "bile acid receptor", "inflammatory bowel disease", "intestinal microbiota" and "targeted drugs". RESULTS IImbalance in bile acid levels can lead to intestinal inflammation, while IBD can disrupt the balance of microbes, result in alterations in the bile acid pool's composition and amount. This change can damage of intestinal mucosa healing ability. Bile acids are vital for keeping the gut barrier function intact, regulating gene expression, managing metabolic equilibrium, and influencing the properties and roles of the gut's microbial community. Consequently, focusing on bile acids could offer a potential treatment strategy for IBD. CONCLUSION IIBD can induce intestinal homeostasis imbalance and changes in BA pool, leading to fluctuations in levels of relevant metabolic enzymes, transporters, and nuclear receptors. Therefore, by regulating the balance of BA and key signaling molecules of bile acids, we can treat IBD. Traditional Chinese medicine has great potential and promising prospects in treating IBD. We should focus on the characteristics and advantages of Chinese medicine, promote the development and clinical application of innovative Chinese medicine, and ultimately make Chinese medicine targeting bile acids the mainstream treatment for IBD.
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Affiliation(s)
- Yueyue Ma
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Haoze Yang
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Xiaoming Wang
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Yuhong Huang
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300250, PR China
| | - Yuhong Li
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China.
| | - Guixiang Pan
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300250, PR China.
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Holani R, Bar-Yoseph H, Krekhno Z, Serapio-Palacios A, Moon KM, Stacey RG, Donald KA, Deng W, Bressler B, Magaña AA, Foster LJ, Atser MG, Johnson JD, Finlay B. Bile acid-induced metabolic changes in the colon promote Enterobacteriaceae expansion and associate with dysbiosis in Crohn's disease. Sci Signal 2024; 17:eadl1786. [PMID: 39689182 DOI: 10.1126/scisignal.adl1786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 06/10/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024]
Abstract
Bile acids (BAs) affect the growth of potentially pathogenic commensals, including those from the Enterobacteriaceae family, which are frequently overrepresented in inflammatory bowel disease (IBD). BAs are normally reabsorbed in the ileum for recycling and are often increased in the colonic lumina of patients with IBD, including those with Crohn's disease (CD). Here, we investigated the influence of BAs on gut colonization by Enterobacteriaceae. We found increased abundance of Enterobacteriaceae in the colonic mucosae of patients with CD with a concomitant decrease in the transporters that resorb BAs in the ileum. The increase in Enterobacteriaceae colonization was greater in the colons of patients who had undergone terminal ileum resection compared with those with intact ileum, leading us to hypothesize that BAs promote intestinal colonization by Enterobacteriaceae. Exposure of human colonic epithelial cell lines to BAs reduced mitochondrial respiration, increased oxygen availability, and enhanced the epithelial adherence of several Enterobacteriaceae members. In a publicly available human dataset, mucosal Enterobacteriaceae was negatively associated with the expression of genes related to mitochondrial function. In a murine model, increased intestinal BA availability enhanced colonization by Escherichia coli in a manner that depended on bacterial respiration. Together, our findings demonstrate that BAs reduce mitochondrial respiration in the colon, leading to an increase in oxygen availability that facilitates Enterobacteriaceae colonization. This identification of BAs as facilitators of host-commensal interactions may be relevant to multiple intestinal diseases.
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Affiliation(s)
- Ravi Holani
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Haggai Bar-Yoseph
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
- Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Zakhar Krekhno
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Antonio Serapio-Palacios
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kyung-Mee Moon
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Biochemistry and Molecular Biology Department, University of British Columbia, Vancouver, British Columbia, Canada
| | - Richard G Stacey
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
| | - Katherine A Donald
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Wanyin Deng
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Brian Bressler
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Armando A Magaña
- Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Leonard J Foster
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Biochemistry and Molecular Biology Department, University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael G Atser
- Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - James D Johnson
- Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Barton Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
- Biochemistry and Molecular Biology Department, University of British Columbia, Vancouver, British Columbia, Canada
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Walraven T, Busch M, Wang J, Donkers JM, Duijvestein M, van de Steeg E, Kramer NI, Bouwmeester H. Elevated risk of adverse effects from foodborne contaminants and drugs in inflammatory bowel disease: a review. Arch Toxicol 2024; 98:3519-3541. [PMID: 39249550 PMCID: PMC11489187 DOI: 10.1007/s00204-024-03844-w] [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: 06/04/2024] [Accepted: 08/19/2024] [Indexed: 09/10/2024]
Abstract
The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments.
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Affiliation(s)
- Tom Walraven
- Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands.
| | - Mathias Busch
- Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands
| | - Jingxuan Wang
- Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands
| | - Joanne M Donkers
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Marjolijn Duijvestein
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Evita van de Steeg
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Nynke I Kramer
- Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands
| | - Hans Bouwmeester
- Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands
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Shi Y, Zhong G, Huang H, Li N, Zeng J, Zhu J, Yuan J, Liang J. Comparative pharmacokinetics of five primary constituents in Huai-hua powder: a study on normal rats and rats with ulcerative colitis. J Pharm Pharmacol 2024; 76:1160-1168. [PMID: 38913100 DOI: 10.1093/jpp/rgae062] [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: 09/27/2023] [Accepted: 05/08/2024] [Indexed: 06/25/2024]
Abstract
OBJECTIVES The goal of this research was to develop a fast, reliable, and sensitive method to simultaneously quantify five key components of Huai-hua Powder (HHP) in rat plasma with genistein served as the internal standard. Furthermore, the established method was used to perform a comparative evaluation of the pharmacokinetic properties of HHP in normal rats and rats with ulcerative colitis (UC). METHODS Chromatographic separation was conducted using an ACQUITY HSS T3 column held at a constant temperature of 35°C, with acetonitrile and a 0.1% formic acid solution in water employed as the mobile phases. Multiple-reaction monitoring facilitated MS operation in positive-negative-ion-switching mode. The method's validation demonstrated exceptional linearity (with a correlation coefficient of r ≥ 0.9970), and the validation tests, encompassing precision within and between days, accuracy, recovery, matrix effect, and stability; all met the predefined acceptable criteria. KEY FINDINGS The results revealed significant variations in the pharmacokinetic characteristics of the five components between normal and UC rats, suggesting altered drug metabolism rates and extents in the latter group. CONCLUSIONS These findings offer crucial scientific insights into the potential clinical application of HHP, particularly in the context of treating UC.
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Affiliation(s)
- Yiwei Shi
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Guoyue Zhong
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Huilian Huang
- Key Lab of Modern Preparations of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Nazhi Li
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jinxiang Zeng
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jixiao Zhu
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jinbin Yuan
- Key Lab of Modern Preparations of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jian Liang
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
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Yang Y, Yu S, Rong H, Lei Z, Yang C, Wu H, Zhang T, Yang F, Nie Y, Chen L, Hu Q, Song Q, Guo J. Sodium sulphate ameliorates hypercholesterolemia via the upregulation of Cyp7a1 in hepatocytes and alleviates hepatic insulin resistance via the downregulation of Trib3 in mice with high cholesterol diets. Exp Ther Med 2024; 28:361. [PMID: 39071912 PMCID: PMC11273247 DOI: 10.3892/etm.2024.12650] [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: 07/02/2023] [Accepted: 12/06/2023] [Indexed: 07/30/2024] Open
Abstract
Amelioration of hypercholesterolemia is essential for the treatment of atherosclerotic cardiovascular disease. Sodium sulphate is the effective component of mirabilite, which has been used in traditional Chinese medicine for the treatment of various diseases. In the present study, C57BL/6 mice were fed with a high-cholesterol diet (HCD) for 7 weeks and were treated with sodium sulphate in the last three of those weeks. Sodium sulphate significantly reduced the total cholesterol level and the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio in the serum of mice fed the HCD. In addition, cytochrome P450 7a1 and 39a1 were significantly upregulated in the livers of mice treated with sodium sulphate. Furthermore, tribbles pseudokinase 3 expression was significantly increased in the livers of mice fed the HCD, but was significantly reduced by sodium sulphate treatment. In terms of the insulin signaling pathway, the ratio of phosphorylated AKT to total AKT in the livers of mice fed the HCD was significantly lower compared with that of control mice fed a normal diet, but was significantly increased by sodium sulphate treatment. Sodium sulphate treatment also reduced the levels of fibroblast growth factor (FGF)15 in the ileum and inhibited the FGF15/FGF receptor 4-Klotho β/c-Jun N-terminal kinase/c-Jun signaling pathway in the livers of mice fed the HCD. In addition, sodium sulphate changed the composition of the gut microbiota of mice fed the HCD. In conclusion, sodium sulphate may mitigate hypercholesterolemia and hepatic insulin resistance in mice fed an HCD.
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Affiliation(s)
- Yanhong Yang
- School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080, P.R. China
| | - Siping Yu
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
| | - Hedong Rong
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
| | - Zili Lei
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
| | - Changyuan Yang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
| | - Huijuan Wu
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
| | - Tianle Zhang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
| | - Fei Yang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
| | - Ya Nie
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
| | - Lei Chen
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
| | - Qing Hu
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
| | - Qi Song
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong 510006, P.R. China
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8
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Guo Z, Xu C, Fang Z, Yu X, Yang K, Liu C, Ning X, Dong Z, Liu C. Inflammatory bowel disease and breast cancer: A two-sample bidirectional Mendelian randomization study. Medicine (Baltimore) 2024; 103:e38392. [PMID: 38847661 PMCID: PMC11155618 DOI: 10.1097/md.0000000000038392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/08/2024] [Indexed: 06/10/2024] Open
Abstract
There is a correlation between IBD and breast cancer according to previous observational studies. However, so far there is no evidence to support if there is a causal relationship between these 2 diseases. We acquired comprehensive Genome-Wide Association Study (GWAS) summary data on IBD (including ulcerative colitis [UC] and Crohn disease [CD]) as well as breast cancer of completely European descent from the IEU GWAS database. The estimation of bidirectional causality between IBD (including UC and CD) and breast cancer was achieved through the utilization of 2-sample Mendelian randomization (MR). The MR results were also assessed for any potential bias caused by heterogeneity and pleiotropy through sensitivity analyses. Our study found a bidirectional causal effect between IBD and breast cancer. Genetic susceptibility to IBD was associated with an increased risk of breast cancer (OR = 1.053, 95% CI: 1.016-1.090, P = .004). Similarly, the presence of breast cancer may increase the risk of IBD (OR = 1.111, 95% CI: 1.035-1.194, P = .004). Moreover, the bidirectional causal effect between IBD and breast cancer can be confirmed by another GWAS of IBD. Subtype analysis showed that CD was associated with breast cancer (OR = 1.050, 95% CI: 1.020-1.080, P < .001), but not UC and breast cancer. There was a suggestive association between breast cancer and UC (OR = 1.106, 95% CI: 1.011-1.209, P = .028), but not with CD. This study supports a bidirectional causal effect between IBD and breast cancer. There appear to be considerable differences in the specific associations of UC and CD with AD. Understanding that IBD including its specific subtypes and breast cancer constitute common risk factors can contribute to the clinical management of both diseases.
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Affiliation(s)
- Zihao Guo
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Changyu Xu
- Department of Ultrasound, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhihao Fang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoxiao Yu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kai Yang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Changxu Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinwei Ning
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhichao Dong
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chang Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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9
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Gulnaz A, Lee KR, Kang MJ, Chang JE, Chae YJ. Roles of breast cancer resistance protein and organic anion transporting polypeptide 2B1 in gastrointestinal toxicity induced by SN-38 under inflammatory conditions. Toxicol Lett 2024; 394:57-65. [PMID: 38423481 DOI: 10.1016/j.toxlet.2024.02.011] [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: 09/19/2023] [Revised: 01/29/2024] [Accepted: 02/25/2024] [Indexed: 03/02/2024]
Abstract
Drug transporters are among the factors that determine the pharmacokinetic profiles after drug administration. In this study, we investigated the roles of drug transporters involved in transport of SN-38, which is an active metabolite of irinotecan, in the intestine under inflammatory conditions in vitro and determined their functional consequences. The expression alterations of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 2B1 were determined at the mRNA and protein levels, and the subsequent functional alterations were evaluated via an accumulation study with the representative transporter substrates [prazosin and dibromofluorescein (DBF)] and SN-38. We also determined the cytotoxicity of SN-38 under inflammatory conditions. Decreased BCRP expression and increased OATP2B1 expression were observed under inflammatory conditions in vitro, which led to altered accumulation profiles of prazosin, DBF, and SN-38, and the subsequent cytotoxic profiles of SN-38. Treatment with rifampin or novobiocin supported the significant roles of BCRP and OATP2B1 in the transport and cytotoxic profile of SN-38. Collectively, these results suggest that BCRP and OATP2B1 are involved in the increased cytotoxicity of SN-38 under inflammatory conditions in vitro. Further comprehensive research is warranted to completely understand SN-38-induced gastrointestinal cytotoxicity and aid in the successful treatment of cancer with irinotecan.
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Affiliation(s)
- Aneela Gulnaz
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Bioscience, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Min-Ji Kang
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Ji-Eun Chang
- College of Pharmacy, Dongduk Women's University, Seoul 02748, Republic of Korea
| | - Yoon-Jee Chae
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea; Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju 55338, Republic of Korea.
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10
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Di Ciaula A, Bonfrate L, Khalil M, Portincasa P. The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease. Intern Emerg Med 2023; 18:2181-2197. [PMID: 37515676 PMCID: PMC10635993 DOI: 10.1007/s11739-023-03343-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 06/08/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy.
| | - Mohamad Khalil
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
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11
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Wang J, Bakker W, de Haan L, Bouwmeester H. Deoxynivalenol increases pro-inflammatory cytokine secretion and reduces primary bile acid transport in an inflamed intestinal in vitro co-culture model. Food Res Int 2023; 173:113323. [PMID: 37803634 DOI: 10.1016/j.foodres.2023.113323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 10/08/2023]
Abstract
The fungal secondary metabolite deoxynivalenol (DON) that can contaminate cereal-based food products not only induces inflammation but also reduces bile acid absorption by a healthy human intestine. Bile acid malabsorption is commonly observed in individuals with an inflamed intestine. Here we studied the effects of DON on inflammation and primary bile acid transport using an in vitro model for an inflamed intestine. An inflamed intestinal in vitro model was established by co-culturing a Caco-2 cell-layer and LPS-pre-stimulated THP-1 macrophages in Transwells. We observed a decreased transport of 5 primary bile acids across inflamed co-cultures compared to healthy co-cultures but not of chenodeoxycholic acid. DON exposure further reduced the transport of the affected primary bile acids across the inflamed co-cultures. DON exposure also enhanced the secretion of pro-inflammatory cytokines in the inflamed co-cultures, while it did not increase the pro-inflammatory cytokines secretion from LPS-pre-stimulated THP-1 monocultures. Exposure of Caco-2 cell-layers to pro-inflammatory cytokines or THP-1 conditioned media partly mimicked the DON-induced effects of the co-culture model. Local activation of intestinal immune cells reinforces the direct pro-inflammatory effects of DON on intestinal epithelial cells. This affects the bile acid intestinal kinetics in an inflamed intestine.
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Affiliation(s)
- Jingxuan Wang
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands.
| | - Wouter Bakker
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Laura de Haan
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Hans Bouwmeester
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
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12
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Comito R, Porru E, Interino N, Conti M, Terragni R, Gotti R, Candela M, Simoni P, Roda A, Fiori J. Metabolic Bile Acid Profile Impairments in Dogs Affected by Chronic Inflammatory Enteropathy. Metabolites 2023; 13:980. [PMID: 37755260 PMCID: PMC10535270 DOI: 10.3390/metabo13090980] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/22/2023] [Accepted: 08/28/2023] [Indexed: 09/28/2023] Open
Abstract
Bile acids (BAs), endogenous acidic steroids synthetized from cholesterol in the liver, play a key role in the gut-liver axis physiopathology, including in hepatotoxicity, intestinal inflammatory processes, and cholesterol homeostasis. Faecal Oxo-BAs, relatively stable intermediates of oxidation/epimerization reactions of the BA hydroxyls, could be relevant to investigating the crosstalk in the liver-gut axis and the relationship between diseases and alterations in microbiota composition. A paucity of information currently exists on faecal BA profiles in dogs with and without chronic inflammatory enteropathy (CIE). Comprehensive assessment of 31 molecules among faecal BAs and related microbiota metabolites was conducted with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Odds ratios (ORs) for associations of BAs with CIE were estimated using logistic regression. Principal component analysis was performed to find differences between the control and pathological dogs. Higher levels of primary BAs and muricholic acids, and lower levels of secondary BAs were found in pathological dogs. Higher concentrations in faecal oxo-metabolites were associated with the absence of CIE (OR < 1). This study shows a marked difference in faecal BA profiles between dogs with and without CIE. Further research will be needed to better understand the role of oxo-BAs and muricholic acids in CIE dogs.
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Affiliation(s)
- Rossana Comito
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.C.); (E.P.); (P.S.)
- Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy;
| | - Emanuele Porru
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.C.); (E.P.); (P.S.)
- Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy;
| | - Nicolò Interino
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy;
| | - Matteo Conti
- Department of Public Health, Local Unit of Imola, Health Service of the Emilia-Romagna Region, 40026 Imola, Italy;
| | - Rossella Terragni
- Veterinary Clinic dell’Orologio/Veterinary Oncology Center, 40100 Bologna, Italy;
| | - Roberto Gotti
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (R.G.); (M.C.)
| | - Marco Candela
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (R.G.); (M.C.)
| | - Patrizia Simoni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy; (R.C.); (E.P.); (P.S.)
| | - Aldo Roda
- Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy;
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy;
| | - Jessica Fiori
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy;
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13
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Long XQ, Liu MZ, Liu ZH, Xia LZ, Lu SP, Xu XP, Wu MH. Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease. World J Gastroenterol 2023; 29:4252-4270. [PMID: 37545642 PMCID: PMC10401658 DOI: 10.3748/wjg.v29.i27.4252] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/19/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
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Affiliation(s)
- Xiong-Quan Long
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Zhu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Zi-Hao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Lv-Zhou Xia
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Shi-Peng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Xiao-Ping Xu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
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14
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Li S, Xu K, Cheng Y, Chen L, Yi A, Xiao Z, Zhao X, Chen M, Tian Y, Meng W, Tang Z, Zhou S, Ruan G, Wei Y. The role of complex interactions between the intestinal flora and host in regulating intestinal homeostasis and inflammatory bowel disease. Front Microbiol 2023; 14:1188455. [PMID: 37389342 PMCID: PMC10303177 DOI: 10.3389/fmicb.2023.1188455] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/10/2023] [Indexed: 07/01/2023] Open
Abstract
Pharmacological treatment of inflammatory bowel disease (IBD) is inefficient and difficult to discontinue appropriately, and enterobacterial interactions are expected to provide a new target for the treatment of IBD. We collected recent studies on the enterobacterial interactions among the host, enterobacteria, and their metabolite products and discuss potential therapeutic options. Intestinal flora interactions in IBD are affected in the reduced bacterial diversity, impact the immune system and are influenced by multiple factors such as host genetics and diet. Enterobacterial metabolites such as SCFAs, bile acids, and tryptophan also play important roles in enterobacterial interactions, especially in the progression of IBD. Therapeutically, a wide range of sources of probiotics and prebiotics exhibit potential therapeutic benefit in IBD through enterobacterial interactions, and some have gained wide recognition as adjuvant drugs. Different dietary patterns and foods, especially functional foods, are novel therapeutic modalities that distinguish pro-and prebiotics from traditional medications. Combined studies with food science may significantly improve the therapeutic experience of patients with IBD. In this review, we provide a brief overview of the role of enterobacteria and their metabolites in enterobacterial interactions, discuss the advantages and disadvantages of the potential therapeutic options derived from such metabolites, and postulate directions for further research.
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Affiliation(s)
- Siyu Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Basic Medicine College of Army Medical University, Army Medical University, Chongqing, China
| | - Kan Xu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Basic Medicine College of Army Medical University, Army Medical University, Chongqing, China
| | - Yi Cheng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lu Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ailin Yi
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhifeng Xiao
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xuefei Zhao
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Minjia Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yuting Tian
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wei Meng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zongyuan Tang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shuhong Zhou
- Department of Laboratory Animal Center, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guangcong Ruan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yanling Wei
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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15
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Wang J, Sijs B, Bakker W, de Haan L, Bouwmeester H. Ribotoxin deoxynivalenol induces taurocholic acid malabsorption in an in vitro human intestinal model. Toxicol Lett 2023; 383:S0378-4274(23)00201-1. [PMID: 37315771 DOI: 10.1016/j.toxlet.2023.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/23/2023] [Accepted: 06/10/2023] [Indexed: 06/16/2023]
Abstract
The trichothecene toxin deoxynivalenol (DON) is a ribotoxic mycotoxin that contaminates cereal-based food. DON binds to ribosomes, thereby inhibiting protein translation and activating stress mitogen-activated protein kinases (MAPK). The activation of MAPK induces pro-inflammatory cytokine production. Emerging evidence showed that DON decreased bile acid reabsorption and apical sodium-dependent bile acid transporter (ASBT) expression in Caco-2 cell layers. We hypothesized that the effect of DON on decreased ASBT mRNA expression is regulated via pro-inflammatory cytokines. We observed that MAPK inhibitors prevented DON to induce IL-8 secretion and prevented the DON-induced downregulation of ASBT mRNA expression. However, DON-induced taurocholic acid (TCA) transport reduction was not prevent by the MAPK inhibitors. We next observed a similarity between the activity of the non-inflammatory ribotoxin cycloheximide and DON to decrease TCA transport, which is consistent with their common ability to inhibit protein synthesis. Together, our results suggest that DON-induced TCA malabsorption is regulated by MAPK activation-induced pro-inflammatory cytokine production and protein synthesis inhibition, both of which are initiated by DON binding to the ribosomes which therefore is the molecular initiating event for the adverse outcome of bile acid malabsorption. This study provides insights into the mechanism of ribotoxins-induced bile acid malabsorption in human intestine.
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Affiliation(s)
- Jingxuan Wang
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands.
| | - Bas Sijs
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Wouter Bakker
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Laura de Haan
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Hans Bouwmeester
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
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16
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Wu EH, Guo Z, Zhu WM. Postoperative diarrhea in Crohn's disease: Pathogenesis, diagnosis, and therapy. World J Clin Cases 2023; 11:7-16. [PMID: 36687182 PMCID: PMC9846968 DOI: 10.12998/wjcc.v11.i1.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/08/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023] Open
Abstract
Diarrhea is a frequent symptom in postoperative patients with Crohn's diseases (CD), and several different mechanisms likely account for postoperative diarrhea in CD. A targeted strategy based on a comprehensive understanding of postoperative diarrhea is helpful for better postoperative recovery.
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Affiliation(s)
- En-Hao Wu
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen Guo
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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17
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Manoharan N, Parasuraman R, Jayamurali D, Govindarajulu SN. The therapeutic role of microbial metabolites in human health and diseases. RECENT ADVANCES AND FUTURE PERSPECTIVES OF MICROBIAL METABOLITES 2023:1-38. [DOI: 10.1016/b978-0-323-90113-0.00002-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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18
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The impact of inflammation on the expression of drug transporters and metabolic enzymes in colonic tissue from ulcerative colitis patients. Int J Pharm 2022; 628:122282. [DOI: 10.1016/j.ijpharm.2022.122282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/04/2022] [Accepted: 10/07/2022] [Indexed: 12/08/2022]
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19
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Li L, Liu T, Gu Y, Wang X, Xie R, Sun Y, Wang B, Cao H. Regulation of gut microbiota-bile acids axis by probiotics in inflammatory bowel disease. Front Immunol 2022; 13:974305. [PMID: 36211363 PMCID: PMC9539765 DOI: 10.3389/fimmu.2022.974305] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammation of gastrointestinal tract, with steadily increased incidence and prevalence worldwide. Although the precise pathogenesis remains unclear, gut microbiota, bile acids (BAs), and aberrant immune response play essential roles in the development of IBD. Lately, gut dysbiosis including certain decreased beneficial bacteria and increased pathogens and aberrant BAs metabolism have been reported in IBD. The bacteria inhabited in human gut have critical functions in BA biotransformation. Patients with active IBD have elevated primary and conjugated BAs and decreased secondary BAs, accompanied by the impaired transformation activities (mainly deconjugation and 7α-dehydroxylation) of gut microbiota. Probiotics have exhibited certain positive effects by different mechanisms in the therapy of IBD. This review discussed the effectiveness of probiotics in certain clinical and animal model studies that might involve in gut microbiota-BAs axis. More importantly, the possible mechanisms of probiotics on regulating gut microbiota-BAs axis in IBD were elucidated, which we focused on the elevated gut bacteria containing bile salt hydrolase or BA-inducible enzymes at genus/species level that might participate in the BA biotransformation. Furthermore, beneficial effects exerted by activation of BA-activated receptors on intestinal immunity were also summarized, which might partially explain the protect effects and mechanisms of probiotics on IBD. Therefore, this review will provide new insights into a better understanding of probiotics in the therapy targeting gut microbiota-BAs axis of IBD.
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Boix-Amorós A, Monaco H, Sambataro E, Clemente JC. Novel technologies to characterize and engineer the microbiome in inflammatory bowel disease. Gut Microbes 2022; 14:2107866. [PMID: 36104776 PMCID: PMC9481095 DOI: 10.1080/19490976.2022.2107866] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
We present an overview of recent experimental and computational advances in technology used to characterize the microbiome, with a focus on how these developments improve our understanding of inflammatory bowel disease (IBD). Specifically, we present studies that make use of flow cytometry and metabolomics assays to provide a functional characterization of microbial communities. We also describe computational methods for strain-level resolution, temporal series, mycobiome and virome data, co-occurrence networks, and compositional data analysis. In addition, we review novel techniques to therapeutically manipulate the microbiome in IBD. We discuss the benefits and drawbacks of these technologies to increase awareness of specific biases, and to facilitate a more rigorous interpretation of results and their potential clinical application. Finally, we present future lines of research to better characterize the relation between microbial communities and IBD pathogenesis and progression.
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Affiliation(s)
- Alba Boix-Amorós
- Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY, USA
| | - Hilary Monaco
- Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY, USA
| | - Elisa Sambataro
- Department of Biological Sciences, CUNY Hunter College, New York, NY, USA
| | - Jose C. Clemente
- Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY, USA,CONTACT Jose C. Clemente Department of Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai. New York, NY10029USA
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21
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Alrubia S, Mao J, Chen Y, Barber J, Rostami-Hodjegan A. Altered Bioavailability and Pharmacokinetics in Crohn's Disease: Capturing Systems Parameters for PBPK to Assist with Predicting the Fate of Orally Administered Drugs. Clin Pharmacokinet 2022; 61:1365-1392. [PMID: 36056298 PMCID: PMC9553790 DOI: 10.1007/s40262-022-01169-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2022] [Indexed: 12/12/2022]
Abstract
Backgrond and Objective Crohn’s disease (CD) is a chronic inflammatory bowel disease that affects a wide age range. Hence, CD patients receive a variety of drugs over their life beyond those used for CD itself. The changes to the integrity of the intestine and its drug metabolising enzymes and transporters (DMETs) can alter the oral bioavailability of drugs. However, there are other changes in systems parameters determining the fate of drugs in CD, and understanding these is essential for dose adjustment in patients with CD. Methods The current analysis gathered all the available clinical data on the kinetics of drugs in CD (by March 2021), focusing on orally administered small molecule drugs. A meta-analysis of the systems parameters affecting oral drug pharmacokinetics was conducted. The systems information gathered on intestine, liver and blood proteins and other physiological parameters was incorporated into a physiologically based pharmacokinetic (PBPK) platform to create a virtual population of CD patients, with a view for guiding dose adjustment in the absence of clinical data in CD. Results There were no uniform trends in the reported changes in reported oral bioavailability. The nature of the drug as well as the formulation affected the direction and magnitude of variation in kinetics in CD patients relative to healthy volunteers. Even for the same drug, the reported changes in exposure varied, possibly due to a lack of distinction between the activity states of CD. The highest alteration was seen with S-verapamil and midazolam, 8.7- and 5.3-fold greater exposure, respectively, in active CD patients relative to healthy volunteers. Only one report was available on liver DMETs in CD, and indicated reduced CYP3A4 activity. In a number of reports, mRNA expression of DMETs in the ileum and colon of CD patients was measured, focussing on P-glycoprotein (p-gp) transporter and CYP3A4 enzyme, and showed contradictory results. No data were available on protein expression in duodenum and jejunum despite their dominant role in oral drug absorption. Conclusion There are currently inadequate dedicated clinical or quantitative proteomic studies in CD to enable predictive PBPK models with high confidence and adequate verification. The PBPK models for CD with the available systems parameters were able to capture the major physiological influencers and the gaps to be filled by future research. Quantification of DMETs in the intestine and the liver in CD is warranted, alongside well-defined clinical drug disposition studies with a number of index drugs as biomarkers of changes in DMETs in these patients, to avoid large-scale dedicated studies for every drug to determine the effects of disease on the drug’s metabolism and disposition and the consequential safety and therapeutic concerns. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01169-4.
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Affiliation(s)
- Sarah Alrubia
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.,Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Jialin Mao
- Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Yuan Chen
- Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK. .,Certara UK Ltd, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, UK.
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22
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Huang L, Zheng J, Sun G, Yang H, Sun X, Yao X, Lin A, Liu H. 5-Aminosalicylic acid ameliorates dextran sulfate sodium-induced colitis in mice by modulating gut microbiota and bile acid metabolism. Cell Mol Life Sci 2022; 79:460. [PMID: 35913641 PMCID: PMC11071811 DOI: 10.1007/s00018-022-04471-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/27/2022] [Accepted: 07/04/2022] [Indexed: 11/03/2022]
Abstract
Colitis develops via the convergence of environmental, microbial, immunological, and genetic factors. The medicine 5-aminosalicylic acid (5-ASA) is widely used in clinical practice for colitis (especially ulcerative colitis) treatment. However, the significance of gut microbiota in the protective effect of 5-ASA on colitis has not been explored. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we found that 5-ASA ameliorated colitis symptoms in DSS-treated mice, accompanied by increased body weight gain and colon length, and a decrease in disease activity index (DAI) score and spleen index. Also, 5-ASA alleviated DSS-induced damage to colonic tissues, as indicated by suppressed inflammation and decreased tight junction, mucin, and water-sodium transport protein levels. Moreover, the 16S rDNA gene sequencing results illustrated that 5-ASA reshaped the disordered gut microbiota community structure in DSS-treated mice by promoting the abundance of Bifidobacterium, Lachnoclostridium, and Anaerotruncus, and reducing the content of Alloprevotella and Desulfovibrio. Furthermore, 5-ASA improved the abnormal metabolism of bile acids (BAs) by regulating the Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5) signaling pathways in DSS-treated mice. In contrast, 5-ASA did not prevent the occurrence of colitis in mice with gut microbiota depletion, confirming the essential role of gut microbiota in colitis treatment by 5-ASA. In conclusion, 5-ASA can ameliorate DSS-induced colitis in mice by modulating gut microbiota and bile acid metabolism. These findings documented the new therapeutic mechanisms of 5-ASA in clinical colitis treatment.
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Affiliation(s)
- Ling Huang
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, People's Republic of China
- China Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, People's Republic of China
| | - Junping Zheng
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, People's Republic of China
| | - Guangjun Sun
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, People's Republic of China
| | - Huabing Yang
- China Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, People's Republic of China
| | - Xiongjie Sun
- China Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, People's Republic of China
| | - Xiaowei Yao
- China Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, People's Republic of China
| | - Aizhen Lin
- China Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, People's Republic of China.
| | - Hongtao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, People's Republic of China.
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Alrubia S, Al-Majdoub ZM, Achour B, Rostami-Hodjegan A, Barber J. Quantitative Assessment of the Impact of Crohn's Disease on Protein Abundance of Human Intestinal Drug-Metabolising Enzymes and Transporters. J Pharm Sci 2022; 111:2917-2929. [PMID: 35872023 DOI: 10.1016/j.xphs.2022.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/17/2022] [Accepted: 07/17/2022] [Indexed: 10/17/2022]
Abstract
Crohn's disease affects the mucosal layer of the intestine, predominantly ileum and colon segments, with the potential to affect the expression of intestinal enzymes and transporters, and consequently, oral drug bioavailability. We carried out a quantitative proteomic analysis of inflamed and non-inflamed ileum and colon tissues from Crohn's disease patients and healthy donors. Homogenates from samples in each group were pooled and protein abundance determined by liquid chromatography-mass spectrometry (LC-MS). In inflamed Crohn's ileum, CYP3A4, CYP20A1, CYP51A1, ADH1B, ALPI, FOM1, SULT1A2, SULT1B1 and ABCB7 showed ≥10-fold reduction in abundance compared with healthy baseline. By contrast, only MGST1 showed ≥10 fold reduction in inflamed colon. Ileal UGT1A1, MGST1, MGST2, and MAOA levels increased by ≥2 fold in Crohn's patients, while only ALPI showed ≥2 fold increase in the colon. Counter-intuitively, non-inflamed ileum had a higher magnitude of fold change than inflamed tissue when compared with healthy tissue. Marked but non-uniform alterations were observed in the expression of various enzymes and transporters in ileum and colon compared with healthy samples. Modelling will allow improved understanding of the variable effects of Crohn's disease on bioavailability of orally administered drugs.
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Affiliation(s)
- Sarah Alrubia
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK; Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
| | - Brahim Achour
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island, USA
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK; Certara UK Ltd, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, UK
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
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Role of Bile Acids and Nuclear Receptors in Acupuncture in Improving Crohn's Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5814048. [PMID: 35600949 PMCID: PMC9122672 DOI: 10.1155/2022/5814048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/13/2021] [Accepted: 04/15/2022] [Indexed: 11/30/2022]
Abstract
Nuclear receptors (NRs) are ligand-dependent transcription factors that regulate the transcription of target genes. Bile acids (BAs) can be used as effector molecules to regulate physiological processes in the gut, and NRs are important receptors for bile acid signaling. Relevant studies have shown that NRs are closely related to the occurrence of Crohn's disease (CD). Although the mechanism of NRs in CD has not been clarified completely, growing evidence shows that NRs play an important role in regulating intestinal immunity, mucosal barrier, and intestinal flora. NRs can participate in the progress of CD by mediating inflammation, immunity, and autophagy. As the important parts of traditional Chinese medicine (TCM) therapy, acupuncture and moxibustion in the treatment of CD curative mechanism can get a lot of research support. At the same time, acupuncture and moxibustion can regulate the changes of related NRs. Therefore, to explore whether acupuncture can regulate BA circulation and NRs expression and then participate in the disease progression of CD, a new theoretical basis for acupuncture treatment of CD is provided.
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25
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A potent HNF4α agonist reveals that HNF4α controls genes important in inflammatory bowel disease and Paneth cells. PLoS One 2022; 17:e0266066. [PMID: 35385524 PMCID: PMC8985954 DOI: 10.1371/journal.pone.0266066] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/11/2022] [Indexed: 11/19/2022] Open
Abstract
HNF4α has been implicated in IBD through a number of genome-wide association studies. Recently, we developed potent HNF4α agonists, including N-trans caffeoyltyramine (NCT). NCT was identified by structural similarity to previously the previously identified but weak HNF4α agonists alverine and benfluorex. Here, we administered NCT to mice fed a high fat diet, with the goal of studying the role of HNF4α in obesity-related diseases. Intestines from NCT-treated mice were examined by RNA-seq to determine the role of HNF4α in that organ. Surprisingly, the major classes of genes altered by HNF4α were involved in IBD and Paneth cell biology. Multiple genes downregulated in IBD were induced by NCT. Paneth cells identified by lysozyme expression were reduced in high fat fed mice. NCT reversed the effect of high fat diet on Paneth cells, with multiple markers being induced, including a number of defensins, which are critical for Paneth cell function and intestinal barrier integrity. NCT upregulated genes that play important role in IBD and that are downregulated in that disease. It reversed the loss of Paneth cell markers that occurred in high fat diet fed mice. These data suggest that HNF4α could be a therapeutic target for IBD and that the agonists that we have identified could be candidate therapeutics.
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26
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Bile Acids and the Microbiome: Making Sense of This Dynamic Relationship in Their Role and Management in Crohn's Disease. Can J Gastroenterol Hepatol 2022; 2022:8416578. [PMID: 35360442 PMCID: PMC8964223 DOI: 10.1155/2022/8416578] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/05/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Bile acids help maintain the physiological balance of the gut microbiome and the integrity of the intestinal epithelial barrier. Similarly, intestinal bacteria play a major role in bile acid metabolism as they are involved in crucial biotransformation steps in the enterohepatic circulation pathway. Understanding the relationship between bile acid signalling and the gut microbiome in Crohn's disease can help target new and innovative treatment strategies. AIMS This review summarises the relationship between bile acids and the microbiome in Crohn's disease and discusses potential novel therapeutic options. METHODS We performed a literature review on bile acid signalling, its effect on the gut microbiome, and therapeutic applications in Crohn's disease. RESULTS Current research suggests that there is a strong interplay between the dysregulated microbiota, bile acid metabolism, and the mucosal immune system that can result in a changed immunological function, triggering the inflammatory response in Crohn's disease. Recent studies have demonstrated an association with altering the enterohepatic circulation and activating the farnesoid X receptor signalling pathway with the use of probiotics and faecal microbial transplantation, respectively. Bile acid sequestrants have been shown to have anti-inflammatory, cytoprotective, and anti-apoptotic properties with the potential to alter the intestinal microbial composition, suggesting a possible role in inducing and maintaining Crohn's disease. CONCLUSIONS Active Crohn's disease has been correlated with changes in bacterial concentrations, which may be associated with changes in bile acid modification. Further research should focus on targeting these areas for future therapeutic options.
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27
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Li J, Zhang Y, Yu M, Wang A, Qiu Y, Fan W, Hovgaard L, Yang M, Li Y, Wang R, Li X, Gan Y. The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery. Acta Pharm Sin B 2022; 12:1460-1472. [PMID: 35530154 PMCID: PMC9072239 DOI: 10.1016/j.apsb.2021.07.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/10/2021] [Accepted: 07/13/2021] [Indexed: 11/29/2022] Open
Abstract
Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.
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Affiliation(s)
- Jingyi Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yaqi Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Miaorong Yu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Aohua Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yu Qiu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Weiwei Fan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Lars Hovgaard
- Oral Formulation Development, Novo Nordisk A/S, Maalov 2760, Denmark
| | - Mingshi Yang
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Yiming Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Rui Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Corresponding authors. Tel.: +86 021 51322181, fax: +86 021 51322193 (Rui Wang); Tel.: +01 972 883 4480, fax: +01 972 883 4440 (Xiuying Li); Tel.: +86 021 20231975, fax: +86 021 20231000 1425 (Yong Gan).
| | - Xiuying Li
- University of Texas at Dallas, Richardson, TX 75080, USA
- Corresponding authors. Tel.: +86 021 51322181, fax: +86 021 51322193 (Rui Wang); Tel.: +01 972 883 4480, fax: +01 972 883 4440 (Xiuying Li); Tel.: +86 021 20231975, fax: +86 021 20231000 1425 (Yong Gan).
| | - Yong Gan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, National Institutes for Food and Drug Control, Beijing 100050, China
- Corresponding authors. Tel.: +86 021 51322181, fax: +86 021 51322193 (Rui Wang); Tel.: +01 972 883 4480, fax: +01 972 883 4440 (Xiuying Li); Tel.: +86 021 20231975, fax: +86 021 20231000 1425 (Yong Gan).
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28
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Núñez F P, Castro F, Mezzano G, Quera R, Diaz D, Castro L. Hepatobiliary manifestations in inflammatory bowel disease: A practical approach. World J Hepatol 2022; 14:319-337. [PMID: 35317174 PMCID: PMC8891676 DOI: 10.4254/wjh.v14.i2.319] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/10/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. They can occur at any moment in the course of the disease or associated with the treatment. The prevalence of liver dysfunction can reach up to 50% in different studies. Nonalcoholic fatty liver disease is considered the most common hepatobiliary complication in IBD, while primary sclerosing cholangitis is the most specific. Management of hepatic manifestations in IBD involves a multidisciplinary approach that includes a high index of suspicion and joint management with hepatologists. The medical confrontation with abnormal liver tests must include an exhaustive study to determine if these patterns can be related to IBD, associated diseases or to the therapies used.
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Affiliation(s)
- Paulina Núñez F
- Universidad de los Andes,Inflammatory Bowel Disease Program, Digestive Disease Center, Santiago 7600976, RM, Chile
- Inflammatory Bowel Disease Program, Hospital San Juan de Dios, Universidad de Chile, Santiago 7701230, RM, Chile
| | - Fabiola Castro
- Universidad de los Andes,Hepatology Program, Digestive Disease Center, Santiago 7600976, RM, Chile
| | - Gabriel Mezzano
- Universidad de los Andes,Hepatology Program, Digestive Disease Center, Santiago 7600976, RM, Chile
- Department of Gastroenterology, Hospital del Salvador/Universidad de Chile, Santiago 7600976, RM, Chile
| | - Rodrigo Quera
- Universidad de los Andes,Inflammatory Bowel Disease Program, Digestive Disease Center, Santiago 7600976, RM, Chile
| | - Diego Diaz
- Medicine, Universidad de los Andes, Santiago 770976, RM, Chile
| | - Lorena Castro
- Universidad de los Andes,Hepatology Program, Digestive Disease Center, Santiago 7600976, RM, Chile
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29
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Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates. Front Pharmacol 2022; 12:802539. [PMID: 35095509 PMCID: PMC8793843 DOI: 10.3389/fphar.2021.802539] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022] Open
Abstract
Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.
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Affiliation(s)
- Erkka Järvinen
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Feng Deng
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Wilma Kiander
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Alli Sinokki
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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Simultaneous Determination of Ten Bioactive Components from Shenling Baizhu San in Rat Plasma by UHPLC-MS/MS: Application to a Comparative Pharmacokinetic Study in Normal and Two Models of Ulcerative Colitis Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2021:3518241. [PMID: 35003297 PMCID: PMC8731286 DOI: 10.1155/2021/3518241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022]
Abstract
Shenling Baizhu San, a traditional formula, has a long history of treating spleen asthenic diarrhea by invigorating the spleen and dispelling dampness in China. A rapid and accurate UHPLC-MS/MS method was developed and fully validated for the simultaneous determination of ten active constituents in rat plasma: panaxadiol, ginsenoside Rg1, atractylenolide I, atractylenolide III, pachymic acid, neferine, nuciferine, diosgenin, platycodin D, and isoliquiritigenin. The plasma samples were pretreated by the protein precipitation method with acetonitrile. The analytes and puerarin (internal standard) were determined with high selectivity and sensitivity (LLOQ, 0.31–0.68 ng·mL−1) within 10 minutes. The validation parameters, including intra-/interday precisions, accuracy, recovery, matrix effect, and stability, were within acceptable ranges. The validated method was successfully applied to the pharmacokinetics study of ten components in normal and two rat models of ulcerative colitis (i.e., spleen deficiency with dampness retention-ulcerative colitis (SDDR-UC) rats and pure-ulcerative colitis (P-UC) rats). The pharmacokinetic parameters were significantly different among the three groups of rats. Overall, the absorption of the components was shown as follows: normal group > SDDR-UC group > P-UC group. The study could provide a scientific basis for further studies on pharmacokinetics and clinical differential application of SDDR-UC and P-UC patients.
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Gong C, Xu R, Zou P, Zhang Y, Wang X. Inflammatory bowel disease and risk of breast cancer: a meta-analysis of cohort studies. Eur J Cancer Prev 2022; 31:54-63. [PMID: 34871199 DOI: 10.1097/cej.0000000000000667] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Inflammatory bowel disease (IBD) has been found to be correlated to increased risk of both gastrointestinal and extraintestinal malignancies. It still remains conflicting whether IBD has influence on risk of breast cancer, requesting further investigations. A systematic literature research before June 2020 was conducted in PubMed and Web of Science databases. Observational studies reporting incident breast cancer after IBD diagnosis and providing measures of association were included in the meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the associations between IBD and risk of breast cancer. Our analysis included 16 cohort studies and the overall pooled OR in patients with IBD was 0.94 (95% CI, 0.82-1.06). In further subgroup analysis, no significant association with breast cancer risk among patients with Crohn's disease (OR, 0.91; 95% CI, 0.70-1.12) and ulcerative colitis (OR, 0.99; 95% CI, 0.90-1.08). For geographic differences, the summary OR of populations in Asia (OR, 1.01; 95% CI, 0.73-1.30) was only numerically larger than that in European populations (OR, 0.90; 95% CI, 0.75-1.06). Our findings indicated that IBD had no significant influence on breast cancer risk regardless of different IBD types and geographical areas.
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Affiliation(s)
- Can Gong
- Department of Breast Surgery, West China Hospital, Sichuan University
| | - Renyuan Xu
- Department of Breast Surgery, West China Hospital, Sichuan University
| | - Ping Zou
- Department of Breast Surgery, The People's Hospital of Pengzhou, Chengdu, Sichuan Province, China
| | - Yuna Zhang
- Department of Breast Surgery, West China Hospital, Sichuan University
| | - Xiaodong Wang
- Department of Breast Surgery, West China Hospital, Sichuan University
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Ma Y, Nenkov M, Chen Y, Press AT, Kaemmerer E, Gassler N. Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis. World J Hepatol 2021; 13:1512-1533. [PMID: 34904027 PMCID: PMC8637682 DOI: 10.4254/wjh.v13.i11.1512] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/28/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis, designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.
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Affiliation(s)
- Yunxia Ma
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Miljana Nenkov
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Elke Kaemmerer
- Department of Pediatrics, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany.
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Dunvald ACD, Järvinen E, Mortensen C, Stage TB. Clinical and Molecular Perspectives on Inflammation-Mediated Regulation of Drug Metabolism and Transport. Clin Pharmacol Ther 2021; 112:277-290. [PMID: 34605009 DOI: 10.1002/cpt.2432] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022]
Abstract
Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug-metabolizing enzymes and transporters (DMETs) in humans. Here, we evaluate the clinical and in vitro evidence on inflammation-mediated modulation of DMETs, and the impact on drug metabolism in humans. Furthermore, we identify and discuss the gaps in our current knowledge. A systematic literature search on PubMed, Embase, and grey literature was performed in the period of February to September 2020. A total of 203 papers was included. In vitro studies in primary human hepatocytes revealed strong evidence that CYP3A4 is strongly downregulated by inflammatory cytokines IL-6 and IL-1β. CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were downregulated to a lesser extent. In clinical studies, acute and chronic inflammatory diseases were observed to cause downregulation of CYP enzymes in a similar pattern. However, there is no clear correlation between in vitro studies and clinical studies, mainly because most in vitro studies use supraphysiological cytokine doses. Moreover, clinical studies demonstrate considerable variability in terms of methodology and inconsistencies in evaluation of the inflammatory state. In conclusion, we find inflammation and pro-inflammatory cytokines to be important factors in regulation of drug-metabolizing enzymes and transporters. The observed downregulation is clinically relevant, and we emphasize caution when treating patients in an inflammatory state with narrow therapeutic index drugs. Further research is needed to identify the full extent of inflammation-mediated changes in DMETs and to further support personalized medicine.
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Affiliation(s)
- Ann-Cathrine Dalgård Dunvald
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense C, Denmark
| | - Erkka Järvinen
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense C, Denmark
| | - Christina Mortensen
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense C, Denmark
| | - Tore B Stage
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense C, Denmark
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Li M, Lan L, Zhang S, Xu Y, He W, Xiang D, Liu D, Ren X, Zhang C. IL-6 downregulates hepatic carboxylesterases via NF-κB activation in dextran sulfate sodium-induced colitis. Int Immunopharmacol 2021; 99:107920. [PMID: 34217990 DOI: 10.1016/j.intimp.2021.107920] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/13/2021] [Accepted: 06/21/2021] [Indexed: 10/21/2022]
Abstract
Ulcerative colitis (UC) is associated with increased levels of inflammatory factors, which is attributed to the abnormal expression and activity of enzymes and transporters in the liver, affecting drug disposition in vivo. This study aimed to examine the impact of intestinal inflammation on the expression of hepatic carboxylesterases (CESs) in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Two major CESs isoforms, CES1 and CES2, were down-regulated, accompanied by decreases in hepatic microsomal metabolism of clopidogrel and irinotecan. Meanwhile, IL-6 levels significantly increased compared with other inflammatory factors in the livers of UC mice. In contrast, using IL-6 antibody simultaneously reversed the down-regulation of CES1, CES2, pregnane X receptor (PXR), and constitutive androstane receptor (CAR), as well as the nuclear translocation of NF-κB in the liver. We further confirmed that treatment with NF-κB inhibitor abolished IL-6-induced down-regulation of CES1, CES2, PXR, and CAR in vitro. Thus, it was concluded that IL-6 represses hepatic CESs via the NF-κB pathway in DSS-induced colitis. These findings indicate that caution should be exercised concerning the proper and safe use of therapeutic drugs in patients with UC.
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Affiliation(s)
- Min Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China
| | - Lulu Lan
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China
| | - Si Zhang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China
| | - Yanjiao Xu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China
| | - Wenxi He
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China
| | - Dong Xiang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China.
| | - Xiuhua Ren
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China.
| | - Chengliang Zhang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China.
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Bromke MA, Krzystek-Korpacka M. Bile Acid Signaling in Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:9096. [PMID: 34445800 PMCID: PMC8396648 DOI: 10.3390/ijms22169096] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/15/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease is a chronic, idiopathic and complex condition, which most often manifests itself in the form of ulcerative colitis or Crohn's disease. Both forms are associated with dysregulation of the mucosal immune system, compromised intestinal epithelial barrier, and dysbiosis of the gut microbiome. It has been observed for a long time that bile acids are involved in inflammatory disorders, and recent studies show their significant physiological role, reaching far beyond being emulsifiers helping in digestion of lipids. Bile acids are also signaling molecules, which act, among other things, on lipid metabolism and immune responses, through several nuclear and membrane receptors in hepatocytes, enterocytes and cells of the immune system. Gut microbiota homeostasis also seems to be affected, directly and indirectly, by bile acid metabolism and signaling. This review summarizes recent advances in the field of bile acid signaling, studies of inflamed gut microbiome, and the therapeutic potential of bile acids in the context of inflammatory bowel disease.
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Affiliation(s)
- Mariusz A. Bromke
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wrocław, Poland;
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Li N, Zhan S, Tian Z, Liu C, Xie Z, Zhang S, Chen M, Zeng Z, Zhuang X. Alterations in Bile Acid Metabolism Associated With Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1525-1540. [PMID: 33399195 DOI: 10.1093/ibd/izaa342] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder closely related to gut dysbiosis, which is associated with alterations in an important bacterial metabolite, bile acids (BAs). Although certain findings pertinent to BA changes in IBD vary among studies owing to the differences in sample type, quantitated BA species, study methodology, and patient characteristics, a specific trend concerning variations of BAs in IBD has been identified. In elaborating on this observation, it was noted that primary BAs and conjugated BAs are augmented in fecal samples but there is a reduction in secondary BAs in fecal samples. It is not entirely clear why patients with IBD manifest these changes and what role these changes play in the onset and development of IBD. Previous studies have shown that IBD-associated BA changes may be caused by alterations in BA absorption, synthesis, and bacterial modification. The complex relationship between bacteria and BAs may provide additional and deeper insight into host-gut microbiota interactions in the pathogenesis of IBD. The characteristic BA changes may generate profound effects in patients with IBD by shaping the gut microbiota community, affecting inflammatory processes, causing BA malabsorption associated with diarrhea, and even leading to intestinal dysplasia and cancer. Thus, therapeutic strategies correcting the alterations in the composition of BAs, including the elimination of excess BAs and the supplementation of deficient BAs, may prove promising in IBD.
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Affiliation(s)
- Na Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shukai Zhan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhenyi Tian
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zonglin Xie
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaojun Zhuang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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37
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Sun R, Xu C, Feng B, Gao X, Liu Z. Critical roles of bile acids in regulating intestinal mucosal immune responses. Therap Adv Gastroenterol 2021; 14:17562848211018098. [PMID: 34104213 PMCID: PMC8165529 DOI: 10.1177/17562848211018098] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/27/2021] [Indexed: 02/04/2023] Open
Abstract
Bile acids are a class of cholesterol derivatives that have been known for a long time for their critical roles in facilitating the digestion and absorption of lipid from the daily diet. The transformation of primary bile acids produced by the liver to secondary bile acids appears under the action of microbiota in the intestine, greatly expanding the molecular diversity of the intestinal environment. With the discovery of several new receptors of bile acids and signaling pathways, bile acids are considered as a family of important metabolites that play pleiotropic roles in regulating many aspects of human overall health, especially in the maintenance of the microbiota homeostasis and the balance of the mucosal immune system in the intestine. Accordingly, disruption of the process involved in the metabolism or circulation of bile acids is implicated in many disorders that mainly affect the intestine, such as inflammatory bowel disease and colon cancer. In this review, we discuss the different metabolism profiles in diseases associated with the intestinal mucosa and the diverse roles of bile acids in regulating the intestinal immune system. Furthermore, we also summarize recent advances in the field of new drugs that target bile acid signaling and highlight the importance of bile acids as a new target for disease intervention.
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Affiliation(s)
| | | | | | - Xiang Gao
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
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38
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Ye J, Erland LAE, Gill SK, Bishop SL, Verdugo-Meza A, Murch SJ, Gibson DL. Metabolomics-Guided Hypothesis Generation for Mechanisms of Intestinal Protection by Live Biotherapeutic Products. Biomolecules 2021; 11:738. [PMID: 34063522 PMCID: PMC8156236 DOI: 10.3390/biom11050738] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 12/12/2022] Open
Abstract
The use of live biotherapeutic products (LBPs), including single strains of beneficial probiotic bacteria or consortiums, is gaining traction as a viable option to treat inflammatory-mediated diseases like inflammatory bowel disease (IBD). However, LBPs' persistence in the intestine is heterogeneous since many beneficial bacteria lack mechanisms to tolerate the inflammation and the oxidative stress associated with IBD. We rationalized that optimizing LBPs with enhanced colonization and persistence in the inflamed intestine would help beneficial bacteria increase their bioavailability and sustain their beneficial responses. Our lab developed two bioengineered LBPs (SBT001/BioPersist and SBT002/BioColoniz) modified to enhance colonization or persistence in the inflamed intestine. In this study, we examined colon-derived metabolites via ultra-high performance liquid chromatography-mass spectrometry in colitic mice treated with either BioPersist or BioColoniz as compared to their unmodified parent strains (Escherichia coli Nissle 1917 [EcN] and Lactobacillus reuteri, respectively) or to each other. BioPersist administration resulted in lowered concentrations of inflammatory prostaglandins, decreased stress hormones such as adrenaline and corticosterone, increased serotonin, and decreased bile acid in comparison to EcN. In comparison to BioColoniz, BioPersist increased serotonin and antioxidant production, limited bile acid accumulation, and enhanced tissue restoration via activated purine and pyrimidine metabolism. These data generated several novel hypotheses for the beneficial roles that LBPs may play during colitis.
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Affiliation(s)
- Jiayu Ye
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Lauren A E Erland
- Department of Chemistry, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Sandeep K Gill
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Stephanie L Bishop
- Department of Chemistry, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Andrea Verdugo-Meza
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Susan J Murch
- Department of Chemistry, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Deanna L Gibson
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
- Department of Medicine, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
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39
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Grüner N, Mattner J. Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver-Gut Axis. Int J Mol Sci 2021; 22:1397. [PMID: 33573273 PMCID: PMC7866539 DOI: 10.3390/ijms22031397] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 12/12/2022] Open
Abstract
After their synthesis from cholesterol in hepatic tissues, bile acids (BAs) are secreted into the intestinal lumen. Most BAs are subsequently re-absorbed in the terminal ileum and are transported back for recycling to the liver. Some of them, however, reach the colon and change their physicochemical properties upon modification by gut bacteria, and vice versa, BAs also shape the composition and function of the intestinal microbiota. This mutual interplay of both BAs and gut microbiota regulates many physiological processes, including the lipid, carbohydrate and energy metabolism of the host. Emerging evidence also implies an important role of this enterohepatic BA circuit in shaping mucosal colonization resistance as well as local and distant immune responses, tissue physiology and carcinogenesis. Subsequently, disrupted interactions of gut bacteria and BAs are associated with many disorders as diverse as Clostridioides difficile or Salmonella Typhimurium infection, inflammatory bowel disease, type 1 diabetes, asthma, metabolic syndrome, obesity, Parkinson's disease, schizophrenia and epilepsy. As we cannot address all of these interesting underlying pathophysiologic mechanisms here, we summarize the current knowledge about the physiologic and pathogenic interplay of local site microbiota and the enterohepatic BA metabolism using a few selected examples of liver and gut diseases.
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Affiliation(s)
- Niklas Grüner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany;
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany
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40
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Yang N, Dong YQ, Jia GX, Fan SM, Li SZ, Yang SS, Li YB. ASBT(SLC10A2): A promising target for treatment of diseases and drug discovery. Biomed Pharmacother 2020; 132:110835. [PMID: 33035828 DOI: 10.1016/j.biopha.2020.110835] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/17/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022] Open
Abstract
Bile acids has gradually become a new focus in various diseases, and ASBT as a transporter responsible for the reabsorption of ileal bile acids, is a key hinge associated to the bile acids-cholesterol balance and bile acids of enterohepatic circulation. The cumulative studies have also shown that ASBT is a promising target for treatment of liver, gallbladder, intestinal and metabolic diseases. This article briefly reviewed the process of bile acids enterohepatic circulation, as well as the regulations of ASBT expression, covering transcription factors, nuclear receptors and gut microbiota. In addition, the relationship between ASBT and various diseases were discussed in this paper. According to the structural classification of ASBT inhibitors, the research status of ASBT inhibitors and potential ASBT inhibitors of traditional Chinese medicine (such resveratrol, jatrorrhizine in Coptis chinensis) were summarized. This review provides a basis for the development of ASBT inhibitors and the treatment strategy of related diseases.
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Affiliation(s)
- Na Yang
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Ya-Qian Dong
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Guo-Xiang Jia
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Si-Miao Fan
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Shan-Ze Li
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Shen-Shen Yang
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China.
| | - Yu-Bo Li
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China.
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Poppe J, van Baarle L, Matteoli G, Verbeke K. How Microbial Food Fermentation Supports a Tolerant Gut. Mol Nutr Food Res 2020; 65:e2000036. [PMID: 32996681 DOI: 10.1002/mnfr.202000036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/21/2020] [Indexed: 12/13/2022]
Abstract
The gastrointestinal tract harbors a complex resident microbial ecosystem, comprising over 500 species, spanning commensals, mutualist, opportunistic, and professional pathogens thriving on undigested food components originating from the diet and endogenous secretions. Despite this high concentration of food and bacterial antigens, a healthy gut has a near absent level of inflammation, a status called intestinal immune homeostasis. This immune homeostasis is built and maintained in the presence, and interestingly, with cooperation of the microbiota. The microbiota ferments undigested food components into a wide variety of metabolites, some of which interact with the intestinal immune system. In particular short-chain fatty acids, aryl hydrocarbon receptor ligands, and bile acid metabolites have been involved in the induction of intestinal immune homeostasis. The production of these metabolites is influenced by the microbial load and community structure, as well as the availability of substrates and the gut environment which are directly or indirectly modulated by food intake. In this manuscript, the factors that influence the production of these metabolites and their interaction with the immune cells that play key roles in maintaining intestinal immune homeostasis in the healthy gut are reviewed.
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Affiliation(s)
- Jonas Poppe
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Targid - Herestraat 49, O&N1, Leuven, Box 701 - 3000, Belgium
| | - Lies van Baarle
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Targid - Herestraat 49, O&N1, Leuven, Box 701 - 3000, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Targid - Herestraat 49, O&N1, Leuven, Box 701 - 3000, Belgium
| | - Kristin Verbeke
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Targid - Herestraat 49, O&N1, Leuven, Box 701 - 3000, Belgium
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Abstract
There are ten good reasons why it is important to think about abnormalities in bile acid control in inflammatory bowel disease. Before reviewing these reasons, it is relevant to review essential elements in the enterohepatic circulation, synthesis and actions of bile acids.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Corresponding author: Michael Camilleri, MD, Mayo Clinic, Charlton 8–110, 200 First St. S.W., Rochester, MN 55905, USA. Tel: 507-266-2305;
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43
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Drozdzik M, Czekawy I, Oswald S, Drozdzik A. Intestinal drug transporters in pathological states: an overview. Pharmacol Rep 2020; 72:1173-1194. [PMID: 32715435 PMCID: PMC7550293 DOI: 10.1007/s43440-020-00139-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Marek Drozdzik
- Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111, Szczecin, Poland.
| | - Izabela Czekawy
- Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111, Szczecin, Poland
| | - Stefan Oswald
- Department of Pharmacology, Medicine University Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17489, Greifswald, Germany.,Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18051, Rostock, Germany
| | - Agnieszka Drozdzik
- Department of Integrated Dentistry, Pomeranian Medical University, Powstancow Wlkp 72, 70-111, Szczecin, Poland
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44
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Fitzpatrick LR, Jenabzadeh P. IBD and Bile Acid Absorption: Focus on Pre-clinical and Clinical Observations. Front Physiol 2020; 11:564. [PMID: 32595517 PMCID: PMC7303840 DOI: 10.3389/fphys.2020.00564] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/07/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) causes chronic inflammation affecting the GI tract. It is classified as consisting of Crohn’s Disease (CD) and Ulcerative Colitis (UC). Bile Acid absorption is altered in both pre-clinical models of Inflammatory Bowel Disease (IB) and in human IBD. The bile acid transporter apical sodium dependent bile acid transporter (ASBT) showed decreased expression in rats with TNBS colitis. Decreased ASBT expression has also been described in murine, canine and rabbit models of intestinal inflammation. Human IBD studies have shown that an inflamed ileum can interrupt enterohepatic recirculation of bile acid, which could be due to inflammatory cytokine induced repression of the ASBT promoter. There are different hypotheses as to why ASBT is downregulated during CD. In addition, one study has demonstrated the beneficial effect of a glucocorticoid on ASBT expression, when treating IBD. Our aim in this paper was to systematically review various aspects of bile acid malabsorption in animal models of intestinal inflammation, as well as in IBD.
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Affiliation(s)
- Leo R Fitzpatrick
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
| | - Paniz Jenabzadeh
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
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45
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An Inverse Correlation of Serum Fibroblast Growth Factor 19 with Abdominal Pain and Inflammatory Markers in Patients with Ulcerative Colitis. Gastroenterol Res Pract 2020; 2020:2389312. [PMID: 32565779 PMCID: PMC7275953 DOI: 10.1155/2020/2389312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background and Aims Bile acids (BA) play an important role in the modulation of numerous gut functions. Fibroblast growth factor 19 (FGF19) is the ileal hormone regulating BA homeostasis. The aim of the study was to evaluate serum FGF19 level and its correlation with clinical and endoscopic disease activity indices along with inflammatory biomarkers including serum CRP and fecal calprotectin levels in patients with ulcerative colitis (UC). Methods Fasting serum FGF19 level was measured using ELISA test in 16 patients with active UC (7 F, 9 M), 15 patients with nonactive UC (8 F, 7 M), and 19 healthy controls (11 F, 8 M). The disease activity was assessed based on the clinical and endoscopic evaluations as well as serum CRP and fecal calprotectin level measurement. Results The median serum FGF19 level was higher in patients with nonactive UC (175.3 pg/ml (108.7-342.3)) than in patients with active UC (114.3 pg/ml (68.9-155.3), p = 0.093). The median FGF19 level in healthy controls amounted to 151.6 pg/ml (90.6-224.2), and there were no statistically significant differences between the patients with active and nonactive UC compared to the healthy controls. An inverse correlation was observed between FGF19 level and abdominal pain intensity (R = –0.48, p = 0.007) as well as fecal calprotectin (R = –0.38, p = 0.036) and CRP levels (R = –0.36, p = 0.045). The serum FGF19 level was not correlated neither with clinical nor endoscopic disease activity indices. Conclusions The inverse correlations between FGF19 level and abdominal pain as well as inflammatory markers in UC may imply its potential analgesic and anti-inflammatory effects.
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Colquhoun C, Duncan M, Grant G. Inflammatory Bowel Diseases: Host-Microbial-Environmental Interactions in Dysbiosis. Diseases 2020; 8:E13. [PMID: 32397606 PMCID: PMC7348996 DOI: 10.3390/diseases8020013] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/12/2022] Open
Abstract
Crohn's Disease (CD) and Ulcerative Colitis (UC) are world-wide health problems in which intestinal dysbiosis or adverse functional changes in the microbiome are causative or exacerbating factors. The reduced abundance and diversity of the microbiome may be a result of a lack of exposure to vital commensal microbes or overexposure to competitive pathobionts during early life. Alternatively, many commensal bacteria may not find a suitable intestinal niche or fail to proliferate or function in a protective/competitive manner if they do colonize. Bacteria express a range of factors, such as fimbriae, flagella, and secretory compounds that enable them to attach to the gut, modulate metabolism, and outcompete other species. However, the host also releases factors, such as secretory IgA, antimicrobial factors, hormones, and mucins, which can prevent or regulate bacterial interactions with the gut or disable the bacterium. The delicate balance between these competing host and bacteria factors dictates whether a bacterium can colonize, proliferate or function in the intestine. Impaired functioning of NOD2 in Paneth cells and disrupted colonic mucus production are exacerbating features of CD and UC, respectively, that contribute to dysbiosis. This review evaluates the roles of these and other the host, bacterial and environmental factors in inflammatory bowel diseases.
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Affiliation(s)
| | | | - George Grant
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; (C.C.); (M.D.)
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Song M, Yang Q, Zhang F, Chen L, Su H, Yang X, He H, Liu F, Zheng J, Ling M, Lai X, Zhu X, Wang L, Gao P, Shu G, Jiang Q, Wang S. Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR-PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria. FASEB J 2020; 34:7103-7117. [PMID: 32246800 DOI: 10.1096/fj.201903244r] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 03/03/2020] [Accepted: 03/20/2020] [Indexed: 12/13/2022]
Abstract
Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC-J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC-J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR-dependent inhibition of PI3K/AKT pathway was involved in HDCA-suppressed IPEC-J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA-suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR-PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.
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Affiliation(s)
- Min Song
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Qiang Yang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Fenglin Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Lin Chen
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Han Su
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Xiaohua Yang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Haiwen He
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Fangfang Liu
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Jisong Zheng
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Mingfa Ling
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Xumin Lai
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Xiaotong Zhu
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Lina Wang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Ping Gao
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Gang Shu
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Qingyan Jiang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
| | - Songbo Wang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, P. R. China.,National Engineering Research Center for Breeding Swine Industry and ALLTECH-SCAU Animal Nutrition Control Research Alliance, South China Agricultural University, Guangzhou, P. R. China
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48
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Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:223-237. [PMID: 32076145 DOI: 10.1038/s41575-019-0258-z] [Citation(s) in RCA: 1150] [Impact Index Per Article: 230.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2019] [Indexed: 02/06/2023]
Abstract
A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.
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Singh S, Arthur S, Sundaram U. Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases. Compr Physiol 2020; 10:673-686. [PMID: 32163200 DOI: 10.1002/cphy.c190016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Intestinal absorption of dietary amino acids/peptides is essential for protein homeostasis, which in turn is crucial for maintaining health as well as restoration of health from significant diseases. Dietary amino acids/peptides are absorbed by unique transporter processes present in the brush border membrane of absorptive villus cells, which line the entire length of the intestine. To date, the only nutrient absorptive system described in the secretory crypt cells in the mammalian intestine is the one that absorbs the amino acid glutamine. Majority of the amino acid transporters are sodium dependent and therefore require basolateral membrane Na-K-ATPase to maintain an efficient transcellular Na gradient for their activity. These transport processes are tightly regulated by various cellular and molecular mechanisms that facilitate their optimal activity during normal physiological processes. Malabsorption of amino acids, recently described in pathophysiological states such as in inflammatory bowel disease (IBD), is undoubtedly responsible for the debilitating symptoms of IBD such as malnutrition, weight loss and ultimately a failure to thrive. Also recently, in vivo models of IBD and in vitro studies have demonstrated that specific immune-inflammatory mediators/pathways regulate specific amino acid transporters. This provides possibilities to derive novel nutrition and immune-based treatment options for conditions such as IBD. © 2020 American Physiological Society. Compr Physiol 10:673-686, 2020.
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Affiliation(s)
- Soudamani Singh
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
| | - Subha Arthur
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
| | - Uma Sundaram
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
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50
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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