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Villanueva-Millan MJ, Leite G, Morales W, Sanchez M, Parodi G, Weitsman S, Celly S, Cohrs D, Do H, Barlow GM, Mathur R, Rezaie A, Pimentel M. Hydrogen Sulfide Producers Drive a Diarrhea-Like Phenotype and a Methane Producer Drives a Constipation-Like Phenotype in Animal Models. Dig Dis Sci 2024; 69:426-436. [PMID: 38060167 PMCID: PMC10861391 DOI: 10.1007/s10620-023-08197-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 08/23/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND We recently demonstrated that diarrhea-predominant irritable bowel syndrome (IBS-D) subjects have higher relative abundance (RA) of hydrogen sulfide (H2S)-producing Fusobacterium and Desulfovibrio species, and constipation-predominant IBS (IBS-C) subjects have higher RA of methanogen Methanobrevibacter smithii. AIMS In this study, we investigate the effects of increased methanogens or H2S producers on stool phenotypes in rat models. METHODS Adult Sprague-Dawley rats were fed high-fat diet (HFD) for 60 days to increase M. smithii levels, then gavaged for 10 days with water (controls) or methanogenesis inhibitors. To increase H2S producers, rats were gavaged with F. varium or D. piger. Stool consistency (stool wet weight (SWW)) and gas production were measured. 16S rRNA gene sequencing was performed on stool samples. RESULTS In HFD diet-fed rats (N = 30), stool M. smithii levels were increased (P < 0.001) after 52 days, correlating with significantly decreased SWW (P < 0.0001) at 59 days (R = - 0.38, P = 0.037). Small bowel M. smithii levels decreased significantly in lovastatin lactone-treated rats (P < 0.0006), and SWW increased (normalized) in lovastatin hydroxyacid-treated rats (P = 0.0246), vs. controls (N = 10/group). SWW increased significantly in D. piger-gavaged rats (N = 16) on day 10 (P < 0.0001), and in F. varium-gavaged rats (N = 16) at all timepoints, vs. controls, with increased stool H2S production. 16S sequencing revealed stool microbiota alterations in rats gavaged with H2S producers, with higher relative abundance (RA) of other H2S producers, particularly Lachnospiraceae and Bilophila in F. varium-gavaged rats, and Sutterella in D. piger-gavaged rats. CONCLUSIONS These findings suggest that increased M. smithii levels result in a constipation-like phenotype in a rat model that is partly reversible with methanogenesis inhibitors, whereas gavage with H2S producers D. piger or F. varium results in increased colonization with other H2S producers and diarrhea-like phenotypes. This supports roles for the increased RA of methanogens and H2S producers identified in IBS-C and IBS-D subjects, respectively, in contributing to stool phenotypes.
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Affiliation(s)
- Maria J Villanueva-Millan
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Gabriela Leite
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Walter Morales
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Maritza Sanchez
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Gonzalo Parodi
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Stacy Weitsman
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Shreya Celly
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Daniel Cohrs
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Huongly Do
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Gillian M Barlow
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
| | - Ruchi Mathur
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
- Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai, Los Angeles, CA, USA
| | - Ali Rezaie
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai, Los Angeles, CA, USA
| | - Mark Pimentel
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, 770 N. San Vicente Blvd, Suite G271, West Hollywood, CA, 90069, USA.
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai, Los Angeles, CA, USA.
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OUP accepted manuscript. Pathog Dis 2022; 80:6521441. [DOI: 10.1093/femspd/ftac003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/30/2021] [Accepted: 02/01/2022] [Indexed: 11/15/2022] Open
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Barbara G, Grover M, Bercik P, Corsetti M, Ghoshal UC, Ohman L, Rajilić-Stojanović M. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology 2019; 156:46-58.e7. [PMID: 30009817 PMCID: PMC6309514 DOI: 10.1053/j.gastro.2018.07.011] [Citation(s) in RCA: 143] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 07/03/2018] [Accepted: 07/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The existence of postinfection irritable bowel syndrome (PI-IBS) has been substantiated by epidemiology studies conducted in diverse geographic and clinical settings. However, the available evidence has not been well summarized, and there is little guidance for diagnosis and treatment of PI-IBS. The ROME Foundation has produced a working team report to summarize the available evidence on the pathophysiology of PI-IBS and provide guidance for diagnosis and treatment, based on findings reported in the literature and clinical experience. METHODS The working team conducted an evidence-based review of publication databases for articles describing the clinical features (diagnosis), pathophysiology (intestinal sensorimotor function, microbiota, immune dysregulation, barrier dysfunction, enteroendocrine pathways, and genetics), and animal models of PI-IBS. We used a Delphi-based consensus system to create guidelines for management of PI-IBS and a developed treatment algorithm based on published findings and experiences of team members. RESULTS PI-IBS develops in about 10% of patients with infectious enteritis. Risk factors include female sex, younger age, psychological distress during or before acute gastroenteritis, and severity of the acute episode. The pathogenesis of PI-PBS appears to involve changes in the intestinal microbiome as well as epithelial, serotonergic, and immune system factors. However, these mechanisms are incompletely understood. There are no evidence-based, effective pharmacologic strategies for treatment of PI-IBS. We provide a consensus-based treatment algorithm, based on clinical presentation and potential disease mechanisms. CONCLUSIONS Based on a systematic review of the literature and team experience, we summarize the clinical features, pathophysiology (from animal models and human studies), and progression of PI-IBS. Based on these findings, we present an algorithm for diagnosis and treatment of PI-IBS based on team consensus. We also propose areas for future investigation.
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Affiliation(s)
- Giovanni Barbara
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
| | - Madhusudan Grover
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Maura Corsetti
- Nottingham Digestive Diseases Biomedical Research Centre, National Institute for Health Research, Nottingham University Hospitals NHS Trust, University of Nottingham, UK
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Lena Ohman
- Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mirjana Rajilić-Stojanović
- Department of Biochemical Engineering and Biotechnology, Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia
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Riddle MS, Connor BA, Beeching NJ, DuPont HL, Hamer DH, Kozarsky P, Libman M, Steffen R, Taylor D, Tribble DR, Vila J, Zanger P, Ericsson CD. Guidelines for the prevention and treatment of travelers' diarrhea: a graded expert panel report. J Travel Med 2017; 24:S57-S74. [PMID: 28521004 PMCID: PMC5731448 DOI: 10.1093/jtm/tax026] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND : Travelers' diarrhea causes significant morbidity including some sequelae, lost travel time and opportunity cost to both travelers and countries receiving travelers. Effective prevention and treatment are needed to reduce these negative impacts. METHODS : This critical appraisal of the literature and expert consensus guideline development effort asked several key questions related to antibiotic and non-antibiotic prophylaxis and treatment, utility of available diagnostics, impact of multi-drug resistant (MDR) colonization associated with travel and travelers' diarrhea, and how our understanding of the gastrointestinal microbiome should influence current practice and future research. Studies related to these key clinical areas were assessed for relevance and quality. Based on this critical appraisal, guidelines were developed and voted on using current standards for clinical guideline development methodology. RESULTS : New definitions for severity of travelers' diarrhea were developed. A total of 20 graded recommendations on the topics of prophylaxis, diagnosis, therapy and follow-up were developed. In addition, three non-graded consensus-based statements were adopted. CONCLUSIONS : Prevention and treatment of travelers' diarrhea requires action at the provider, traveler and research community levels. Strong evidence supports the effectiveness of antimicrobial therapy in most cases of moderate to severe travelers' diarrhea, while either increasing intake of fluids only or loperamide or bismuth subsalicylate may suffice for most cases of mild diarrhea. Further studies are needed to address knowledge gaps regarding optimal therapies, the individual, community and global health risks of MDR acquisition, manipulation of the microbiome in prevention and treatment and the utility of laboratory testing in returning travelers with persistent diarrhea.
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Affiliation(s)
| | - Bradley A. Connor
- Weill Cornell Medical College and The New York Center for Travel and
Tropical Medicine, New York, NY, USA
| | - Nicholas J. Beeching
- Clinical Science Group, Liverpool School of Tropical Medicine, Pembroke
Place, Liverpool, UK and National Institute of Health Research (NIHR) Health Protection Unit
in Gastrointestinal Infections, Farr Institute, University of Liverpool, Liverpool, UK
| | | | - Davidson H. Hamer
- Department of Global Health, Center for Global Health and Development,
Boston University School of Public Health, Section of Infectious Diseases, Department of
Medicine, Boston University School of Medicine, Boston, MA, USA
| | | | - Michael Libman
- J.D. MacLean Centre for Tropical Diseases, McGill University, Montreal,
Québec, Canada
| | - Robert Steffen
- Epidemiology, Biostatistics and Prevention Institute, World Health
Organization Collaborating Centre for Traveller's Health, University of Zurich, Zurich,
Switzerland
| | | | - David R. Tribble
- Uniformed Services University of the Health Sciences, Bethesda, MD,
USA
| | - Jordi Vila
- ISGlobal, Barcelona Centre for International Health Research, Hospital
Clínic–Universitat de Barcelona, Barcelona, Spain
| | - Philipp Zanger
- Institute of Public Health, University Hospitals,
Ruprecht-Karls-Universität, Heidelberg, Germany
| | - Charles D. Ericsson
- Department of Medicine, Division of Infectious Diseases, University of
Texas Medical School at Houston, Houston, TX, USA
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Grundmann O, Yoon SL. Complementary and alternative medicines in irritable bowel syndrome: an integrative view. World J Gastroenterol 2014; 20:346-362. [PMID: 24574705 PMCID: PMC3923011 DOI: 10.3748/wjg.v20.i2.346] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 11/11/2013] [Accepted: 12/12/2013] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with a high incidence in the general population. The diagnosis of IBS is mainly based on exclusion of other intestinal conditions through the absence of inflammatory markers and specific antigens. The current pharmacological treatment approaches available focus on reducing symptom severity while often limiting quality of life because of significant side effects. This has led to an effectiveness gap for IBS patients that seek further relief to increase their quality of life. Complementary and alternative medicines (CAM) have been associated with a higher degree of symptom management and quality of life in IBS patients. Over the past decade, a number of important clinical trials have shown that specific herbal therapies (peppermint oil and Iberogast(®)), hypnotherapy, cognitive behavior therapy, acupuncture, and yoga present with improved treatment outcomes in IBS patients. We propose an integrative approach to treating the diverse symptoms of IBS by combining the benefits of and need for pharmacotherapy with known CAM therapies to provide IBS patients with the best treatment outcome achievable. Initial steps in this direction are already being considered with an increasing number of practitioners recommending CAM therapies to their patients if pharmacotherapy alone does not alleviate symptoms sufficiently.
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Louwen R, Hays JP. Is there an unrecognised role for Campylobacter infections in (chronic) inflammatory diseases? World J Clin Infect Dis 2013; 3:58-69. [DOI: 10.5495/wjcid.v3.i4.58] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Revised: 10/30/2013] [Accepted: 11/16/2013] [Indexed: 02/06/2023] Open
Abstract
Campylobacter species are one of the major causes of global bacterial-related diarrheal disease worldwide. The disease is most frequently associated with the ingestion of contaminated meat, raw milk, pets, contaminated water, and the organism may be frequently cultured from the faeces of chicken and other domesticated farm animals. Of the 17 established Campylobacter species, the most important pathogens for humans are Campylobacter jejuni (C. jejuni), Campylobacter coli (C. coli) and Campylobacter fetus (C. fetus), which are all associated with diarrheal disease. Further, C. jejuni and C. coli are also associated with the neuroparalytic diseases Guillain-Barré syndrome and Miller Fischer syndrome, respectively, whereas C. fetus is linked with psoriatic arthritis. The discovery of both “molecular mimicry” and translocation-related virulence in the pathogenesis of C. jejuni-induced disease, indicates that Campylobacter-related gastrointestinal infections may not only generate localized, acute intestinal infection in the human host, but may also be involved in the establishment of chronic inflammatory diseases. Indeed, pathogenicity studies on several Campylobacter species now suggest that molecular mimicry and translocation-related virulence is not only related to C. jejuni, but may play a role in human disease caused by other Campylobacter spp. In this review, the authors provide a review based on the current literature describing the potential links between Campylobacter spp. and (chronic) inflammatory diseases, and provide their opinions on the likely role of Campylobacter in such diseases.
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Collins SM, Chang C, Mearin F. Postinfectious Chronic Gut Dysfunction: From Bench to Bedside. ACTA ACUST UNITED AC 2012. [DOI: 10.1038/ajgsup.2012.2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Larauche M, Mulak A, Taché Y. Stress and visceral pain: from animal models to clinical therapies. Exp Neurol 2012; 233:49-67. [PMID: 21575632 PMCID: PMC3224675 DOI: 10.1016/j.expneurol.2011.04.020] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 04/07/2011] [Accepted: 04/28/2011] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.
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Affiliation(s)
- Muriel Larauche
- CURE/Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90073, USA.
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Gastrointestinal infections and the development of irritable bowel syndrome. Curr Opin Infect Dis 2011; 24:503-8. [PMID: 21844806 DOI: 10.1097/qco.0b013e32834a962d] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Approximately 10% of the millions of persons with functional gastrointestinal disorders (FGDs) including irritable bowel syndrome (IBS) had their illness onset following an acute bout of infectious diarrhea and are referred to as having postinfectious (PI) FGD or PI-IBS. Recent studies have helped to identify the pathogenesis and natural history of these disorders. RECENT FINDINGS Groups of patients with acute diarrhea or dysentery (passage of grossly bloody stools) are being followed for development of PI-IBS. Persistent mucosal inflammation, air trapping in the gut, and alteration of intestinal motility contribute to the disease symptoms in genetically susceptible persons. The prognosis of postinfectious forms of IBS is more favorable compared with people with idiopathic forms of the disorder. SUMMARY With full characterization of postdiarrhea forms of FGDs, we should be able to define the mechanisms of disease early in the course of chronic illness and to better understand the more common idiopathic forms of the disease. We are likely to identify specific alteration of gut pathophysiology in postinfectious FGDs and to then classify them not as a poorly characterized group of functional disorders but as specific gastrointestinal disorders.
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Larauche M, Mulak A, Taché Y. Stress and visceral pain: from animal models to clinical therapies. Exp Neurol 2011. [PMID: 21575632 DOI: 10.1016/j.expneurol.2011.04.020.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.
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Affiliation(s)
- Muriel Larauche
- CURE/Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90073, USA.
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