1
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Rodiño-Janeiro BK, Khannous-Lleiffe O, Pigrau M, Willis JR, Salvo-Romero E, Nieto A, Expósito E, Fortea M, Pardo-Camacho C, Albert-Bayo M, González-Castro AM, Guagnozzi D, Martínez C, Lobo B, Vicario M, Santos J, Gabaldón T, Alonso-Cotoner C. Acute stress triggers sex-dependent rapid alterations in the human small intestine microbiota composition. Front Microbiol 2025; 15:1441126. [PMID: 39881982 PMCID: PMC11778178 DOI: 10.3389/fmicb.2024.1441126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 12/16/2024] [Indexed: 01/31/2025] Open
Abstract
Background/aims Digestive disorders of gut-brain interaction (DGBI) are very common, predominant in females, and usually associated with intestinal barrier dysfunction, dysbiosis, and stress. We previously found that females have increased susceptibility to intestinal barrier dysfunction in response to acute stress. However, whether this is associated with changes in the small bowel microbiota remains unknown. We have evaluated changes in the small intestinal microbiota in response to acute stress to better understand stress-induced intestinal barrier dysfunction. Methods Jejunal biopsies were obtained at baseline and 90 min after cold pain or sham stress. Autonomic (blood pressure and heart rate), hormonal (plasma cortisol and adrenocorticotropic hormone) and psychological (Subjective Stress Rating Scale) responses to cold pain and sham stress were monitored. Microbial DNA from the biopsies was analyzed using a 16S metabarcoding approach before and after cold pain stress and sham stress. Differences in diversity and relative abundance of microbial taxa were examined. Results Cold pain stress was associated with a significant decrease in alpha diversity (P = 0.015), which was more pronounced in females, along with significant sex differences in the abundance of specific taxa and the overall microbiota composition. Microbiota alterations significantly correlated with changes in psychological responses, hormones, and gene expression in the intestinal mucosal. Cold pain stress was also associated with activation of autonomic, hormonal and psychological response, with no differences between sexes. Conclusions Acute stress elicits rapid alterations in bacterial composition in the jejunum of healthy subjects and these changes are more pronounced in females. Our results may contribute to the understanding of female predominance in DGBI.
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Affiliation(s)
- Bruno K. Rodiño-Janeiro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Olfat Khannous-Lleiffe
- Barcelona Supercomputing Centre (BSC-CNS), Barcelona, Spain
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marc Pigrau
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Jesse R. Willis
- Barcelona Supercomputing Centre (BSC-CNS), Barcelona, Spain
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Eloísa Salvo-Romero
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Adoración Nieto
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Marina Fortea
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Cristina Pardo-Camacho
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Mercé Albert-Bayo
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Ana María González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Danila Guagnozzi
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Martínez
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Renal Physiopathology Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - María Vicario
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Laboratory of Translational Mucosal Immunology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Toni Gabaldón
- Barcelona Supercomputing Centre (BSC-CNS), Barcelona, Spain
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
- Centro de Investigación Biomédica En Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
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2
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Castiglione R, Bertino G, Vicari BO, Rizzotto A, Sidoti G, D’Agati P, Salemi M, Malaguarnera G, Vicari E. Inflammatory Prostatitis Plus IBS-D Subtype and Correlation with Immunomodulating Agent Imbalance in Seminal Plasma: Novel Combined Treatment. Diseases 2024; 12:260. [PMID: 39452503 PMCID: PMC11508116 DOI: 10.3390/diseases12100260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/12/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
We recently demonstrated the effectiveness of long-term treatment with rifaximin and the probiotic DSF (De Simone formulation) in improving urogenital and gastrointestinal symptoms in patients with both chronic inflammatory prostatitis (IIIa prostatitis) and diarrhea-predominant irritable bowel syndrome (IBS-D), relative to patients with IBS-D alone. Because the low-grade inflammation of the intestine and prostate may be one of the reasons for co-developing both IIIa prostatitis and IBS-D, we designed the present study to once again evaluate the efficacy of combined rifaximin and DSF treatment in patients affected by IIIa prostatitis plus IBS-D, but we also measured seminal plasma pro-inflammatory (IL-6) and anti-inflammatory (IL-10) cytokines before and after treatment. Methods: We consecutively enrolled 124 patients with IIIa prostatitis and IBS-D (diagnosed using the Rome III criteria). Patients were randomized into two groups: group A (n = 64) was treated with rifaximin (seven days per month for three months) followed by DSF, and group B (n = 60) was treated with a placebo. By the end of the intervention, 68.7% and 62.5% of patients from group A reported improved NIH-CPSI (National Institute of Health's Chronic Prostatitis Symptom Index) and IBS-SSS (Irritable Bowel Syndrome Severity Scoring System) scores, respectively, compared to only 3.3% and 5% of the placebo group. Group A patients also had significantly lower mean seminal plasma levels of IL-6 (11.3 vs. 32.4 pg/mL) and significantly higher mean levels of IL-10 (7.9 vs. 4.4 pg/mL) relative to baseline, whereas the levels of IL-6 and IL-10 did not change in the placebo group. Conclusions: The combined treatment with rifaximin and DSF appears to represent the optimal approach for addressing a syndrome such as irritable bowel syndrome (IBS-D plus), which frequently co-occurs with prostatitis (IIIa prostatitis). This approach is particularly beneficial in cases where the symptoms are not always clearly delineated, the etiology is multifactorial, and the diagnosis is multilevel.
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Affiliation(s)
- Roberto Castiglione
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Gaetano Bertino
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | | | - Agostino Rizzotto
- Center of Rare Diseases, Policlinico Catania, University of Catania, 95100 Catania, Italy
| | - Giuseppe Sidoti
- Simple Departmental Operating Unit, Internal Medicine Ambulatory Andrology & Endocrinology, ARNAS-Garibaldi, 95123 Catania, Italy
| | - Placido D’Agati
- Department “GF Ingrassia” Hygiene and Public Health, University of Catania, 95123 Catania, Italy
| | | | - Giulia Malaguarnera
- Research Center “The Great Senescence”, University of Catania, 95100 Catania, Italy
| | - Enzo Vicari
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
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3
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Hussein H, Van Remoortel S, Boeckxstaens GE. Irritable bowel syndrome: When food is a pain in the gut. Immunol Rev 2024; 326:102-116. [PMID: 39037230 DOI: 10.1111/imr.13374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.
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Affiliation(s)
- Hind Hussein
- Center for Intestinal Neuro-Immune Interactions, Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Samuel Van Remoortel
- Center for Intestinal Neuro-Immune Interactions, Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Center for Intestinal Neuro-Immune Interactions, Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
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4
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Ihara E, Manabe N, Ohkubo H, Ogasawara N, Ogino H, Kakimoto K, Kanazawa M, Kawahara H, Kusano C, Kuribayashi S, Sawada A, Takagi T, Takano S, Tomita T, Noake T, Hojo M, Hokari R, Masaoka T, Machida T, Misawa N, Mishima Y, Yajima H, Yamamoto S, Yamawaki H, Abe T, Araki Y, Kasugai K, Kamiya T, Torii A, Nakajima A, Nakada K, Fukudo S, Fujiwara Y, Miwa H, Kataoka H, Nagahara A, Higuchi K. Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023. Digestion 2024; 105:480-497. [PMID: 39197422 PMCID: PMC11633876 DOI: 10.1159/000541121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/22/2024] [Indexed: 09/01/2024]
Abstract
The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide.
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Affiliation(s)
- Eikichi Ihara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriaki Manabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hidenori Ohkubo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Naotaka Ogasawara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Haruei Ogino
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kazuki Kakimoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hidejiro Kawahara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Chika Kusano
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shiko Kuribayashi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akinari Sawada
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tomohisa Takagi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shota Takano
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Toshihiko Tomita
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Toshihiro Noake
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Mariko Hojo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tatsuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tomohiko Machida
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Noboru Misawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yoshiyuki Mishima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroshi Yajima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Sayuri Yamamoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroshi Yamawaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tatsuya Abe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yasumi Araki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kunio Kasugai
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Atsushi Nakajima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Koji Nakada
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shin Fukudo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yasuhiro Fujiwara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiromi Kataoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akihito Nagahara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kazuhide Higuchi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
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5
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Chi ZC. Recent studies on gut-brain axis and irritable bowel syndrome. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:468-483. [DOI: 10.11569/wcjd.v32.i7.468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2024]
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6
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Zhang Y, Liao J, Fan W. Role of autoantibodies in the pathophysiology of irritable bowel syndrome: a review. Front Physiol 2024; 15:1359003. [PMID: 38505711 PMCID: PMC10948515 DOI: 10.3389/fphys.2024.1359003] [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: 12/20/2023] [Accepted: 02/26/2024] [Indexed: 03/21/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic, recurrent disorder that is characterized by abdominal pain associated with defecation. IBS was previously considered to manifest without any structural alterations until the discovery of post-infection IBS. An increasing body of published evidence indicates that immune activation plays an important role in the development of IBS. Nevertheless, the pathophysiology of IBS, including mainly visceral hypersensitivity and gastrointestinal dysmotility, has not yet been explicitly elucidated. The observation of potential inflammatory degenerative neuropathy, including neuronal degeneration, spearheaded research on autoimmune responses targeting the enteric nervous system. Subsequently, several autoantibodies were detected in the sera of IBS patients, among which some were presumed to exert a pathogenic influence or be associated with the etiology of gastrointestinal dysmotility in IBS. Moreover, certain specific autoantibodies evidently served as biomarkers to facilitate the differentiation between IBS and other related diseases. Therefore, we aimed to present an overview of autoantibodies reported in the sera of IBS patients and highlight their significance in diagnosing and comprehending the pathophysiology of IBS. Consequently, we propose a therapeutic strategy from an autoimmune perspective.
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Affiliation(s)
| | | | - Wenjuan Fan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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7
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Shah A, Lee YY, Suzuki H, Tan-Loh J, Siah KTH, Gwee KA, Fairlie T, Talley NJ, Ghoshal UC, Wang YP, Kim YS, Holtmann G. A pathophysiologic framework for the overlap of disorders of gut-brain interaction and the role of the gut microbiome. Gut Microbes 2024; 16:2413367. [PMID: 39482844 PMCID: PMC11540069 DOI: 10.1080/19490976.2024.2413367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/24/2024] [Accepted: 10/02/2024] [Indexed: 11/03/2024] Open
Abstract
The International Rome Committee defines Disorders of Gut-Brain Interactions (DGBI) based upon distinct combinations of chronic and/or recurrent unexplained gastrointestinal symptoms. Yet patients often experience overlapping DGBI. Patients with DGBI frequently also suffer from extraintestinal symptoms, including fatigue, sleep disturbances, anxiety, and depression. Patients with overlapping DGBI typically experience more severe GI symptoms and increased psychosocial burden. Concerning the pathophysiology, DGBI are associated with disruptions in gut motility, function of the brain and enteric neurons, immune function, and genetic markers, with recent findings revealing gut microbiome alterations linked to these mechanisms of DGBI. Emerging evidence summarized in this review suggests that the microbiome influences various established disease mechanisms of different DGBI groups. Overall, changes in the gastrointestinal microbiome do not seem to be linked to a specific DGBI subgroup but may play a key role in the manifestation of different DGBI and, subsequently, overlap of DGBI. Understanding these shared mechanisms and the role of the gastrointestinal microbiome, particularly for overlapping DGBI, might aid in developing more precise diagnostic criteria and treatment strategies while developing personalized interventions that target specific mechanisms to improve patient outcomes.
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Affiliation(s)
- Ayesha Shah
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Joash Tan-Loh
- Division of Gastroenterology Hepatology, Department of Internal Medicine, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Kok-Ann Gwee
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Thomas Fairlie
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| | - Nicholas J. Talley
- School of Medicine and Public Health, and Hunter Medical Research Institute, the University of Newcastle, Newcastle, Australia
| | - Uday C Ghoshal
- Institute of Gastrosciences & Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, India
| | - Yen-Po Wang
- Endoscopy centre for Diagnosis of Treatment, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yong Sung Kim
- Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea
- Good Breath Clinic, Gunpo, Korea
| | - Gerald Holtmann
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
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8
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Panarelli NC. Mast Cell Disorders of the Gastrointestinal Tract: Clarity out of Chaos. Surg Pathol Clin 2023; 16:755-764. [PMID: 37863564 DOI: 10.1016/j.path.2023.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2023]
Abstract
Pathologists are increasingly asked to evaluate mast cell infiltrates in the gastrointestinal tract when there is clinical concern for systemic mastocytosis or a variety of functional disorders, including irritable bowel syndrome and mast cell activation syndrome. Neoplastic mast cells have established quantitative, morphologic, and immunohistochemical features that facilitate their identification in gastrointestinal mucosal biopsies. Specific qualitative and quantitative findings are lacking for inflammatory mast cell-mediated disorders. This review covers histopathologic features of mast cell disorders that affect the gastrointestinal tract and offers practical guidance for their assessment in mucosal biopsies.
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Affiliation(s)
- Nicole C Panarelli
- Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
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9
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Fan W, Fang X, Fei G, Li X, Guan H. Sera anti-neuronal antibodies in patients with irritable bowel syndrome and their correlations with clinical profiles. Neurogastroenterol Motil 2023; 35:e14682. [PMID: 37743699 DOI: 10.1111/nmo.14682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 08/16/2023] [Accepted: 09/07/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Immune factors were involved in the pathophysiology of irritable bowel syndrome (IBS). The aim of the study was to test anti-neuronal antibodies in sera of IBS patients and demonstrate their correlations with IBS profiles and psychological disorders. METHODS Patients with IBS met Rome III criteria and excluded organic diseases were enrolled. Controls included healthy subjects (HS), slow transit functional constipation, autoimmune diseases, and so on. Indirect immunofluorescence with monkey cerebellum and small intestine as substrates was used to detect anti-neuronal antibodies including anti-cerebral neuronal antibodies (ACNA) and anti-enteric neuronal antibodies (AENA). RESULTS A total of 293 IBS patients, 100 HS and 153 disease controls were included in this study. The ACNA positive rate of IBS patients was significantly higher than HS (14% vs. 6%, p = 0.033). The positive rate of ACNA was significantly lower than AENA (14.0% vs. 76.8%, p = 0.028) in IBS patients. The prevalence of headache and sleeping disorder were higher in ACNA-positive IBS patients than ACNA-negative IBS patients (61% vs. 42.9%, p = 0.03; 75.6% vs. 57.1%, p = 0.03, respectively). Among IBS patients, ACNA and AENA were both negative in 21.8% patients, ACNA negative and AENA positive in 64.2% patients, and ACNA and AENA were both positive in 12.6% patients. There were no significant differences of intestinal symptoms among the three groups, while the prevalence of headache (64.9% vs. 37.5% and 44.7%, p = 0.03) and sleeping disorder (78.4% vs. 50.0% and 59.6%, p = 0.02) were higher in patients with both ACNA and AENA positive than patients with both ACNA and AENA negative, patients with ACNA negative and AENA positive. There were no significant differences of the prevalence of depression and anxiety, HAMD, and HAMA scores among the three groups. CONCLUSIONS AND INFERENCES Anti-neuronal antibodies in sera of IBS patients were mainly targeted to enteric neurons and in a small part to cerebral neurons. ACNA were closely related to headache and sleeping disorder but unrelated to intestinal symptoms, depression, or anxiety of IBS patients.
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Affiliation(s)
- Wenjuan Fan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiucai Fang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guijun Fei
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoqing Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongzhi Guan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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10
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Wilson B, Kanno T, Slater R, Rossi M, Irving PM, Lomer MC, Probert C, Mason AJ, Whelan K. Faecal and urine metabolites, but not gut microbiota, may predict response to low FODMAP diet in irritable bowel syndrome. Aliment Pharmacol Ther 2023; 58:404-416. [PMID: 37313992 DOI: 10.1111/apt.17609] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 05/12/2023] [Accepted: 05/29/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND The low FODMAP diet (LFD) leads to clinical response in 50%-80% of patients with irritable bowel syndrome (IBS). It is unclear why only some patients respond. AIMS To determine if differences in baseline faecal microbiota or faecal and urine metabolite profiles may separate clinical responders to the diet from non-responders allowing predictive algorithms to be proposed. METHODS We recruited adults fulfilling Rome III criteria for IBS to a blinded randomised controlled trial. Patients were randomised to sham diet with a placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.8 g/d B-galactooligosaccharide (LFD/B-GOS), for 4 weeks. Clinical response was defined as adequate symptom relief at 4 weeks after the intervention (global symptom question). Differences between responders and non-responders in faecal microbiota (FISH, 16S rRNA sequencing) and faecal (gas-liquid chromatography, gas-chromatography mass-spectrometry) and urine (1 H NMR) metabolites were analysed. RESULTS At 4 weeks, clinical response differed across the 3groups with adequate symptom relief of 30% (7/23) in controls, 50% (11/22) in the LFD group and 67% (16/24) in the LFD/B-GOS group (p = 0.048). In the control and the LFD/B-GOS groups, microbiota and metabolites did not separate responders from non-responders. In the LFD group, higher baseline faecal propionate (sensitivity 91%, specificity 89%) and cyclohexanecarboxylic acid esters (sensitivity 80%, specificity 78%), and urine metabolite profile (Q2 0.296 vs. randomised -0.175) predicted clinical response. CONCLUSIONS Baseline faecal and urine metabolites may predict response to the LFD.
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Affiliation(s)
- Bridgette Wilson
- Department of Nutritional Sciences, King's College London, London, UK
- Department of Nutrition and Dietetics, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Tokuwa Kanno
- King's College London, Institute of Pharmaceutical Science, London, UK
| | - Rachael Slater
- University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Liverpool, UK
| | - Megan Rossi
- Department of Nutritional Sciences, King's College London, London, UK
| | - Peter M Irving
- Department of Gastroenterology, Guys and St Thomas' NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Miranda C Lomer
- Department of Nutritional Sciences, King's College London, London, UK
- Department of Nutrition and Dietetics, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Chris Probert
- University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Liverpool, UK
| | - A James Mason
- King's College London, Institute of Pharmaceutical Science, London, UK
| | - Kevin Whelan
- Department of Nutritional Sciences, King's College London, London, UK
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11
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Sun Z, Wang X, Feng S, Xie C, Xing Y, Guo L, Zhao J, Ji C. A review of neuroendocrine immune system abnormalities in IBS based on the brain–gut axis and research progress of acupuncture intervention. Front Neurosci 2023; 17:934341. [PMID: 36968497 PMCID: PMC10034060 DOI: 10.3389/fnins.2023.934341] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 02/07/2023] [Indexed: 03/11/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common digestive disorder observed in clinics. Current studies suggest that the pathogenesis of the disease is closely related to abnormal brain–gut interactions, hypokinesia, visceral sensory hypersensitivity in the gastrointestinal tract, and alterations in the intestinal microenvironment. However, it is difficult for a single factor to explain the heterogeneity of symptoms. The Rome IV criteria emphasized the holistic biologic-psycho-social model of IBS, suggesting that symptoms of the disease are closely related to neurogastroenterology and various abnormalities in brain–gut interaction. This study comprehensively reviewed the relationship between the brain–gut axis and IBS, the structure of the brain–gut axis, and the relationship between the brain–gut axis and intestinal microenvironment, and discussed the relationship between the abnormal regulation of the nervous system, endocrine system, and immune system and the incidence of IBS on the basis of brain–gut axis. In terms of treatment, acupuncture therapy can regulate the neuroendocrine-immune system of the body and improve the intestinal microenvironment, and it has the advantages of safety, economy, and effectiveness. We study the pathogenesis of IBS from local to global and micro to macro, and review the use of acupuncture to treat the disease as a whole so as to provide new ideas for the treatment of the disease.
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Affiliation(s)
- Zhangyin Sun
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Xuejiao Wang
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Shangsheng Feng
- MOE Key Laboratory of Biomedical Information Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Chaoju Xie
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Yu Xing
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Liang Guo
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Jingyu Zhao
- Department of Acupuncture and Moxibustion, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, China
- *Correspondence: Jingyu Zhao
| | - Changchun Ji
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
- Department of Acupuncture and Moxibustion, Shaanxi Provincial Institute of Traditional Chinese Medicine, Xi'an, China
- Changchun Ji
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12
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Camilleri M, Boeckxstaens G. Irritable bowel syndrome: treatment based on pathophysiology and biomarkers. Gut 2023; 72:590-599. [PMID: 36307180 PMCID: PMC9990119 DOI: 10.1136/gutjnl-2022-328515] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/16/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To appraise the evidence that pathophysiological mechanisms and individualised treatment directed at those mechanisms provide an alternative approach to the treatment of patients with irritable bowel syndrome (IBS). DESIGN A PubMED-based literature review of mechanisms and treatment of IBS was conducted independently by the two authors, and any differences of perspective or interpretation of the literature were resolved following discussion. RESULTS The availability of several noninvasive clinical tests can appraise the mechanisms responsible for symptom generation in IBS, including rectal evacuation disorders, abnormal transit, visceral hypersensitivity or hypervigilance, bile acid diarrhoea, sugar intolerances, barrier dysfunction, the microbiome, immune activation and chemicals released by the latter mechanism. The basic molecular mechanisms contributing to these pathophysiologies are increasingly recognised, offering opportunities to intervene with medications directed specifically to food components, receptors and potentially the microbiome. Although the evidence supporting interventions for each mechanism is not at the same level of proof, the current state-of-the-art provides the opportunity to advance the practice from treatment based on symptoms to individualisation of treatment guided by pathophysiology and clinically identified biomarkers. CONCLUSION These advances augur well for the implementation of evidence-based individualised treatment for patients with IBS based on actionable biomarkers or psychological disturbances.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guy Boeckxstaens
- Center of Intestinal Neuroimmune Interaction, Division of Gastroenterology, Translational Research Center for GI Disorders (TARGID), Leuven University, Leuven, Belgium
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Acute Stress Regulates Sex-Related Molecular Responses in the Human Jejunal Mucosa: Implications for Irritable Bowel Syndrome. Cells 2023; 12:cells12030423. [PMID: 36766765 PMCID: PMC9913488 DOI: 10.3390/cells12030423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/17/2023] [Accepted: 01/23/2023] [Indexed: 02/03/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder linked to intestinal barrier dysfunction and life stress. We have previously reported that female sex per se determines an increased susceptibility to intestinal barrier dysfunction after cold pain stress (CPS). We aimed to identify sex-related molecular differences in response to CPS in healthy subjects to understand the origin of sex bias predominance in IBS. In 13 healthy males and 21 females, two consecutive jejunal biopsies were obtained using Watson's capsule, at baseline, and ninety minutes after CPS. Total mucosal RNA and protein were isolated from jejunal biopsies. Expression of genes related to epithelial barrier (CLDN1, CLDN2, OCLN, ZO-1, and ZO-3), mast cell (MC) activation (TPSAB1, SERPINA1), and the glucocorticoid receptor (NR3C1) were analyzed using RT-qPCR. NR3C1, ZO-1 and OCLN protein expression were evaluated through immunohistochemistry and western blot, and mucosal inflammation through MC, lymphocyte, and eosinophil numbering. Autonomic, hormonal, and psychological responses to CPS were monitored. We found an increase in jejunal MCs, a reduced CLDN1 and OCLN expression, and an increased CLDN2 and SERPINA1 expression 90 min after CPS. We also found a significant decrease in ZO-1, OCLN, and NR3C1 gene expression, and a decrease in OCLN protein expression only in females, when compared to males. CPS induced a significant increase in blood pressure, plasma cortisol and ACTH, and subjective stress perception in all participants. Specific and independent sex-related molecular responses in epithelial barrier regulation are unraveled by acute stress in the jejunum of healthy subjects and may partially explain female predominance in IBS.
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Chi ZC. Progress in research of low-grade inflammation in irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2022; 30:1051-1065. [DOI: 10.11569/wcjd.v30.i24.1051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common intestinal disease with a prevalence of 10%-15%. However, its pathophysiology is still not completely clear, and it has long been considered as a functional disease. In recent years, it has been found that low-grade inflammation plays a pathogenic role in IBS. Studies have confirmed that there is persistent mucosal inflammation at the microscopic and molecular levels. This review discusses the evidence, role, and clinical relevance of mucosal inflammation in IBS. In addition to mucosal inflammation, neuroinflammation may lead to changes in neuroendocrine pathways and glucocorticoid receptor genes through the "gut-brain" axis, and thus cause IBS through proinflammatory phenotype and hypothalamic pituitary adrenal axis and 5-hydroxytryptamine dysfunction. The observation that IBS patients can benefit from anti-inflammatory therapy also confirms that IBS is associated with inflammation.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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15
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Mucosal Plasma Cell Activation and Proximity to Nerve Fibres Are Associated with Glycocalyx Reduction in Diarrhoea-Predominant Irritable Bowel Syndrome: Jejunal Barrier Alterations Underlying Clinical Manifestations. Cells 2022; 11:cells11132046. [PMID: 35805133 PMCID: PMC9265332 DOI: 10.3390/cells11132046] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/19/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells and epithelial integrity to gain understanding of IBS-D pathophysiology. One mucosal jejunal biopsy and one stool sample were obtained from healthy controls and IBS-D patients. Gastrointestinal symptoms, stress, and depression scores were recorded. In the jejunal mucosa, RNAseq and gene set enrichment analyses were performed. A morphometric analysis by electron microscopy quantified plasma cell activation and proximity to enteric nerves and glycocalyx thickness. Immunoglobulins concentration was assessed in the stool. IBS-D patients showed differential expression of humoral pathways compared to controls. Activation and proximity of plasma cells to nerves and IgG concentration were also higher in IBS-D. Glycocalyx thickness was lower in IBS-D compared to controls, and this reduction correlated with plasma cell activation, proximity to nerves, and clinical symptoms. These results support humoral activity and loss of epithelial integrity as important contributors to gut dysfunction and clinical manifestations in IBS-D. Additional studies are needed to identify the triggers of these alterations to better define IBS-D pathophysiology.
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16
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Olyaiee A, Sadeghi A, Yadegar A, Mirsamadi ES, Mirjalali H. Gut Microbiota Shifting in Irritable Bowel Syndrome: The Mysterious Role of Blastocystis sp. Front Med (Lausanne) 2022; 9:890127. [PMID: 35795640 PMCID: PMC9251125 DOI: 10.3389/fmed.2022.890127] [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: 03/07/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic disorder, which its causative agent is not completely clear; however, the interaction between microorganisms and gastrointestinal (GI) epithelial cells plays a critical role in the development of IBS and presenting symptoms. During recent decades, many studies have highlighted the high prevalence of Blastocystis sp. in patients with IBS and suggested a probable role for this protist in this disease. Recent studies have documented changes in the gut microbiota composition in patients with IBS regarding the presence of Blastocystis sp., but it is not clear that either disturbance of the gut during GI disorders is a favorable condition for Blastocystis sp. colonization or the presence of this protist may lead to alteration in the gut microbiota in IBS patients. In this review, we comprehensively gather and discuss scientific findings covering the role of Blastocystis sp. in IBS via gut microbiota shifting.
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Affiliation(s)
- Alireza Olyaiee
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elnaz Sadat Mirsamadi
- Department of Microbiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamed Mirjalali
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Huang H, Lu L, Chen Y, Zeng Y, Xu C. The efficacy of vitamin D supplementation for irritable bowel syndrome: a systematic review with meta-analysis. Nutr J 2022; 21:24. [PMID: 35509010 PMCID: PMC9069731 DOI: 10.1186/s12937-022-00777-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 04/14/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder involving gut-brain interactions with limited effective treatment options. Vitamin D deficiency is commonly observed in patients with IBS, but whether vitamin D supplementation ameliorates IBS is controversial in randomized controlled trials. The present systematic review and meta-analysis explored the efficacy of vitamin D supplementation in patients with IBS. METHODS We performed a systematic search of potentially relevant publications from PubMed, EMBASE, the Cochrane Central Register of Controlled Studies and the Web of Science up until January 2022. We assessed the weighted mean difference (WMD) and 95% confidence interval (95% CI) of the IBS severity scoring system (IBS-SSS), IBS quality of life (IBS-QoL) and IBS total score (IBS-TS) before and after vitamin D supplementation intervention. RESULTS We included four randomized, placebo-controlled trials involving 335 participants. The differences in IBS-SSS score between participants in the intervention group and the placebo group increased after intervention (WMD: -55.55, 95% CI: -70.22 to -40.87, I2 = 53.7%, after intervention; WMD: -3.17, 95% CI: -18.15 to 11.81, I2 = 0.0%, before intervention). Participants receiving vitamin D supplementation showed greater improvement in IBS-SSS after intervention than participants receiving placebo treatment (WMD: -84.21, 95% CI: -111.38 to -57.05, I2 = 73.2%; WMD: -28.29, 95% CI: -49.95 to -6.62, I2 = 46.6%, respectively). Vitamin D supplementation was also superior to placebo in IBS-QoL improvement (WMD: 14.98, 95% CI: 12.06 to 17.90, I2 = 0.0%; WMD: 6.55, 95% CI: -2.23 to 15.33, I2 = 82.7%, respectively). Sensitivity analyses revealed an unstable pooled effect on IBS-TS in participants receiving vitamin D supplementation. Therefore, we did not evaluate the efficacy of vitamin D intervention in IBS-TS. CONCLUSIONS This systematic review and meta-analysis suggested that vitamin D supplementation was superior to placebo for IBS treatment.
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Affiliation(s)
- Hangkai Huang
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
| | - Linjie Lu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
- Department of Gastroenterology, Haining Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, 314499, Haining, China
| | - Yishu Chen
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
| | - Yan Zeng
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
| | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China.
- Department of Gastroenterology, Haining Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, 314499, Haining, China.
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Kurin M, Elangovan A, Alikhan MM, Dulaijan BA, Silver E, Kaelber DC, Cooper G. Irritable bowel syndrome is strongly associated with the primary and idiopathic mast cell disorders. Neurogastroenterol Motil 2022; 34:e14265. [PMID: 34535952 PMCID: PMC9191257 DOI: 10.1111/nmo.14265] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/12/2021] [Accepted: 08/18/2021] [Indexed: 01/12/2023]
Abstract
BACKGROUND Mounting evidence supports a mechanistic association between irritable bowel syndrome (IBS) symptoms and mast cell hyperactivity. Yet, association between IBS and mast cell disorders (MCDs) has not been studied. We examined this association using two large databases and verified with manual chart review. METHODS The IBM Watson Health Explorys database (Somers, NY), an aggregate of electronic health record (EHR) data from over two dozen US healthcare systems, and Epic's SlicerDicer tool, a self-service tool containing de-identified data from the Epic EHR, were used to identify patients with IBS and MCDs. Patients with organic gastrointestinal disease or diseases associated with secondary mast cell hyperproliferation were excluded. Results were verified with manual chart review from two academic centers. KEY RESULTS Up to 4% of IBS patients had a comorbid MCD. IBS was strongly associated with all MCDs. The strongest association was between IBS and mast cell activation syndrome (OR 16.3; 95% CI 13.1-20.3). Odds ratios for IBS+urticaria, IBS+idiopathic urticaria, IBS+non-malignant mastocytosis, and IBS+mast cell malignancy ranged from 4.5 to 9.9. Patients from each of these overlap cohorts were predominantly female, and the overlap occurred with all IBS subtypes. Thorough endoscopic evaluation and comorbid mood disorders and migraines are more common in the overlap cohorts than in IBS alone. CONCLUSIONS/INFERENCES In a large US database encompassing >53 million patients over >20 years, patients with IBS are at least 4 times more likely to have a MCD than the general population. Further study of mast cell involvement in the pathogenesis of IBS is warranted.
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Affiliation(s)
- Michael Kurin
- Division of Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Abbinaya Elangovan
- Internal Medicine-Pediatrics Residency Program, MetroHealth Medical Center, Cleveland, OH
| | - Muhammed Mustafa Alikhan
- Internal Medicine Residency Program, Department of General Internal Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Basmah Al Dulaijan
- Internal Medicine Residency Program, Department of General Internal Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Eli Silver
- Division of Pediatric Allergy and Immunology, University Hospitals Cleveland Medical Center, Assistant Professor of Pediatrics, Case Western Reserve University, Cleveland, OH
| | - David C. Kaelber
- Center for Clinical Informatics Research and Education, The MetroHealth System and Departments of Internal Medicine, Pediatrics and Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland OH
| | - Gregory Cooper
- Gastroenterology Fellowship Program director, University Hospitals Cleveland Medical Center, Professor of Medicine, Oncology, Population and Quantitative Health Sciences, Case Western Reserve University
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Burns GL, Talley NJ, Keely S. Immune responses in the irritable bowel syndromes: time to consider the small intestine. BMC Med 2022; 20:115. [PMID: 35354471 PMCID: PMC8969236 DOI: 10.1186/s12916-022-02301-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction (DGBI), presenting as chronic abdominal pain and altered defaecation. Symptoms are often food related. Much work in the field has focused on identifying physiological, immune and microbial abnormalities in the colon of patients; however, evidence of small intestinal immune activation and microbial imbalance has been reported in small studies. The significance of such findings has been largely underappreciated despite a growing body of work implicating small intestinal homeostatic imbalance in the pathogenesis of DGBIs. MAIN TEXT Small intestinal mechanosensation is a characteristic feature of IBS. Furthermore, altered small intestinal barrier functions have been demonstrated in IBS patients with the diarrhoea-predominant subtype. Small intestinal bacterial overgrowth and increased populations of small intestinal mast cells are frequently associated with IBS, implicating microbial imbalance and low-grade inflammation in the pathogenesis of IBS. Furthermore, reports of localised food hypersensitivity responses in IBS patients implicate the small intestine as the site of immune-microbial-food interactions. CONCLUSIONS Given the association of IBS symptoms with food intake in a large proportion of patients and the emerging evidence of immune activation in these patients, the current literature suggests the pathogenesis of IBS is not limited to the colon but rather may involve dysfunction of the entire intestinal tract. It remains unclear if regional variation in IBS pathology explains the various symptom phenotypes and further work should consider the intestinal tract as a whole to answer this question.
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Affiliation(s)
- Grace L Burns
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Callaghan, New South Wales, Australia.,College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia.,Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Nicholas J Talley
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Callaghan, New South Wales, Australia.,College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia.,Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Simon Keely
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Callaghan, New South Wales, Australia. .,College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia. .,Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
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20
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Aguilera-Lizarraga J, Hussein H, Boeckxstaens GE. Immune activation in irritable bowel syndrome: what is the evidence? Nat Rev Immunol 2022; 22:674-686. [PMID: 35296814 DOI: 10.1038/s41577-022-00700-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2022] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS.
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Affiliation(s)
- Javier Aguilera-Lizarraga
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
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21
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Yoshimoto T, Oshima T, Huang X, Tomita T, Fukui H, Miwa H. Microinflammation in the intestinal mucosa and symptoms of irritable bowel syndrome. J Gastroenterol 2022; 57:62-69. [PMID: 34854984 DOI: 10.1007/s00535-021-01838-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/21/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Potential etiological mechanisms of irritable bowel syndrome (IBS) have been reported, and emerging data suggest that immune activation is present in a major subset of IBS, especially in those with diarrhea. Intestinal mucosal mast cell and intraepithelial lymphocyte (IEL) infiltration and related factors were examined in patients with IBS. In addition, the correlations of symptoms and micro-inflammation were assessed. METHODS Intestinal biopsy specimens were obtained from patients with IBS and controls. Mast cells and IELs were stained with specific antibodies. The mRNA levels of cytokines and chemokines were assessed by quantitative reverse transcription polymerase chain reaction. RESULTS Infiltration of mast cells in the duodenum was significantly higher in IBS patients than in control subjects. The infiltration of IELs was higher in the duodenum and terminal ileum of IBS patients compared to the control subjects. The numbers of duodenal and ileal IELs were significantly correlated. The number of IELs but not mast cells in the duodenum and terminal ileum was significantly correlated with diarrhea frequency in control subjects and IBS patients. The expression level of the chemotactic chemokine CXCL11 was significantly higher in the duodenum of IBS patients. CONCLUSION Duodenal mast cells and IELs were increased in IBS patients. In addition, a positive correlation was found between the number of duodenal and ileal IELs and the frequency of diarrhea. Given that the present study was strictly observational, further studies are needed to clarify the pathophysiological functions associated with micro-inflammation in IBS.
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Affiliation(s)
- Takanori Yoshimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Xinyi Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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22
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Lv Y, Wen J, Fang Y, Zhang H, Zhang J. Corticotropin-releasing factor receptor 1 (CRF-R1) antagonists: Promising agents to prevent visceral hypersensitivity in irritable bowel syndrome. Peptides 2022; 147:170705. [PMID: 34822913 DOI: 10.1016/j.peptides.2021.170705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022]
Abstract
Corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that coordinates the endocrine system, autonomic nervous system, immune system, and physiological behavior. CRF is a signaling regulator in the neuro-endocrine-immune (NEI) network that mediates visceral hypersensitivity. Rodent models to simulate changes in intestinal motility similar to those reported in the irritable bowel syndrome (IBS), demonstrate that the CRF receptor 1 (CRF-R1) mediates intestinal hypersensitivity under many conditions. However, the translation of preclinical studies into clinical trials has not been successful possibly due to the lack of sufficient understanding of the multiple variants of CRF-R1 and CRF-R1 antagonists. Investigating the sites of action of central and peripheral CRF is critical for accelerating the translation from preclinical to clinical studies.
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Affiliation(s)
- Yuanxia Lv
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
| | - Jing Wen
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
| | - Yingying Fang
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
| | - Haoyuan Zhang
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong City, China.
| | - Jianwu Zhang
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
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23
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A Survey of Methodologies for Assessing Mast Cell Density and Activation in Patients with Functional Abdominal Pain Disorders. GASTROINTESTINAL DISORDERS 2021. [DOI: 10.3390/gidisord3040016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim was to assess methods utilized in assessing mast cell involvement in functional abdominal pain disorders (FAPDs), specifically to describe variability in methods utilized to assess both mast cell density and activation and determine if a consensus exists. After a literature search identified 70 manuscripts assessing mast cell density, data were extracted including FAPD diagnosis, site of biopsy, selection of microscopic fields analyzed, selection of mucosal region analyzed, method of mast cell identification, method to assess mast cell density, and if performed, method to assess mast cell activation. There appears to be some consensus favoring inmmunohistochemical stains over histochemical stains for identifying mast cells. Otherwise, considerable variability exists in methodology for assessing mast cell density and activation. Regardless of method, approximately 80% of studies found increased mast cell density and/or activation in comparison to controls with no method being superior. A wide variety of methods have been employed to assess mast cell density and activation with no well-established consensus and inadequate data to recommend specific approaches. The current methodology providing physiologic information needs to be translated to a standard methodology providing clinical information with the development of criteria establishing abnormal density and/or activation, and more importantly, predicting treatment response.
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24
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Zhang YW, Li YJ, Lu PP, Dai GC, Chen XX, Rui YF. The modulatory effect and implication of gut microbiota on osteoporosis: from the perspective of "brain-gut-bone" axis. Food Funct 2021; 12:5703-5718. [PMID: 34048514 DOI: 10.1039/d0fo03468a] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Osteoporosis (OP) is a kind of systemic metabolic disease characterized by decreased bone mass and destruction of the bone microstructure. In recent years, it has become an expected research trend to explore the cross-linking relationship in the pathogenesis process of OP so as to develop reasonable and effective intervention strategies. With the further development of intestinal microbiology and the profound exploration of the gut microbiota (GM), it has been further revealed that the "brain-gut" axis may be a potential target for the bone, thereby affecting the occurrence and progression of OP. Hence, based on the concept of "brain-gut-bone" axis, we look forward to deeply discussing and summarizing the cross-linking relationship of OP in the next three parts, including the "brain-bone" connection, "gut-bone" connection, and "brain-gut" connection, so as to provide an emerging thought for the prevention strategies and mechanism researches of OP.
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Affiliation(s)
- Yuan-Wei Zhang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China. and Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China and School of Medicine, Southeast University, Nanjing, Jiangsu, China and Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, China and Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Ying-Juan Li
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China and Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Pan-Pan Lu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China. and Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China and School of Medicine, Southeast University, Nanjing, Jiangsu, China and Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, China and Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Guang-Chun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China. and Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China and School of Medicine, Southeast University, Nanjing, Jiangsu, China and Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, China and Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Xiang-Xu Chen
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China. and Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China and School of Medicine, Southeast University, Nanjing, Jiangsu, China and Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, China and Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China. and Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China and School of Medicine, Southeast University, Nanjing, Jiangsu, China and Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, China and Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
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25
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Jalanka J, Lam C, Bennett A, Hartikainen A, Crispie F, Finnegan LA, Cotter PD, Spiller R. Colonic Gene Expression and Fecal Microbiota in Diarrhea-predominant Irritable Bowel Syndrome: Increased Toll-like Receptor 4 but Minimal Inflammation and no Response to Mesalazine. J Neurogastroenterol Motil 2021; 27:279-291. [PMID: 33795545 PMCID: PMC8026366 DOI: 10.5056/jnm20205] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/23/2020] [Accepted: 11/09/2020] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Diarrhea-predominant irritable bowel syndrome (IBS-D) has been previously associated with evidence of immune activation and altered microbiota. Our aim is to assess the effect of the anti-inflammatory agent, mesalazine, on inflammatory gene expression and microbiota composition in IBS-D. Methods We studied a subset of patients (n = 43) from a previously published 12-week radomized placebo-controlled trial of mesalazine. Mucosal biopsies were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction for a range of markers of inflammation, altered permeability, and sensory receptors including Toll-like receptors (TLRs) at randomization after treatment. All biopsy data were compared to 21 healthy controls. Patient’s stool microbiota composition was analysed through 16S ribosomal RNA sequencing. Results We found no evidence of increased immune activation compared to healthy controls. However, we did find increased expression of receptors in both sensory pathways and innate immune response including TLR4. Higher TLR4 expression was associated with greater urgency. TLR4 expression correlated strongly with the expression of the receptors bradykinin receptor B2, chemerin chemokine-like receptor 1, and transient receptor potential cation channel, subfamily A, member 1 as well as TLR4’s downstream adaptor myeloid differentiation factor 88. Mesalazine had minimal effect on either gene expression or microbiota composition. Conclusions Biopsies from a well-characterized IBS-D cohort showed no substantial inflammation. Mesalazine has little effect on gene expression and its previous reported effect on fecal microbiota associated with much greater inflammation found in inflammatory bowel diseases is likely secondary to reduced inflammation. Increased expression of TLR4 and correlated receptors in IBS may mediate a general increase in sensitivity to external stimuli, particularly those that signal via the TLR system.
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Affiliation(s)
- Jonna Jalanka
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
| | - Ching Lam
- Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
| | - Andrew Bennett
- Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK.,FRAME Alternatives Laboratory, School of Life Sciences, University of Nottingham, Medical School, QMC, Nottingham, Notts, UK
| | - Anna Hartikainen
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Fiona Crispie
- Teagasc Food Research Center, Moorepark, Fermoy, Co. Cork, Ireland.,APC Microbiome Ireland, Cork, Ireland
| | - Laura A Finnegan
- Teagasc Food Research Center, Moorepark, Fermoy, Co. Cork, Ireland.,APC Microbiome Ireland, Cork, Ireland
| | - Paul D Cotter
- Teagasc Food Research Center, Moorepark, Fermoy, Co. Cork, Ireland.,APC Microbiome Ireland, Cork, Ireland
| | - Robin Spiller
- Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
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26
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Wang XJ, Carlson P, Chedid V, Maselli DB, Taylor AL, McKinzie S, Camilleri M. Differential mRNA Expression in Ileal Mucosal Biopsies of Patients With Diarrhea- or Constipation-Predominant Irritable Bowel Syndrome. Clin Transl Gastroenterol 2021; 12:e00329. [PMID: 33843785 PMCID: PMC8043738 DOI: 10.14309/ctg.0000000000000329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/17/2021] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Previous studies in patients with irritable bowel syndrome (IBS) showed immune activation, secretion, and barrier dysfunction in duodenal, jejunal, or colorectal mucosa. This study aimed to measure ileal mucosal expression of genes and proteins associated with mucosal functions. METHODS We measured by reverse transcription polymerase chain reaction messenger RNA (mRNA) expression of 78 genes (reflecting tight junction proteins, chemokines, innate immunity, ion channels, and transmitters) and 5 proteins (barrier, bile acid receptor, and ion exchanger) in terminal ileal mucosa from 11 patients with IBS-diarrhea (IBS-D), 17 patients with IBS-constipation (IBS-C), and 14 healthy controls. Fold changes in mRNA were calculated using 2(-Δ, ΔCT) formula. Group differences were measured using analysis of variance. Protein ratios relative to healthy controls were based on Western blot analysis. Nominal P values (P < 0.05) are reported. RESULTS In ileal mucosal biopsies, significant differences of mRNA expression in IBS-D relative to IBS-C were upregulation of barrier proteins (TJP1, FN1, CLDN1, and CLDN12), repair function (TFF1), and cellular functions. In ileal mucosal biopsies, mRNA expression in IBS-C relative to healthy controls was reduced GPBAR1 receptor, myosin light chain kinase (MYLK in barrier function), and innate immunity (TLR3), but increased mRNA expression of cadherin cell adhesion mechanisms (CTNNB1) and transport genes SLC9A1 (Na-H exchanger [NHE1]) and INADL (indirect effect on ion transport). DISCUSSION These data support a role of ileal mucosal dysfunction in IBS, including barrier dysfunction in IBS-D and alterations in absorption/secretion mechanisms in IBS-C.
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Affiliation(s)
- Xiao Jing Wang
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Paula Carlson
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Victor Chedid
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel B. Maselli
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Ann L. Taylor
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Sanna McKinzie
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
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Cheng L, Luo QQ, Chen SL. The role of intestinal mast cell infiltration in irritable bowel syndrome. J Dig Dis 2021; 22:143-151. [PMID: 33511763 DOI: 10.1111/1751-2980.12971] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 01/17/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
As an essential part of the immune system, mast cells (MCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Accumulating evidence has identified altered MC count and density in intestinal mucosa of patients with IBS; however, conflicting findings yield inconsistent conclusions. Currently, most studies have suggested intestinal MC infiltration in IBS patients. Considering the pivotal role of MCs in IBS, it is necessary to achieve a better understanding about the pathological changes in the intestine. The risk factors for IBS, including dietary habits, psychological factors, infection, and dysbiosis, are implicated to induce intestinal MC infiltration. Mechanistically, food may trigger immune-related allergic reactions and affect the intestinal microbiota activity. Some exogenous pathogens and altered profile of commensal bacteria promote intestinal MC recruitment through promoted release of chemokines from epithelial cells or direct activation of the immune system. In addition, psychological factors may affect the microenvironment where MCs live. MCs have been proven to interact with the enteric neurons and other immunocytes, evidenced by the close proximity of MCs to neurons and regional altered immune system components. A variety of mediators released by the enteric neurons, immunocytes, and MCs per se, such as neurotrophins, neuropeptides, cytokines, and chemokines, may have stimulant effects on MCs by modulating the survival, proliferation, and recruitment process of MCs in the intestine. In this review, the associations between IBS and intestinal MC density and the underlying mechanisms are discussed.
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Affiliation(s)
- Li Cheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qing Qing Luo
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Sheng Liang Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
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28
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Bellini M, Berti G, Bonfrate L, Ciranni F, Di Ciaula A, Di Ruscio M, Dell’Era A, Lambiase C, Noto A, Pancetti A, Portincasa P, Rettura F. Use of GELSECTAN ® in Patients with Irritable Bowel Syndrome (IBS): an Italian Experience. Patient Prefer Adherence 2021; 15:1763-1774. [PMID: 34413634 PMCID: PMC8370582 DOI: 10.2147/ppa.s318859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/04/2021] [Indexed: 02/05/2023] Open
Abstract
Irritable bowel syndrome is a chronic functional gastrointestinal disorder characterized by recurrent chronic abdominal pain and impaired bowel habits, which affects daily activity and work productivity, and is associated with a significant healthcare economic burden as well as an impaired quality of life and psycho-affective profile. Management of patients is a great challenge for physicians; at the present, the therapeutic strategy aimed to treat the different symptoms, and no medical therapy is proven to modify the natural history of the disease. GELSECTAN® (xyloglucan, pea protein and tannins, xylo-oligosaccharides) is a medical device with both protective and prebiotic actions on the intestinal mucosa, able to restore intestinal permeability and to improve gastrointestinal symptoms, controlling diarrhoea, abdominal pain and bloating in adult patients with irritable bowel syndrome. We report and discuss four cases of different patients with irritable bowel syndrome successfully managed with Gelsectan in the real clinical practice. Literature data, as well as these case reports, show that this device is effective and safe in improving symptoms and bowel habits associated to irritable bowel syndrome; its efficacy and safety were confirmed for the long-term use too. Agents with film-forming protective properties, such as Gelsectan, represent a new alternative therapeutic option for the management of patients with irritable bowel syndrome.
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Affiliation(s)
- Massimo Bellini
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Ginevra Berti
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Leonilde Bonfrate
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Flavia Ciranni
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Agostino Di Ciaula
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Mirko Di Ruscio
- IBD Unit, IRCCS Ospedale Sacro Cuore-Don Calabria, Negrar di Valpolicella, Verona, Italy
| | - Alessandra Dell’Era
- Department of Biomedical and Clinical Sciences, “Luigi Sacco”, University of Milan, Milan, Italy
- Gastroenterology and Endoscopy Unit – ASST Fatebenefratelli Sacco, Milan, Italy
| | - Christian Lambiase
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Antonino Noto
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Andrea Pancetti
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Piero Portincasa
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Francesco Rettura
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Correspondence: Francesco Rettura Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyTel +39 50 997411Fax +39 50 997412 Email
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McClain JL, Mazzotta EA, Maradiaga N, Duque-Wilckens N, Grants I, Robison AJ, Christofi FL, Moeser AJ, Gulbransen BD. Histamine-dependent interactions between mast cells, glia, and neurons are altered following early-life adversity in mice and humans. Am J Physiol Gastrointest Liver Physiol 2020; 319:G655-G668. [PMID: 32996781 PMCID: PMC7792668 DOI: 10.1152/ajpgi.00041.2020] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Early-life adversity contributes to the development of functional bowel disorders later in life through unresolved mechanisms. Here, we tested the hypothesis that early-life adversity alters anatomical and functional interactions between mast cells and enteric glia. The effects of early-life stress were studied using the neonatal maternal separation (NMS) stress mouse model. Anatomical relationships between mast cells and enteric glia were assessed using immunohistochemistry and mast cell reporter mice (Mcpt5Cre;GCaMP5g-tdT). Immunohistochemistry was used to assess the expression of histamine, histamine 1 (H1) receptors, and glial fibrillary acidic protein. Functional responses of glia to mast cell mediators were assessed in calcium imaging experiments using Sox10CreERT2;GCaMP5g-tdT mice and cultured human enteric glial cells. NMS increases mast cell numbers at the level of the myenteric plexus and their proximity to myenteric ganglia. Myenteric glia respond to mediators released by activated mast cells that are blocked by H1 receptor antagonists in mice and humans and by blocking neuronal activity with tetrodotoxin in mouse tissue. Histamine replicates the effects of mast cell supernatants on enteric glia, and NMS increases histamine production by mast cells. NMS reduces glial responses to mast cell mediators in mouse tissue, while potentiating responses in cultured human enteric glia. NMS increases myenteric glial fibrillary acidic protein expression and reduces glial process length but does not cause neurodegeneration. Histamine receptor expression is not altered by NMS and is localized to neurons in mice, but glia in humans. Early-life stress increases the potential for interactions between enteric glia and mast cells, and histamine is a potential mediator of mast cell-glial interactions through H1 receptors. We propose that glial-mast cell signaling is a mechanism that contributes to enteric neuroplasticity driven by early-life adversity.NEW & NOTEWORTHY Early-life adversity places an individual at risk for developing functional gastrointestinal disorders later in life through unknown mechanisms. Here, we show that interactions between mast cells and glia are disrupted by early-life stress in mice and that histamine is a potential mediator of mast cell-glial interactions.
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Affiliation(s)
- Jonathon L. McClain
- 1Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Elvio A. Mazzotta
- 2Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Nidia Maradiaga
- 3Gastrointestinal Stress Biology Laboratory, Department Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan
| | - Natalia Duque-Wilckens
- 1Department of Physiology, Michigan State University, East Lansing, Michigan,3Gastrointestinal Stress Biology Laboratory, Department Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan
| | - Iveta Grants
- 2Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Alfred J. Robison
- 1Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Fievos L. Christofi
- 2Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Adam J. Moeser
- 1Department of Physiology, Michigan State University, East Lansing, Michigan,3Gastrointestinal Stress Biology Laboratory, Department Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan
| | - Brian D. Gulbransen
- 1Department of Physiology, Michigan State University, East Lansing, Michigan
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Human Leukocyte Antigen (HLA) Haplotype Does Not Influence the Inflammatory Pattern of Duodenal Lymphocytosis Linked to Irritable Bowel Syndrome. ACTA ACUST UNITED AC 2020; 56:medicina56120660. [PMID: 33260434 PMCID: PMC7761368 DOI: 10.3390/medicina56120660] [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: 09/25/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 11/17/2022]
Abstract
Background and objectives: Duodenal lymphocytosis (DL) is a condition characterized by enhanced infiltration of intraepithelial lymphocytes (IELs) in the duodenal mucosa, and it can be linked to both gluten- and non-gluten-related diseases, such as irritable bowel syndrome (IBS). Materials and methods: We retrospectively selected patients with DL linked to IBS. Formalin-embedded biopsy samples of the duodenum were collected. CD3 lymphocyte immunohistochemistry was used for IELs. The real-time polymerase chain reaction was used to quantify the amount of mRNA coding for tissue transglutaminase 2 (tTG2), interferon-gamma (IFNγ), toll-like receptor 2 (TLR2), and myeloid differentiation primary response 88 (MyD88). All subjects underwent DQ2-8 haplotype analysis. Controls were represented by subjects with IBS without DL. Results: Thirty-two patients with IBS-DL were retrospectively recruited. Fourteen subjects (43.8%) had a DQ2-8 haplotype. DQ2-8 positive subjects had similar levels compared to negative ones for tTG2, IFNγ, TLR2, and MyD88. Cigarette smoke did not influence molecular expression in our study. Smokers had a statistically higher IELs count than non-smokers (54.2 ± 7.7 vs. 36.0 ± 8.8, p < 0.001). A significant, direct correlation between IELs and duodenal expression of IFNγ was found (r = 0.36, p = 0.04). Conclusions: IBS with DL showed higher expression of inflammatory markers than controls, but DQ2-8 haplotype did not seem to affect their expression. Smoking might increase IELs infiltration.
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Salvo-Romero E, Martínez C, Lobo B, Rodiño-Janeiro BK, Pigrau M, Sánchez-Chardi AD, González-Castro AM, Fortea M, Pardo-Camacho C, Nieto A, Expósito E, Guagnozzi D, Rodríguez-Urrutia A, de Torres I, Farré R, Azpiroz F, Alonso-Cotoner C, Santos J, Vicario M. Overexpression of corticotropin-releasing factor in intestinal mucosal eosinophils is associated with clinical severity in Diarrhea-Predominant Irritable Bowel Syndrome. Sci Rep 2020; 10:20706. [PMID: 33244004 PMCID: PMC7692489 DOI: 10.1038/s41598-020-77176-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 10/30/2020] [Indexed: 02/07/2023] Open
Abstract
Corticotropin-releasing factor (CRF) has been identified in intestinal mucosal eosinophils and associated with psychological stress and gut dysfunction. Irritable bowel syndrome (IBS) is commonly characterized by altered intestinal motility, immune activation, and increased gut barrier permeability along with heightened susceptibility to psychosocial stress. Despite intensive research, the role of mucosal eosinophils in stress-associated gut dysfunction remains uncertain. In this study, we evaluated eosinophil activation profile and CRF content in the jejunal mucosa of diarrhea-predominant IBS (IBS-D) and healthy controls (HC) by gene/protein expression and transmission electron microscopy. We also explored the association between intestinal eosinophil CRF and chronic stress, and the potential mechanisms underlying the stress response by assessing eosinophil response to neuropeptides. We found that mucosal eosinophils displayed higher degranulation profile in IBS-D as compared to HC, with increased content of CRF in the cytoplasmic granules, which significantly correlated with IBS clinical severity, life stress background and depression. Eosinophils responded to substance P and carbachol by increasing secretory activity and CRF synthesis and release, without promoting pro-inflammatory activity, a profile similar to that found in mucosal eosinophils from IBS-D. Collectively, our results suggest that intestinal mucosal eosinophils are potential contributors to stress-mediated gut dysfunction through CRF production and release.
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Affiliation(s)
- Eloísa Salvo-Romero
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain.
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Cristina Martínez
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
- Lleida Institute for Biomedical Research, Lleida, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Bruno K Rodiño-Janeiro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marc Pigrau
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Ana M González-Castro
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain
| | - Marina Fortea
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain
| | - Cristina Pardo-Camacho
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain
| | - Adoración Nieto
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain
| | - Danila Guagnozzi
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain
| | - Amanda Rodríguez-Urrutia
- Department of Psychiatry, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Inés de Torres
- Department of Pathology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ricard Farré
- Translational Research Center for Gastrointestinal Disorders (TARGID) KU, Leuven, Belgium
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Fernando Azpiroz
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - María Vicario
- Laboratory of Translational Mucosal Immunology, Digestive System Research Unit, Vall D'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Paseo Vall d'Hebron, 119-129, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
- Department of Gastrointestinal Health, Société Des Produits Nestlé S.A, Nestlé Research, Vers-chez-les-Blanc, 1000, Lausanne 26, Switzerland.
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32
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Li JJ, Ren WJ, Yin HY, Zhao YF, Tang Y. Underlying mechanisms for intestinal diseases arising from stress. Shijie Huaren Xiaohua Zazhi 2020; 28:617-627. [DOI: 10.11569/wcjd.v28.i14.617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Stress is an instinctive defense mechanism of the body in the competition for survival, but long-term or chronic stress will lead to systemic pathological manifestations. Intestinal diseases are closely related to pathological stress. This paper reviews the pathogenesis of intestinal diseases arising from stress.
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Affiliation(s)
- Jia-Jia Li
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China,Key Laboratory of Sichuan Province for Acupuncture and Chronobiology, Chengdu 610075, Sichuan Province, China
| | - Wen-Jing Ren
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China,Key Laboratory of Sichuan Province for Acupuncture and Chronobiology, Chengdu 610075, Sichuan Province, China
| | - Hai-Yan Yin
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China,Key Laboratory of Sichuan Province for Acupuncture and Chronobiology, Chengdu 610075, Sichuan Province, China
| | - Ya-Fei Zhao
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China,Key Laboratory of Sichuan Province for Acupuncture and Chronobiology, Chengdu 610075, Sichuan Province, China
| | - Yong Tang
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China,Key Laboratory of Sichuan Province for Acupuncture and Chronobiology, Chengdu 610075, Sichuan Province, China
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33
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Ferreira AI, Garrido M, Castro-Poças F. Irritable Bowel Syndrome: News from an Old Disorder. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2020; 27:255-268. [PMID: 32775547 PMCID: PMC7383263 DOI: 10.1159/000503757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/20/2019] [Indexed: 12/16/2022]
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, which can affect all members of a society, regardless of age, sex, race or socioeconomic status. Because of its high prevalence and chronic nature, it represents a significant economic burden. In fact, these patients have a relevant impairment of their quality of life, which limits their work productivity and daily social activities, especially when it is associated with other disorders, such as anxiety and depression. The diagnosis of IBS relies on symptom-based diagnostic criteria with normal results on a limited number of complementary tests that rule out other possible diagnoses. The aetiology of this condition is incompletely established. However, evidence suggests that it is a multifactorial disorder with several different mechanisms that have been implicated as responsible for the symptoms. Since the treatment strategy is usually based on predominant symptoms and their severity, it is important to recognise the underlying mechanisms in order to successfully relief the visceral pain and altered bowel habits. The aim of this non-systematic review of the literature was to explore the pathophysiology and treatment options of IBS, highlighting the most recent evidence, from the new Rome IV criteria to the new drug armamentarium.
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Affiliation(s)
- Ana Isabel Ferreira
- Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Mónica Garrido
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Fernando Castro-Poças
- Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
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34
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Casado-Bedmar M, Keita ÅV. Potential neuro-immune therapeutic targets in irritable bowel syndrome. Therap Adv Gastroenterol 2020; 13:1756284820910630. [PMID: 32313554 PMCID: PMC7153177 DOI: 10.1177/1756284820910630] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/11/2020] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by recurring abdominal pain and disturbed bowel habits. The aetiology of IBS is unknown but there is evidence that genetic, environmental and immunological factors together contribute to the development of the disease. Current treatment of IBS includes lifestyle and dietary interventions, laxatives or antimotility drugs, probiotics, antispasmodics and antidepressant medication. The gut-brain axis comprises the central nervous system, the hypothalamic pituitary axis, the autonomic nervous system and the enteric nervous system. Within the intestinal mucosa there are close connections between immune cells and nerve fibres of the enteric nervous system, and signalling between, for example, mast cells and nerves has shown to be of great importance during GI disorders such as IBS. Communication between the gut and the brain is most importantly routed via the vagus nerve, where signals are transmitted by neuropeptides. It is evident that IBS is a disease of a gut-brain axis dysregulation, involving altered signalling between immune cells and neurotransmitters. In this review, we analyse the most novel and distinct neuro-immune interactions within the IBS mucosa in association with already existing and potential therapeutic targets.
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Affiliation(s)
- Maite Casado-Bedmar
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Åsa V. Keita
- Department of Biomedical and Clinical Sciences, Medical Faculty, Linköping University, Campus US, Linköping, 581 85, Sweden
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35
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Liu Y, Yuan X, Li L, Lin L, Zuo X, Cong Y, Li Y. Increased Ileal Immunoglobulin A Production and Immunoglobulin A-Coated Bacteria in Diarrhea-Predominant Irritable Bowel Syndrome. Clin Transl Gastroenterol 2020; 11:e00146. [PMID: 32352710 PMCID: PMC7145038 DOI: 10.14309/ctg.0000000000000146] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Immune activation and intestinal microbial dysbiosis could induce diarrhea-predominant irritable bowel syndrome (IBS-D). We examined the roles of ileal immunoglobulin A (IgA) and IgA-coated bacteria in IBS-D pathogenesis. METHODS Peripheral blood, fecal samples, and ileal and cecal biopsies were collected from 32 healthy volunteers and 44 patients with IBS-D. Quantitative reverse transcriptase polymerase chain reaction was used to assess differential gene expression. IgA levels in the blood and fecal samples were quantified by an enzyme-linked immunosorbent assay. IgA cells were assessed by immunofluorescence imaging. Flow-cytometry-based IgA bacterial cell sorting and 16S rRNA gene sequencing (IgA-SEQ) was used to isolate and identify fecal IgA bacteria. RESULTS Fecal IgA, particularly IgA1, was upregulated in patients with IBS-D. IgA class switch and B cell-activating factor-receptor were increased in the terminal ileum of patients. The intestinal microbiota composition was altered in patients compared with that in controls. IgA-SEQ showed that the proportion of fecal IgA-coated bacteria was increased significantly in patients with IBS-D. IgA bacteria in patients with IBS-D showed higher abundances of Escherichia-Shigella, Granulicatella, and Haemophilus compared with healthy controls and IgA bacteria in patients with IBS-D. The Escherichia-Shigella IgA coating index was positively correlated with anxiety and depression. The Escherichia-Shigella relative abundance, luminal IgA activity, and some altered IgA-coated bacteria were positively associated with the clinical manifestations of IBS-D. DISCUSSION Microbial dysbiosis may promote the terminal ileal mucosa to produce higher levels of IgA, increasing the proportion of IgA-coated bacteria by activating IgA class switching, which might regulate local inflammation and clinical manifestations in IBS-D. IgA may mediate the effects of microbial dysbiosis on the pathogenesis of IBS-D.
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Affiliation(s)
- Yi Liu
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xunyi Yuan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lin Lin
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiuli Zuo
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
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36
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Dizdar V, Hausken T, Laerum OD, Gilja OH, Langeland N, Hanevik K. Prolonged Duodenal Mucosal Lymphocyte Alterations in Patients With and Without Postinfectious Functional Gastrointestinal Disorders After Giardia Infection. J Infect Dis 2020; 220:321-329. [PMID: 30500895 PMCID: PMC6581897 DOI: 10.1093/infdis/jiy690] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 11/28/2018] [Indexed: 12/12/2022] Open
Abstract
Background Persisting low-grade inflammation is suggested to play a role in postinfectious functional gastrointestinal disorders (PI-FGIDs). The present study examined alterations in duodenal mucosal lymphocytes during and after Giardia gastroenteritis in patients who did, or did not, develop PI-FGIDs. Methods Duodenal mucosal intraepithelial lymphocytes (IELs) and lamina propria CD3, CD4, CD8, and CD20 lymphocytes were quantified in 28 patients with chronic giardiasis (CG), 66 patients with persistent abdominal symptoms after acute Giardia infection (PI-FGID), 19 recovered controls (RCs), and 16 healthy volunteers (HCs). Associations with illness duration, abdominal symptoms, and histology grade were assessed. Results Duodenal CD4 IELs were significantly elevated in CG, then decreased, followed by an upward trend after 1 year in both the PI-FGID and RC groups. Duodenal lamina propria crypt CD4 T cells were decreased in CG, and stayed low for about 14 months before normalizing in both the PI-FGID and RC groups. Lamina propria CD20 cells were persistently elevated in all 3 Giardia-exposed groups. Biopsies with microscopic inflammation showed increased lamina propria CD20 levels. Conclusions Duodenal mucosal lymphocyte alterations were prolonged after Giardia infection, but similar in patients who developed PI-FGID and recovered asymptomatic controls.
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Affiliation(s)
- Vernesa Dizdar
- Department of Medicine, Section of Gastroenterology, Department of Medicine, Bergen, Norway.,National Centre of Functional Gastrointestinal Disorders, Section of Gastroenterology, Department of Medicine, Bergen, Norway
| | - Trygve Hausken
- National Centre of Functional Gastrointestinal Disorders, Section of Gastroenterology, Department of Medicine, Bergen, Norway.,National Centre of Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
| | - Ole D Laerum
- Gade Laboratory of Pathology, Department of Clinical Research, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Odd Helge Gilja
- Department of Medicine, Section of Gastroenterology, Department of Medicine, Bergen, Norway.,National Centre of Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
| | - Nina Langeland
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.,Haraldsplass Deaconess Hospital, Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Kurt Hanevik
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.,Norwegian National Advisory Unit on Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Abstract
Chronic unexplained gastrointestinal symptoms impact more than 1 in 5 Americans and their families; these disorders include the irritable bowel syndrome (IBS) and functional dyspepsia (FD), currently classified by Rome IV as functional gastrointestinal disorders. By definition, IBS and FD have no established pathology, but emerging evidence suggests this paradigm may need revision. Immune activation and, in subsets, subtle intestinal pathology have been identified in FD (most notably, postprandial distress syndrome) and IBS-diarrhea. A disease model is proposed that accounts for all of the intestinal and extraintestinal symptoms, relationship to food and infection, and the overlap with gastroesophageal reflux disease. It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the intestine with low-grade intestinal inflammation and subsequently neuronal structural and functional alterations, producing regional intestinal hypersensitivity and motor dysfunction. Immune activation may explain the female predominance and fluctuations in immune activity for symptom variability over time. In the future, as further evidence accumulates, the management paradigm may potentially shift to objective pathology-based subtyping based on serological, microbiological, and clinical assessments to identify when targeted therapies should be deployed in subsets. Potential targeted interventions may include therapies to dampen down immune activation or block release of key mediators such as histamine, specific microbial targeted treatments that may reverse disease, and dietary advice to eliminate relevant food antigens after objective in vivo testing. Only by identifying causation can we eventually anticipate cure, and as the true pathology unravels in subsets, this may become a reality.
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38
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Robles A, Perez Ingles D, Myneedu K, Deoker A, Sarosiek I, Zuckerman MJ, Schmulson MJ, Bashashati M. Mast cells are increased in the small intestinal mucosa of patients with irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol Motil 2019; 31:e13718. [PMID: 31498961 DOI: 10.1111/nmo.13718] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/05/2019] [Accepted: 08/20/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Colonic mast cells have been proposed to be related to the pathophysiology of irritable bowel syndrome (IBS). Whether mast cell counts are altered in the small intestine, a less-explored region in patients with IBS is not completely clear. METHODS PubMed and EMBASE were searched for case-control studies on mast cell count/density in the small intestine of patients with IBS vs controls through February 2019. Mast cell counts were separately analyzed in the duodenum, jejunum, and ileum. Data were pooled using the standardized mean difference (SMD) method. When zero was not within the 95% confidence interval (CI), the SMD was considered significant. KEY RESULTS Data from 344 patients with IBS and 229 healthy controls from three studies in the duodenum, six in the jejunum, and five in the ileum were pooled in this meta-analysis. The number of mast cells was significantly higher in the ileum (SMD: 1.78 [95% CI: 0.89, 2.66]) of patients with IBS. Mast cell counts were not significantly different in the duodenum (SMD: 0.81 [-0.06, 1.67]) or the jejunum (SMD: 0.58 [-0.03, 1.19]) of patients with IBS vs healthy controls. CONCLUSIONS AND INFERENCES Mast cells are increased in the small intestine of IBS vs controls, mainly in the ileum. Future studies should address whether such findings are IBS subtype or gender-dependent. Methodological variations, single-center bias, and the limited number of studies included in this meta-analysis may affect the final results.
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Affiliation(s)
- Alejandro Robles
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - David Perez Ingles
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Kanchana Myneedu
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Abhizith Deoker
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Irene Sarosiek
- Division of Gastroenterology, Department of Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Marc J Zuckerman
- Division of Gastroenterology, Department of Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Max J Schmulson
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM)-Unidad de Investigación en Medicina Experimental, Facultad de Medicina-Universidad Nacional Autónoma de México (UNAM), Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Mohammad Bashashati
- Division of Gastroenterology, Department of Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
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Trifan A, Burta O, Tiuca N, Petrisor DC, Lenghel A, Santos J. Efficacy and safety of Gelsectan for diarrhoea-predominant irritable bowel syndrome: A randomised, crossover clinical trial. United European Gastroenterol J 2019; 7:1093-1101. [PMID: 31662866 PMCID: PMC6794699 DOI: 10.1177/2050640619862721] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/18/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is highly prevalent and presents a clinical challenge. Gelsectan is a medical device containing xyloglucan (XG), pea protein and tannins (PPT) from grape seed extract, and xylo-oligosaccharides (XOS), which act together to protect and reinforce the intestinal barrier. OBJECTIVE The objective of this study is to evaluate the efficacy and safety of XG + PPT + XOS in patients with diarrhoea-predominant IBS (IBS-D). METHODS In this double-blind study, 60 patients were randomly assigned to receive XG + PPT + XOS or placebo for 28 days, then crossed over to the alternative treatment. Patients were followed for 60 days. RESULTS At Day 28, a significantly higher proportion of patients starting treatment with XG + PPT + XOS than placebo (87 vs 0%; p = 0.0019) presented normal stools (Bristol Stool Form Scale type 3-4). At Day 56, a significantly higher proportion of patients who crossed over to XG + PPT + XOS than placebo (93% vs 23%; p = 0.0001) presented normal stools. In the group allocated to receive XG + PPT + XOS after placebo, benefits of XG + PPT + XOS were maintained during follow-up. Subjective assessments of abdominal pain, bloating, quality of life and general health indicated significant improvement with XG + PPT + XOS over placebo. There were no related adverse events. CONCLUSION XG + PPT + XOS effectively controlled diarrhoea and alleviated clinical symptoms in patients with IBS-D, and was well tolerated.
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Affiliation(s)
| | - Ovidiu Burta
- Department of Internal Medicine,
Municipal Hospital Dr. Gavril Curteanu, Oradea, Romania
| | - Nicoleta Tiuca
- Department of Internal Medicine,
University
Emergency Hospital Bucharest, Romania
| | | | | | - Javier Santos
- Digestive System Research Unit,
University Hospital Vall d'Hebron, Spain
- Javier Santos, University Hospital Vall
d'Hebron, Digestive System Research Unit, Laboratory of
Neuro-Immuno-Gastroenterology, Passeig Vall d'Hebron 119–129, Barcelona 08035,
Spain.
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Rodiño-Janeiro BK, Pardo-Camacho C, Santos J, Martínez C. Mucosal RNA and protein expression as the next frontier in IBS: abnormal function despite morphologically intact small intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 2019; 316:G701-G719. [PMID: 30767681 DOI: 10.1152/ajpgi.00186.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Irritable bowel syndrome (IBS) is one of the commonest gastrointestinal disorders. Although long-time considered a pure functional disorder, intense research in past years has rendered a very complex and varied array of observations indicating the presence of structural and molecular abnormalities underlying characteristic motor and sensitive changes and clinical manifestations. Analysis of gene and protein expression in the intestinal mucosa has shed light on the molecular mechanisms implicated in IBS physiopathology. This analysis uncovers constitutive and inductive genetic and epigenetic marks in the small and large intestine that highlight the role of epithelial barrier, immune activation, and mucosal processing of foods and toxins and several new molecular pathways in the origin of IBS. The incorporation of innovative high-throughput techniques into IBS research is beginning to provide new insights into highly structured and interconnected molecular mechanisms modulating gene and protein expression at tissue level. Integration and correlation of these molecular mechanisms with clinical and environmental data applying systems biology/medicine and data mining tools emerge as crucial steps that will allow us to get meaningful and more definitive comprehension of IBS-detailed development and show the real mechanisms and causality of the disease and the way to identify more specific diagnostic biomarkers and effective treatments.
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Affiliation(s)
- Bruno Kotska Rodiño-Janeiro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain
| | - Cristina Pardo-Camacho
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas , Madrid , Spain
| | - Cristina Martínez
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain
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Wilson B, Rossi M, Dimidi E, Whelan K. Prebiotics in irritable bowel syndrome and other functional bowel disorders in adults: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2019; 109:1098-1111. [PMID: 30949662 DOI: 10.1093/ajcn/nqy376] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 12/10/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) and other functional bowel disorders (FBDs) are prevalent disorders with altered microbiota. Prebiotics positively augment gut microbiota and may offer therapeutic potential. OBJECTIVES The aim of this study was to investigate the effect of prebiotics compared with placebo on global response, gastrointestinal symptoms, quality of life (QoL), and gut microbiota, via systematic review and meta-analysis of randomized controlled trials (RCTs) in adults with IBS and other FBDs. METHODS Studies were identified using electronic databases, back-searching reference lists, and hand-searching abstracts. RCTs that compared prebiotics to placebo in adults with IBS or other FBDs were included. Two reviewers independently performed screening, data extraction, and bias assessment. Outcome data were synthesized as ORs, weighted mean differences (WMDs) or standardized mean differences (SMDs) with the use of a random-effects model. Subanalyses were performed for type of FBD and dose, type, and duration of prebiotic. RESULTS Searches identified 2332 records, and 11 RCTs were eligible (729 patients). The numbers responding were 52/97 (54%) for prebiotic and 59/94 (63%) for placebo, with no difference between groups (OR: 0.62; 95% CI: 0.07, 5.69; P = 0.67). Similarly, no differences were found for severity of abdominal pain, bloating and flatulence, and QoL score between prebiotics and placebo. However, flatulence severity was improved by prebiotics at doses ≤6 g/d (SMD: -0.35; 95% CI: -0.71, 0.00; P = 0.05) and by non-inulin-type fructan prebiotics (SMD: -0.34; 95% CI: -0.66, -0.01; P = 0.04), while inulin-type fructans worsened flatulence (SMD: 0.85; 95% CI: 0.23, 1.47; P = 0.007). Prebiotics increased absolute abundance of bifidobacteria (WMD: 1.16 log10 copies of the 16S ribosomal RNA gene; 95% CI: 0.06, 2.26; P = 0.04). No studies were at low risk of bias across all bias categories. CONCLUSIONS Prebiotics do not improve gastrointestinal symptoms or QoL in patients with IBS or other FBDs, but they do increase bifidobacteria. Variations in prebiotic type and dose impacted symptom improvement or exacerbation. This review was registered at PROSPERO as CRD42017074072.
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Affiliation(s)
- Bridgette Wilson
- Department of Nutritional Sciences, King's College London, London, United Kingdom
| | - Megan Rossi
- Department of Nutritional Sciences, King's College London, London, United Kingdom
| | - Eirini Dimidi
- Department of Nutritional Sciences, King's College London, London, United Kingdom
| | - Kevin Whelan
- Department of Nutritional Sciences, King's College London, London, United Kingdom
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Barbalho SM, Goulart RDA, Araújo AC, Guiguer ÉL, Bechara MD. Irritable bowel syndrome: a review of the general aspects and the potential role of vitamin D. Expert Rev Gastroenterol Hepatol 2019; 13:345-359. [PMID: 30791775 DOI: 10.1080/17474124.2019.1570137] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Irritable Bowel Syndrome (IBS) is a bowel disorder leading to symptoms such as abdominal pain, modifications in the motility and bowel habits, distention, bloating, and gas. Vitamin D (VD) may interfere in a plethora of cellular mechanisms, and act directly or indirectly in the regulation of the microbiome, the release of anti-microbial peptides, modulation of the immune system and inflammation processes; which in turn, may positively interfere with the altered gut function. The main purpose of this review was to survey studies involving the impacts of VD on IBS. Area covered: Eligible studies including the term VD and IBS were searched in the MEDLINE-PubMed and EMBASE (2009-2018). VD may act direct or indirectly in the regulation of the gut microbiome, immune response, and psychosocial factors that may be included in the list of IBS triggering factors. Expert opinion: Once VD plays an essential role in many processes associated with IBS, its deficiency may be associated with IBS, and the supplementation could help in the therapeutic approach for this condition. For these reasons, the understanding of the association of VD in IBS is indispensable for the development of new strategies that could improve the quality of life of the patient.
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Affiliation(s)
- Sandra Maria Barbalho
- a Medical School of Marília , UNIMAR , São Paulo , Brazil.,b Department of Nutrition , Food Technology School , São Paulo , Brazil
| | | | | | - Élen Landgraf Guiguer
- a Medical School of Marília , UNIMAR , São Paulo , Brazil.,b Department of Nutrition , Food Technology School , São Paulo , Brazil
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Siah KTH. Airborne allergen, allergy & atopic IBS. Neurogastroenterol Motil 2019; 31:e13517. [PMID: 30793844 DOI: 10.1111/nmo.13517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Kewin Tien Ho Siah
- Division of Gastroenterology & Hepatology, University Medicine Cluster, National University Health System, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Burns G, Carroll G, Mathe A, Horvat J, Foster P, Walker MM, Talley NJ, Keely S. Evidence for Local and Systemic Immune Activation in Functional Dyspepsia and the Irritable Bowel Syndrome: A Systematic Review. Am J Gastroenterol 2019; 114:429-436. [PMID: 30839392 DOI: 10.1038/s41395-018-0377-0] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Subtle histopathologic features such as eosinophilia and increased mast cells have been observed in functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and the irritable bowel syndrome (IBS). The mechanisms that drive recruitment of these cells to the gastrointestinal tract remain unexplained, largely due to the heterogeneity in phenotypes among patients diagnosed with such conditions. We aimed to systematically review the literature and collate the evidence for immune activation in FD and IBS, and where possible, detail the nature of activation. METHODS Seven literature databases were searched using the keywords: 'functional gastrointestinal disorder', FGID, 'functional dyspepsia', 'non-ulcer dyspepsia', 'idiopathic dyspepsia', 'irritable bowel syndrome', IBS and 'immun*'. RESULTS Fifty-one papers reporting discordant immune features met the selection criteria for this review. Changes in lymphocyte populations, including B and T lymphocyte numbers and activation status were reported in IBS and FD, in conjunction with duodenal eosinophilia in FD and increased colonic mast cells in IBS. Increases in circulating α4+β7+ gut-homing T cells appear to be linked to the pathophysiology of both FD and IBS. Studies in the area are complicated by poor phenotyping of patients into subgroups and the subtle nature of the immune activity involved in FD and IBS. CONCLUSIONS Alterations in proportions of gut-homing T lymphocytes in both FD and IBS indicate that a loss of mucosal homeostasis may drive the symptoms of FD and IBS. There is indirect evidence that Th17 responses may play a role in FGIDs, however the evidence for a Th2 immune phenotype in FD and IBS is limited. Although immune involvement is evident, large, well-characterised patient cohorts are required to elucidate the immune mechanisms driving the development of FGIDs.
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Affiliation(s)
- Grace Burns
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
- Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, NSW, Australia
| | - Georgia Carroll
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
- Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, NSW, Australia
- School of Medicine & Public Health, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
| | - Andrea Mathe
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
- Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, NSW, Australia
| | - Jay Horvat
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
| | - Paul Foster
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
| | - Marjorie M Walker
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
- Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, NSW, Australia
- School of Medicine & Public Health, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
| | - Nicholas J Talley
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
- Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, NSW, Australia
- School of Medicine & Public Health, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
| | - Simon Keely
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
- Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, NSW, Australia
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Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis. Cells 2019; 8:cells8020135. [PMID: 30744042 PMCID: PMC6407111 DOI: 10.3390/cells8020135] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 02/01/2019] [Accepted: 02/02/2019] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract harbours the largest population of mast cells in the body; this highly specialised leukocyte cell type is able to adapt its phenotype and function to the microenvironment in which it resides. Mast cells react to external and internal stimuli thanks to the variety of receptors they express, and carry out effector and regulatory tasks by means of the mediators of different natures they produce. Mast cells are fundamental elements of the intestinal barrier as they regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuro-immune interactions, which are key to functioning of the gut. Disruption of the intestinal barrier is associated with increased passage of luminal antigens into the mucosa, which further facilitates mucosal mast cell activation, inflammatory responses, and altered mast cell⁻enteric nerve interaction. Despite intensive research showing gut dysfunction to be associated with increased intestinal permeability and mucosal mast cell activation, the specific mechanisms linking mast cell activity with altered intestinal barrier in human disease remain unclear. This review describes the role played by mast cells in control of the intestinal mucosal barrier and their contribution to digestive diseases.
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Fan W, Fei G, Li X, Wang X, Hu C, Xin H, Sun X, Li Y, Wood JD, Fang X. Sera with anti-enteric neuronal antibodies from patients with irritable bowel syndrome promote apoptosis in myenteric neurons of guinea pigs and human SH-Sy5Y cells. Neurogastroenterol Motil 2018; 30:e13457. [PMID: 30230140 DOI: 10.1111/nmo.13457] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 07/29/2018] [Accepted: 08/01/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Sera anti-enteric neuronal antibodies (AENA), neuronal inflammation, and degeneration in myenteric plexus in patients with irritable bowel syndrome (IBS) were reported. Effects of sera AENA in patients with IBS are unclear. METHODS Patients with IBS met Rome III criteria were enrolled. Controls included healthy subjects (HS) and patients with slow transit functional constipation, inflammatory bowel disease, chronic intestinal pseudo-obstruction, and autoimmune diseases. Indirect immunofluorescence was used to detect AENA. Anti-enteric neuronal antibodies intensities were termed as "1" = weak fluorescence (mild positive); "2" = moderate fluorescence (moderate positive); "3" = very high fluorescence (intensive positive). Intensities of ≥1 were defined as positive and ≥2 were defined as obvious positive. Cultured myenteric neurons of small intestine from guinea pigs and human SH-Sy5Y cells were incubated with fetal bovine serum (FBS), HS sera, or IBS sera with or without AENA. Indirect immunofluorescence with anti-PGP9.5/DAPI/anti-active caspase-3 or TUNEL, Western blot, and flow cytometry were used to detect apoptosis. KEY RESULTS Overall, 293 patients with IBS were enrolled (41.7 ± 11.5 years). AENA-positive and obvious positive rates in IBS were higher than HS (76.8% vs 33%; 43.7% vs 7%; all P < 0.001). Myenteric neurons incubated with AENA moderate or intensive positive IBS sera showed higher rates of anti-active caspase-3 and TUNEL-positive cells than HS or FBS (20% ± 7.3% and 35% ± 13.3% vs 4.3% ± 1.5% and 0.9% ± 0.4%, respectively; 6.2% ± 2.0% and 10.2% ± 4.6% vs 1.3% ± 1.9% and 0.5%±0.5%, respectively; all P < 0.05). Human SH-Sy5Y cells incubated with AENA moderate or intensive positive IBS sera showed increased cleaved caspase-3 and Bax expression and decreased Bcl-2 expression. Flow cytometry showed apoptosis rates of these two groups were higher than that of AENA mild positive, negative, HS, and FBS (7.6%±0.8% and 10.7%±1.3% vs 5.0%±0.8%, 3.8%±0.3%, 3.4%±0.2% and, 2.8%±0.2%, P < 0.05). CONCLUSIONS AND INFERENCES The AENA obvious positive rate in patients with IBS was higher than HS, and sera with higher levels of AENA promoted neuronal apoptosis. AENA-mediated neuropathy might exist in a subset of patients with IBS.
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Affiliation(s)
- Wenjuan Fan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guijun Fei
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoqing Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiyu Wang
- Department of Physiology and Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Chaojun Hu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haiwei Xin
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaohong Sun
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongzhe Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jackie D Wood
- Department of Physiology and Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Xiucai Fang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Skonieczna-Żydecka K, Stachowska E, Maciejewska D, Ryterska K, Palma J, Czerwińska-Rogowska M, Kaczmarczyk M, Gudan A, Mruk H, Świniarska B, Kałduńska J, Stachowska Z, Mijal P, Mazur T, Kupczyński M, Marlicz W. The Digestive Health among Participants of the Woodstock Rock Festival in Poland-A Cross-Sectional Survey. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:E2256. [PMID: 30326654 PMCID: PMC6210346 DOI: 10.3390/ijerph15102256] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/08/2018] [Accepted: 10/11/2018] [Indexed: 12/12/2022]
Abstract
Alterations of gut microbiota, intestinal barrier and the gut-brain axis may be involved in pathophysiology of functional gastrointestinal disorders. Our aim was to assess the prevalence of digestive tract symptoms and identify common variables potentially disrupting the gut-brain axis among participants of the Woodstock Festival Poland, 2017. In total 428 people filled in a questionnaire assessing health of their digestive tract. The investigator collected answers on an electronic device, while the study participant responded using a paper version of the same questionnaire. Liver and gallbladder related symptoms were the most prevalent among our study group (n = 266, 62%), however symptoms related to altered intestinal permeability were found to be the most intensive complaints. In females the intensity of gastrointestinal complaints was higher compared to men (p < 0.05), as well as the incidence of factors with the potential to alter gut-brain axis (p < 0.0001). Chronic psychological distress, intake of non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics, were the most common associations with gastrointestinal symptoms, which were the most prevalent in females. Further attention should be focused on stress as one of the main factors negatively influencing public health.
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Affiliation(s)
| | - Ewa Stachowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Dominika Maciejewska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Karina Ryterska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Joanna Palma
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Maja Czerwińska-Rogowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Mariusz Kaczmarczyk
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland.
| | - Anna Gudan
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Honorata Mruk
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Barbara Świniarska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Justyna Kałduńska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Zofia Stachowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Przemysław Mijal
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Tomasz Mazur
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Maciej Kupczyński
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-460 Szczecin, Poland.
| | - Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, 71-252 Szczecin, Poland.
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Moser AM, Spindelboeck W, Halwachs B, Strohmaier H, Kump P, Gorkiewicz G, Högenauer C. Effects of an oral synbiotic on the gastrointestinal immune system and microbiota in patients with diarrhea-predominant irritable bowel syndrome. Eur J Nutr 2018; 58:2767-2778. [PMID: 30251020 PMCID: PMC6768888 DOI: 10.1007/s00394-018-1826-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 09/18/2018] [Indexed: 12/22/2022]
Abstract
Purpose Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disorder. Probiotics and synbiotics have been shown to improve symptoms of IBS, although mechanisms of action are currently not understood. Methods We investigated the effects of a 4-week oral synbiotic treatment (OMNi-BiOTiC® Stress Repair) in ten IBS-D patients on gastrointestinal mucosal and fecal microbiota, mucosa-associated immune cells, and fecal short-chain fatty acids. The upper and lower gastrointestinal tracts were compared before and after a 4-week synbiotic treatment using endoscopic evaluation to collect mucosal specimens for FACS analysis and mucosal 16S rRNA gene analysis. In stool samples, analysis for fecal SCFAs using GC–MS, fecal zonulin using ELISA, and fecal 16S rRNA gene analysis was performed. Results Synbiotics led to an increased microbial diversity in gastric (p = 0.008) and duodenal (p = 0.025) mucosal specimens. FACS analysis of mucosal immune cells showed a treatment-induced reduction of CD4+ T cells (60 vs. 55%, p = 0.042) in the ascending colon. Short-chain fatty acids (acetate 101 vs. 202 µmol/g; p = 0.007) and butyrate (27 vs. 40 µmol/g; p = 0.037) were elevated in fecal samples after treatment. Furthermore, treatment was accompanied by a reduction of fecal zonulin concentration (67 vs. 36 ng/ml; p = 0.035) and disease severity measured by IBS-SSS (237 vs. 54; p = 0.002). Conclusions Our findings indicate that a short-course oral synbiotic trial may influence the human gastrointestinal tract in IBS-D patients on different levels which are region specific. Electronic supplementary material The online version of this article (10.1007/s00394-018-1826-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Adrian Mathias Moser
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Theodor Escherich Laboratory for Microbiome Research, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Walter Spindelboeck
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Theodor Escherich Laboratory for Microbiome Research, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Bettina Halwachs
- Theodor Escherich Laboratory for Microbiome Research, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036, Graz, Austria
| | - Heimo Strohmaier
- Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, 8010, Graz, Austria
| | - Patrizia Kump
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Theodor Escherich Laboratory for Microbiome Research, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Gregor Gorkiewicz
- Theodor Escherich Laboratory for Microbiome Research, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036, Graz, Austria
| | - Christoph Högenauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. .,Theodor Escherich Laboratory for Microbiome Research, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
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Lazaridis N, Germanidis G. Current insights into the innate immune system dysfunction in irritable bowel syndrome. Ann Gastroenterol 2018; 31:171-187. [PMID: 29507464 PMCID: PMC5825947 DOI: 10.20524/aog.2018.0229] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/22/2017] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients' quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.
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Affiliation(s)
- Nikolaos Lazaridis
- Gastroenterology Department, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Georgios Germanidis
- Gastroenterology Department, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
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