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He Y, Shaoyong W, Chen Y, Li M, Gan Y, Sun L, Liu Y, Wang Y, Jin M. The functions of gut microbiota-mediated bile acid metabolism in intestinal immunity. J Adv Res 2025:S2090-1232(25)00307-8. [PMID: 40354934 DOI: 10.1016/j.jare.2025.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/19/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation. AIM OF REVIEW This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Yanmin He
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Weike Shaoyong
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yanli Chen
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Menglin Li
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yujie Gan
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Lu Sun
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yalin Liu
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yizhen Wang
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Mingliang Jin
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China.
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Iaquinto G, Aufiero VR, Mazzarella G, Lucariello A, Panico L, Melina R, Iaquinto S, De Luca A, Sellitto C. Pathogens in Crohn's Disease: The Role of Adherent Invasive Escherichia coli. Crit Rev Eukaryot Gene Expr 2024; 34:83-99. [PMID: 38305291 DOI: 10.1615/critreveukaryotgeneexpr.2023050088] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
In Crohn's disease (CD), gut dysbiosis is marked by the prevalence of pathogenic bacterial species. Although several microbes have been reported as risk factors or causative agents of CD, it is not yet clear which is the real trigger of the disease. Thirty years ago, a new pathovar of Escherichia coli strain was isolated in the ileal mucosa of CD patients. This strain, called adherent invasive E. coli (AIEC), for its ability to invade the intestinal mucosa, could represent the causative agent of the disease. Several authors studied the mechanisms by which the AIEC penetrate and replicate within macrophages, and release inflammatory cytokines sustaining inflammation. In this review we will discuss about the role of AIEC in the pathogenesis of CD, the virulence factors mediating adhesion and invasion of AIEC in mucosal tissue, the environmental conditions improving AIEC survival and replication within macrophages. Finally, we will also give an overview of the new strategies developed to limit AIEC overgrowth.
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Affiliation(s)
- Gaetano Iaquinto
- Gastroenterology Division, S. Rita Hospital, Atripalda, Avellino, Italy
| | - Vera Rotondi Aufiero
- Institute of Food Sciences, CNR, Avellino, Italy and Department of Translational Medical Science and E.L.F.I.D, University "Federico II" Napoli, Italy
| | - Giuseppe Mazzarella
- Institute of Food Sciences, CNR, Avellino, Italy and Department of Translational Medical Science and E.L.F.I.D, University "Federico II" Napoli, Italy
| | - Angela Lucariello
- Department of Sport Sciences and Wellness, University of Naples "Parthenope," 80100, Naples, Italy
| | - Luigi Panico
- Pathological Anatomy and Histology Unit, Monaldi Hospital, Napoli, Italy
| | - Raffaele Melina
- Department of Gastroenterology, San G. Moscati Hospital, Avellino, Italy
| | | | - Antonio De Luca
- Department of Mental Health and Physics, Preventive Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy
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Watanabe D, Kamada N. Contribution of the Gut Microbiota to Intestinal Fibrosis in Crohn's Disease. Front Med (Lausanne) 2022; 9:826240. [PMID: 35198577 PMCID: PMC8859331 DOI: 10.3389/fmed.2022.826240] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/13/2022] [Indexed: 12/16/2022] Open
Abstract
In Crohn's disease (CD), intestinal fibrosis is a critical determinant of a patient's prognosis. Although inflammation may be a prerequisite for the initiation of intestinal fibrosis, research shows that the progression or continuation of intestinal fibrosis can occur independently of inflammation. Thus, once initiated, intestinal fibrosis may persist even if medical treatment controls inflammation. Clearly, an understanding of the pathophysiological mechanisms of intestinal fibrosis is required to diminish its occurrence. Accumulating evidence suggests that the gut microbiota contributes to the pathogenesis of intestinal fibrosis. For example, the presence of antibodies against gut microbes can predict which CD patients will have intestinal complications. In addition, microbial ligands can activate intestinal fibroblasts, thereby inducing the production of extracellular matrix. Moreover, in various animal models, bacterial infection can lead to the development of intestinal fibrosis. In this review, we summarize the current knowledge of the link between intestinal fibrosis in CD and the gut microbiota. We highlight basic science and clinical evidence that the gut microbiota can be causative for intestinal fibrosis in CD and provide valuable information about the animal models used to investigate intestinal fibrosis.
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Affiliation(s)
- Daisuke Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
- WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
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Kitani T, Maddipatla SC, Madupuri R, Greco C, Hartmann J, Baraniuk JN, Vasudevan S. In Search of Newer Targets for Inflammatory Bowel Disease: A Systems and a Network Medicine Approach. NETWORK AND SYSTEMS MEDICINE 2021. [DOI: 10.1089/nsm.2020.0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Takashi Kitani
- Department of Neurology, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Sushma C. Maddipatla
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Ramya Madupuri
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Christopher Greco
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Jonathan Hartmann
- Dahlgren Memorial Library, Graduate Health and Life Sciences Research Library, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - James N. Baraniuk
- Division of Rheumatology, Immunology and Allergy, Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Sona Vasudevan
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia, USA
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Lee SD, Singla A, Rulyak SJ, Clark‐Snustad K. Double‐blind, randomised, placebo‐controlled crossover trial to evaluate the clinical efficacy of rifaximin in patients with moderate to severe active Crohn’s disease. ACTA ACUST UNITED AC 2020. [DOI: 10.1002/ygh2.416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Scott D. Lee
- University of Washington School of Medicine Seattle WA USA
| | - Anand Singla
- University of Washington School of Medicine Seattle WA USA
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Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol 2019; 12:851-861. [PMID: 30952999 DOI: 10.1038/s41385-019-0162-4] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/14/2019] [Accepted: 03/17/2019] [Indexed: 02/06/2023]
Abstract
Bile acids are cholesterol-derived surfactants that circulate actively between the liver and ileum and that are classically recognized for emulsifying dietary lipids to facilitate absorption. More recent studies, however, have revealed new functions of bile acids; as pleotropic signaling metabolites that regulate diverse metabolic and inflammatory pathways in multiple cell types and tissues through dynamic interactions with both germline-encoded host receptors and the microbiota. Accordingly, perturbed bile acid circulation and/or metabolism is now implicated in the pathogenesis of cholestatic liver diseases, metabolic syndrome, colon cancer, and inflammatory bowel diseases (IBDs). Here, we discuss the three-dimensional interplay between bile acids, the microbiota, and the mucosal immune system, focusing on the mechanisms that regulate intestinal homeostasis and inflammation. Although the functions of bile acids in mucosal immune regulation are only beginning to be appreciated, targeting bile acids and their cellular receptors has already proven an important area of new drug discovery.
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7
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Klepsch V, Moschen AR, Tilg H, Baier G, Hermann-Kleiter N. Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD. Front Immunol 2019; 10:1070. [PMID: 31139192 PMCID: PMC6527601 DOI: 10.3389/fimmu.2019.01070] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/26/2019] [Indexed: 12/26/2022] Open
Abstract
Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the intestinal immune cell repertoire. Several NRs are associated with GI pathologies; therefore, systematic analysis of NR biology, the underlying molecular mechanisms, and regulation of target genes can be expected to help greatly in uncovering the course of GI diseases. Recently, an increasing number of NRs has been validated as potential drug targets for therapeutic intervention in patients with inflammatory bowel disease (IBD). Besides the classical glucocorticoids, especially PPARγ, VDR, or PXR-selective ligands are currently being tested with promising results in clinical IBD trials. Also, several pre-clinical animal studies are being performed with NRs. This review focuses on the complex biology of NRs and their context-dependent anti- or pro-inflammatory activities in the regulation of gastrointestinal barrier with special attention to NRs already pharmacologically targeted in clinic and pre-clinical IBD treatment regimens.
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Affiliation(s)
- Victoria Klepsch
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander R. Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Gottfried Baier
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Natascha Hermann-Kleiter
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
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Elloumi-Mseddi J, Msalbi D, Fakhfakh R, Aifa S. Anti-Diarrheal Drug Repositioning in Tumour Cell Cytotoxicity. Anticancer Agents Med Chem 2019; 19:1037-1047. [PMID: 30657046 DOI: 10.2174/1871520619666190118120030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/18/2018] [Accepted: 01/03/2019] [Indexed: 12/07/2022]
Abstract
BACKGROUND Drug repositioning is becoming an ideal strategy to select new anticancer drugs. In particular, drugs treating the side effects of chemotherapy are the best candidates. OBJECTIVE In this present work, we undertook the evaluation of anti-tumour activity of two anti-diarrheal drugs (nifuroxazide and rifaximin). METHODS Anti-proliferative effect against breast cancer cells (MDA-MB-231, MCF-7 and T47D) was assessed by MTT analysis, the Brdu incorporation, mitochondrial permeability and caspase-3 activity. RESULTS Both the drugs displayed cytotoxic effects on MCF-7, T47D and MDA-MB-231 cells. The lowest IC50 values were obtained on MCF-7 cells after 24, 48 and 72 hours of treatment while T47D and MDA-MB-231 were more resistant. The IC50 values on T47D and MDA-MB-231 cells became significantly low after 72 hours of treatment showing a late cytotoxicity effect especially of nifuroxazide but still less important than that of MCF-7 cells. According to the IC50 values, the non-tumour cell line HEK293 seems to be less sensitive to cytotoxicity especially against rifaximin. Both the drugs have shown an accumulation of rhodamine 123 as a function of the rise of their concentrations while the Brdu incorporation decreased. Despite the absence of a significant difference in the cell cycle between the treated and non-treated MCF-7 cells, the caspase-3 activity increased with the drug concentrations rise suggesting an apoptotic effect. CONCLUSION Nifuroxazide and rifaximin are used to overcome the diarrheal side effect of anticancer drugs. However, they have shown to be anti-tumour drugs which make them potential dual effective drugs against cancer and the side effects of chemotherapy.
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Affiliation(s)
- Jihene Elloumi-Mseddi
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, Sidi Mansour Road Km 6, BP 1177, 3018 Sfax, Tunisia
| | - Dhouha Msalbi
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, Sidi Mansour Road Km 6, BP 1177, 3018 Sfax, Tunisia
| | - Raouia Fakhfakh
- Immunology Department, Habib Bourguiba Hospital, 3029 Sfax, Tunisia
| | - Sami Aifa
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, Sidi Mansour Road Km 6, BP 1177, 3018 Sfax, Tunisia
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Lopetuso LR, Napoli M, Rizzatti G, Gasbarrini A. The intriguing role of Rifaximin in gut barrier chronic inflammation and in the treatment of Crohn’s disease. Expert Opin Investig Drugs 2018; 27:543-551. [DOI: 10.1080/13543784.2018.1483333] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Loris R. Lopetuso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS – Università Cattolica del Sacro Cuore, Roma, Italy
| | - Marco Napoli
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS – Università Cattolica del Sacro Cuore, Roma, Italy
| | - Gianenrico Rizzatti
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS – Università Cattolica del Sacro Cuore, Roma, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS – Università Cattolica del Sacro Cuore, Roma, Italy
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10
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The Intricate Link among Gut "Immunological Niche," Microbiota, and Xenobiotics in Intestinal Pathology. Mediators Inflamm 2017; 2017:8390595. [PMID: 29118468 PMCID: PMC5651127 DOI: 10.1155/2017/8390595] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut “immunological niche.” Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.
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11
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Shayto RH, Abou Mrad R, Sharara AI. Use of rifaximin in gastrointestinal and liver diseases. World J Gastroenterol 2016; 22:6638-6651. [PMID: 27547007 PMCID: PMC4970477 DOI: 10.3748/wjg.v22.i29.6638] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/17/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Rifaximin is a broad spectrum oral antibiotic with antimicrobial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. It is poorly absorbed and thus has a highly favorable safety profile. Rifaximin has been shown to be effective in the treatment of traveler's diarrhea, functional bloating and irritable bowel syndrome, small bowel bacterial overgrowth and in the prevention of recurrent overt hepatic encephalopathy. In addition, there is emerging evidence for a possible beneficial effect of rifaximin in the treatment of uncomplicated diverticular disease and in the prevention of recurrent diverticulitis. The use of rifaximin is associated with a low incidence of development, or persistence of spontaneous bacterial mutants. Moreover, the development of important drug resistance among extra-intestinal flora during rifaximin therapy is unlikely because of minimal systemic absorption and limited cross-resistance of rifaximin with other antimicrobials. This review addresses the current and emerging role of rifaximin in the treatment of gastrointestinal and liver disorders.
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12
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Cammarota G, Ianiro G, Cianci R, Bibbò S, Gasbarrini A, Currò D. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther 2015; 149:191-212. [PMID: 25561343 DOI: 10.1016/j.pharmthera.2014.12.006] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 12/29/2014] [Indexed: 12/12/2022]
Abstract
Over the past recent years, a great number of studies have been directed toward the evaluation of the human host-gut microbiota interaction, with the goal to progress the understanding of the etiology of several complex diseases. Alterations in the intestinal microbiota associated with inflammatory bowel disease are well supported by literature data and have been widely accepted by the research community. The concomitant implementation of high-throughput sequencing techniques to analyze and characterize the composition of the intestinal microbiota has reinforced the view that inflammatory bowel disease results from altered interactions between gut microbes and the mucosal immune system and has raised the possibility that some form of modulation of the intestinal microbiota may constitute a potential therapeutic basis for the disease. The aim of this review is to describe the changes of gut microbiota in inflammatory bowel disease, focusing the attention on its involvement in the pathogenesis of the disease, and to review and discuss the therapeutic potential to modify the intestinal microbial population with antibiotics, probiotics, prebiotics, synbiotics and fecal microbiota transplantation.
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Affiliation(s)
- Giovanni Cammarota
- Department of Medical Sciences, Division of Internal Medicine and Gastroenterology, A. Gemelli Hospital, Rome, Italy.
| | - Gianluca Ianiro
- Department of Medical Sciences, Division of Internal Medicine and Gastroenterology, A. Gemelli Hospital, Rome, Italy
| | - Rossella Cianci
- Department of Medical Sciences, Division of Internal Medicine and Gastroenterology, A. Gemelli Hospital, Rome, Italy
| | - Stefano Bibbò
- Department of Medical Sciences, Division of Internal Medicine and Gastroenterology, A. Gemelli Hospital, Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical Sciences, Division of Internal Medicine and Gastroenterology, A. Gemelli Hospital, Rome, Italy
| | - Diego Currò
- Institute of Pharmacology, Catholic University, School of Medicine and Surgery, A. Gemelli Hospital, Rome, Italy
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13
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Kerman DH, Deshpande AR. Gut microbiota and inflammatory bowel disease: the role of antibiotics in disease management. Postgrad Med 2014; 126:7-19. [PMID: 25141239 DOI: 10.3810/pgm.2014.07.2779] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Imbalances in the composition and number of bacteria in the gut microbiota have been implicated in inflammatory bowel disease (IBD), and modulation of the gut microbiota by probiotics and antibiotics in IBD has been an active area of research, with mixed results. This narrative review summarizes the findings of relevant publications identified using the PubMed database. Although antibiotics have been associated with an increased risk of IBD development and flares, several meta-analyses demonstrate that antibiotics are efficacious for the induction of remission and treatment of flares in patients with IBD. Data supporting their use include a large number of antibiotic studies in Crohn's disease and evidence suggests antibiotics are efficacious in both Crohn's disease and ulcerative colitis, although there are fewer studies of the latter. For Crohn's disease, antibiotics have been shown to be useful for the induction of remission and in the postoperative management of patients undergoing surgery. Additionally, patients with fistulizing disease, particularly perianal, can benefit from antibiotics administered short term. Both antimicrobials and probiotics have been shown to be useful for the treatment of pouchitis. Additional randomized controlled trials are needed to further elucidate the role of bacteria in IBD and to better inform clinicians about appropriate antibiotic therapies.
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Affiliation(s)
- David H Kerman
- Assistant Professor of Clinical Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL.
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14
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Jigaranu AO, Nedelciuc O, Blaj A, Badea M, Mihai C, Diculescu M, Cijevschi-Prelipcean C. Is rifaximin effective in maintaining remission in Crohn's disease? Dig Dis 2014; 32:378-83. [PMID: 24969283 DOI: 10.1159/000358141] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Recent studies indicate that persistent intestinal inflammation in patients with Crohn's disease (CD) might be caused by abnormal intestinal microbiota. This hypothesis may suggest a beneficial effect of antibiotics in CD therapy. So far, guidelines do not recommend antibiotics except in the treatment of complicated CD, and there are few studies on the effects of rifaximin in these patients. METHODS Between December 2011 and December 2012, we performed a blinded randomized trial in 168 patients with a previous history of moderately active CD concerning the efficacy of rifaximin. All the patients had previously achieved remission with standard therapy (prednisone/budesonide). Data from patients receiving 800 mg of rifaximin (83 patients) twice a day for 12 weeks were compared with those from patients who received placebo (83 patients). The primary endpoint was maintaining remission during the follow-up. RESULTS All the patients (100%; 83/83) on 800 mg of rifaximin were in remission after 12 weeks of treatment in comparison with 84% (70/83) of the placebo group. This significant difference was also persistent at the 24-week follow-up [78% (65/83) vs. 41% (34/83), respectively]. The last evaluation performed at 48 weeks revealed disease activity in 45% (38/83) of the patients of the rifaximin group, i.e. a significant decrease compared with the placebo group [75% (63 of 83)]. CONCLUSIONS Remission previously obtained with standard treatment can be sustained in patients with moderately active CD after the administration of 800 mg of rifaximin.
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15
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Chamberlin W, Borody TJ, Campbell J. Primary treatment of Crohn’s disease: combined antibiotics taking center stage. Expert Rev Clin Immunol 2014; 7:751-60. [DOI: 10.1586/eci.11.43] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Bandzar S, Gupta S, Platt MO. Crohn's disease: a review of treatment options and current research. Cell Immunol 2013; 286:45-52. [PMID: 24321565 DOI: 10.1016/j.cellimm.2013.11.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 08/25/2013] [Accepted: 11/12/2013] [Indexed: 02/07/2023]
Abstract
Crohn's disease is an autoimmune disorder that affects nearly 1.4 million Americans. The etiology of Crohn's disease is not completely understood, however, research has suggested a genetic link. There is currently no known cure for Crohn's disease and, as a result, most government-funded research is being conducted to increase the quality of life of afflicted patients (i.e. reducing chronic inflammation and alleviating growth impairment in pediatric patients). A number of treatment options are available including an alpha-4 integrin inhibitor and several TNF-alpha inhibitors. Furthermore, research is being conducted on several alternative treatment options to help understand exactly which cellular mechanisms (i.e. inducing apoptosis in leukocytes) are required for clinical efficacy. This review seeks to chronicle the current available treatment options for patients affected by Crohn's disease to aid in understanding potential cellular mechanistic requirements for an efficacious drug, and shed light on potential options for future treatment.
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Affiliation(s)
- Sean Bandzar
- Georgia Regents University, Medical College of Georgia, Augusta, GA, United States.
| | - Shabnam Gupta
- Emory University School of Medicine, Atlanta, GA, United States
| | - Manu O Platt
- Georgia Institute of Technology, Coulter Department of Biomedical Engineering, Atlanta, GA, United States
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Tursi A. Preventing recurrent acute diverticulitis with pharmacological therapies. Ther Adv Chronic Dis 2013; 4:277-86. [PMID: 24179670 DOI: 10.1177/2040622313498809] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Acute diverticulitis of the colon represents a significant burden for national health systems, in terms of direct and indirect costs. Past guidelines claimed that recurrent episodes (two or more) of diverticulitis need surgery, but revised guidelines recommend an individualized approach to patients after an attack of acute diverticulitis. For these reasons, conservative treatment has become the preferred choice after an episode of diverticulitis. Thus, significant efforts are now being focused to identify the correct therapeutic approach to prevent diverticulitis relapses. Nonabsorbable antibiotics, 5-aminosalicylic acid and probiotics are currently being investigated in this way. The effectiveness and the future perspectives of these treatments are discussed herein.
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Affiliation(s)
- Antonio Tursi
- Gastroenterology Service, ASL BAT, Via Torino 49, 76123 Andria (BT), Italy
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Iwamoto J, Saito Y, Honda A, Miyazaki T, Ikegami T, Matsuzaki Y. Bile acid malabsorption deactivates pregnane X receptor in patients with Crohn's disease. Inflamm Bowel Dis 2013; 19:1278-84. [PMID: 23574760 DOI: 10.1097/mib.0b013e318281f423] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent studies have suggested that the downregulation of pregnane X receptor (PXR) may contribute to the susceptibility and exacerbation of Crohn's disease (CD). Because bile acid malabsorption is one of the features of CD and bile acids are potential activators of PXR, we explored the relationship between bile acid malabsorption and PXR activities in patients with CD. METHODS Twenty-one patients with CD (4 ileal-resected and 17 nonresected), 10 with ulcerative colitis (UC), and 26 healthy controls were studied. Serum biomarkers for the activity of CYP3A4, a target gene of PXR, and for cholesterol and bile acid metabolism were quantified by liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay. RESULTS The concentrations of 4β-hydroxycholesterol (4β-HC), a known marker for CYP3A4 activity, and those of 25-hydroxycholesterol (25-HC), another metabolite by CYP3A4, were significantly reduced in all patients with CD, especially in those with the history of ileal resection. The concentration of 7α-hydroxy-4-cholesten-3-one (C4), a marker for hepatic bile acid biosynthesis, was significantly elevated, whereas the levels of fibroblast growth factor 19 (FGF19), a marker for intestinal bile acid flux, were reduced in patients with CD compared with patients with UC and controls. A significant negative correlation was observed between 4β-HC or 25-HC and C4 concentrations in all patients with CD. CONCLUSIONS The degree of bile acid malabsorption was closely associated with the deactivation of PXR in CD. Enterohepatic circulation of bile acids is a key factor for preservation of baseline activity of hepatointestinal PXR.
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Affiliation(s)
- Junichi Iwamoto
- Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
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Rifaximin resistance in Escherichia coli associated with inflammatory bowel disease correlates with prior rifaximin use, mutations in rpoB, and activity of Phe-Arg-β-naphthylamide-inhibitable efflux pumps. Antimicrob Agents Chemother 2012. [PMID: 23183443 DOI: 10.1128/aac.02163-12] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Escherichia coli is implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a nonabsorbable derivative of rifampin effective against E. coli, improves symptoms in mild-to-moderate IBD. However, rifaximin resistance can develop in a single step in vitro. We examined the prevalence and mechanisms of rifaximin resistance in 62 strains of E. coli isolated from the ileal mucosa of 50 patients (19 with ileal Crohn's disease [L1+L3], 6 with colonic Crohn's disease [L2], 13 with ulcerative colitis [UC], 4 with symptomatic non-IBD diagnoses [NI], and 8 healthy [H]). Resistance (MIC > 1,024 mg/liter) was present in 12/48 IBD-associated ileal E. coli strains. Resistance correlated with prior rifaximin treatment (P < 0.00000001) but not with the presence of ileal inflammation (P = 0.73) or E. coli phylogroup. Mutations in a 1,057-bp region of rpoB, which encodes the bacterial target of rifaximin, were identified in 10/12 resistant strains versus 0/50 sensitive strains (P < 0.000000001) and consisted of seven amino acid substitutions. The efflux pump inhibitor Phe-Arg-β-naphthylamide (PAβN) lowered the MIC of 9/12 resistant strains 8- to 128-fold. Resistance was stable in the absence of rifaximin in 10/12 resistant strains after 30 passages. We conclude that IBD-associated ileal E. coli frequently manifest resistance to rifaximin that correlates with prior rifaximin use, amino acid substitutions in rpoB, and activity of PAβN-inhibitable efflux pumps, but not with the presence of ileal inflammation or E. coli phylogroup. These findings have significant implications for treatment trials targeting IBD-associated E. coli.
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Randall C, Vizuete J, Wendorf G, Ayyar B, Constantine G. Current and emerging strategies in the management of Crohn's disease. Best Pract Res Clin Gastroenterol 2012; 26:601-10. [PMID: 23384805 DOI: 10.1016/j.bpg.2012.11.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 10/19/2012] [Accepted: 11/07/2012] [Indexed: 02/08/2023]
Abstract
Diarrhoea is a common manifestation of Crohn's disease (CD). We advocate an evidence-based approach to treat the underlying disease and reduce symptoms. This article reviews disease grading systems, current concepts in medical therapy, and other treatments that may become available in the future. While some drug classes (e.g. salicylates, immunomodulators) have been studied for many decades, newer approaches including anti-TNF monoclonal antibodies (biologics), and gut selective agents are changing the paradigm we use to treat this debilitating condition.
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Affiliation(s)
- Charles Randall
- Gastroenterology Research of San Antonio (GERSA), University of Texas Health Science Center at San Antonio, TX, USA.
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21
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Cheng J, Shah YM, Gonzalez FJ. Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci 2012; 33:323-30. [PMID: 22609277 PMCID: PMC3368991 DOI: 10.1016/j.tips.2012.03.003] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Revised: 02/27/2012] [Accepted: 03/06/2012] [Indexed: 02/07/2023]
Abstract
Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanism of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor (NF)-κB signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.
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Affiliation(s)
- Jie Cheng
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Guslandi M. Rifaximin in the treatment of inflammatory bowel disease. World J Gastroenterol 2011; 17:4643-6. [PMID: 22180705 PMCID: PMC3237300 DOI: 10.3748/wjg.v17.i42.4643] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 05/26/2011] [Accepted: 06/02/2011] [Indexed: 02/06/2023] Open
Abstract
The gut microbiota plays a role in promoting and maintaining inflammation in inflammatory bowel diseases (IBD), hence the rationale for the use of antibiotics in the treatment of those disorders. Antibiotics, however, may induce untoward effects, especially during long-term therapy. Rifaximin α polymer is an antibacterial agent that is virtually unabsorbed after oral administration and is devoid of systemic side effects. Rifaximin has provided promising results in inducing remission of Crohn’s disease (up to 69% in open studies and significantly higher rates than placebo in double blind trials) and ulcerative colitis (76% in open studies and significantly higher rates than placebo in controlled studies) and might also have a role in maintaining remission of ulcerative colitis and pouchitis. The potential therapeutic activity of rifaximin in IBD deserves to be further investigated and confirmed in larger, controlled studies. The optimal dosage still needs to be better defined.
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Herrera AF, Soriano G, Bellizzi AM, Hornick JL, Ho VT, Ballen KK, Baden LR, Cutler CS, Antin JH, Soiffer RJ, Marty FM. Cord colitis syndrome in cord-blood stem-cell transplantation. N Engl J Med 2011; 365:815-24. [PMID: 21879899 DOI: 10.1056/nejmoa1104959] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Diarrhea is a frequent complication of hematopoietic stem-cell transplantation (HSCT). Important causes of diarrhea after HSCT include acute graft-versus-host disease (GVHD), infections, and medications. After the transplantation and engraftment of hematopoietic stem cells from umbilical-cord blood, we observed a new syndrome of culture-negative, antibiotic-responsive diarrhea not attributable to any known cause. METHODS We conducted a retrospective cohort study of all patients undergoing cord-blood HSCT at our center between March 2003 and March 2010. The cord colitis syndrome was defined as a persistent diarrheal illness in such patients that was not due to acute GVHD, viral or bacterial infection, or another identifiable cause. Clinical and histopathological features of patients meeting the case definition were further analyzed. RESULTS Among 104 patients who underwent cord-blood HSCT at our center, the cord colitis syndrome developed in 11 (10.6%). The 1-year Kaplan-Meier cumulative probability of meeting the case definition for the syndrome was 0.16. The median time to onset after transplantation was 131 days (range, 88 to 314). All patients had a response to a 10-to-14-day course of empirical therapy with metronidazole, alone or in combination with a fluoroquinolone. Five of the 11 patients (45%) had recurrent diarrhea shortly after discontinuation of antibiotics, and all patients who had a relapse had a response to reinitiation of antibiotic therapy. On histologic examination, all patients with the cord colitis syndrome had chronic active colitis, with granulomatous inflammation present in 7 of 11 patients (64%). CONCLUSIONS The cord colitis syndrome is clinically and histopathologically distinct from acute GVHD and other causes of diarrhea in patients who have undergone cord-blood HSCT and is relatively common in this patient population. The syndrome should be considered in such patients who have diarrhea that is not attributable to other causes.
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Affiliation(s)
- Alex F Herrera
- Department of Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA.
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Abstract
Aerobic vaginitis (AV) is an alteration in vaginal bacterial flora that differs from bacterial vaginosis (BV). AV is characterised by an abnormal vaginal microflora accompanied by an increased localised inflammatory reaction and immune response, as opposed to the suppressed immune response that is characteristic of BV. Given the increased local production of interleukin (IL)-1, IL-6 and IL-8 associated with AV during pregnancy, not surprisingly AV is associated with an increased risk of preterm delivery, chorioamnionitis and funisitis of the fetus. There is no consensus on the optimal treatment for AV in pregnant or non-pregnant women, but a broader spectrum drug such as clindamycin is preferred above metronidazole to prevent infection-related preterm birth. The exact role of AV in pregnancy, the potential benefit of screening, and the use of newer local antibiotics, disinfectants, probiotics and immune modulators need further study.
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Affiliation(s)
- Ggg Donders
- Department of Obstetrics and Gynaecology, The Regional Hospital Heilig Hart Tienen and University Hospital Gasthuisberg Leuven, Belgium
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Man SM, Kaakoush NO, Mitchell HM. The role of bacteria and pattern-recognition receptors in Crohn's disease. Nat Rev Gastroenterol Hepatol 2011; 8:152-68. [PMID: 21304476 DOI: 10.1038/nrgastro.2011.3] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Crohn's disease is widely regarded as a multifactorial disease, and evidence from human and animal studies suggests that bacteria have an instrumental role in its pathogenesis. Comparison of the intestinal microbiota of patients with Crohn's disease to that of healthy controls has revealed compositional changes. In most studies these changes are characterized by an increase in the abundance of Bacteroidetes and Proteobacteria and a decrease in that of Firmicutes. In addition, a number of specific mucosa-associated bacteria have been postulated to have a role in Crohn's disease, including Mycobacterium avium subspecies paratuberculosis, adherent and invasive Escherichia coli, Campylobacter and Helicobacter species. The association between mutations in pattern-recognition receptors (Toll-like receptors and Nod-like receptors) and autophagy proteins and Crohn's disease provides further evidence to suggest that defective sensing and killing of bacteria may drive the onset of disease. In this Review, we present recent advances in understanding the role of bacteria and the contribution of pattern-recognition receptors and autophagy in the pathogenesis of Crohn's disease.
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Affiliation(s)
- Si Ming Man
- Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK
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Cheng J, Shah YM, Ma X, Pang X, Tanaka T, Kodama T, Krausz KW, Gonzalez FJ. Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of human pregnane X receptor activation. J Pharmacol Exp Ther 2010; 335:32-41. [PMID: 20627999 PMCID: PMC2957776 DOI: 10.1124/jpet.110.170225] [Citation(s) in RCA: 144] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Accepted: 07/08/2010] [Indexed: 12/13/2022] Open
Abstract
Human pregnane X receptor (PXR) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a human PXR activator, is in clinical trials for treatment of IBD and has demonstrated efficacy in Crohn's disease and active ulcerative colitis. In the current study, the protective and therapeutic role of rifaximin in IBD and its respective mechanism were investigated. PXR-humanized (hPXR), wild-type, and Pxr-null mice were treated with rifaximin in the dextran sulfate sodium (DSS)-induced and trinitrobenzene sulfonic acid (TNBS)-induced IBD models to determine the protective function of human PXR activation in IBD. The therapeutic role of rifaximin was further evaluated in DSS-treated hPXR and Pxr-null mice. Results demonstrated that preadministration of rifaximin ameliorated the clinical hallmarks of colitis in DSS- and TNBS-treated hPXR mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. In addition, higher survival rates and recovery from colitis symptoms were observed in hPXR mice, but not in Pxr-null mice, when rifaximin was administered after the onset of symptoms. Nuclear factor κB (NF-κB) target genes were markedly down-regulated in hPXR mice by rifaximin treatment. In vitro NF-κB reporter assays demonstrated inhibition of NF-κB activity after rifaximin treatment in colon-derived cell lines expressing hPXR. These findings demonstrated the preventive and therapeutic role of rifaximin on IBD through human PXR-mediated inhibition of the NF-κB signaling cascade, thus suggesting that human PXR may be an effective target for the treatment of IBD.
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Affiliation(s)
- Jie Cheng
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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