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Quan R, Decraecker L, Appeltans I, Cuende-Estévez M, Van Remoortel S, Aguilera-Lizarraga J, Wang Z, Hicks G, Wykosky J, McLean P, Denadai-Souza A, Hussein H, Boeckxstaens GE. Fecal Proteolytic Bacteria and Staphylococcal Superantigens Are Associated With Abdominal Pain Severity in Irritable Bowel Syndrome. Am J Gastroenterol 2025; 120:603-613. [PMID: 39166748 PMCID: PMC11864055 DOI: 10.14309/ajg.0000000000003042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION Changes in the composition of the gut microbiota have been associated with the development of irritable bowel syndrome (IBS). However, to what extent specific bacterial species relate to clinical symptoms remains poorly characterized. We investigated the clinical relevance of bacterial species linked with increased proteolytic activity, histamine production, and superantigen (SAg) production in patients with IBS. METHODS Fecal (n = 309) and nasal (n = 214) samples were collected from patients with IBS and healthy volunteers (HV). Clinical symptoms and gut transit time were evaluated. Bacterial abundance in feces and nasal swabs as well as fecal trypsin-like activity were assessed. RESULTS The percentage of fecal samples containing Staphylococcus aureus was significantly higher in IBS compared with HV. Forty-nine percent of S. aureus -positive fecal samples from patients with IBS were also positive for SAgs, compared with 12% of HV. Patients with IBS and positive fecal SAg-producing S. aureus reported higher pain scores than those without S. aureus . Moreover, increased fecal proteolytic activity was associated with abdominal pain. Fecal abundance of Paraprevotella clara and Alistipes putredinis was significantly decreased in IBS, particularly in samples with higher proteolytic activity. Patients with lower Alistipes putredinis or Faecalibacterium prausnitzii abundance reported more severe abdominal pain. DISCUSSION In keeping with our preclinical findings, we show that increased presence of SAg-producing S. aureus in fecal samples of patients with IBS is associated with increased levels of abdominal pain. We also show that increased fecal proteolytic activity is associated with increased abdominal pain in patients with IBS.
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Affiliation(s)
- Runze Quan
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Lisse Decraecker
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Iris Appeltans
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - María Cuende-Estévez
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Samuel Van Remoortel
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Javier Aguilera-Lizarraga
- Laboratory of Sensory Neurophysiology and Pain, Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Zheng Wang
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | | | | | | | - Alexandre Denadai-Souza
- Laboratory of Mucosal Biology, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Guy E. Boeckxstaens
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
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Ziegler AR, Anderson BM, Latorre R, McQuade RM, Dufour A, Schmidt BL, Bunnett NW, Scott NE, Edgington‐Mitchell LE. N-terminomics profiling of naïve and inflamed murine colon reveals proteolytic signatures of legumain. J Cell Physiol 2025; 240:e31466. [PMID: 39392222 PMCID: PMC11735880 DOI: 10.1002/jcp.31466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/27/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024]
Abstract
Legumain is a cysteine protease broadly associated with inflammation. It has been reported to cleave and activate protease-activated receptor 2 to provoke pain associated with oral cancer. Outside of gastric and colon cancer, little has been reported on the roles of legumain within the gastrointestinal tract. Using a legumain-selective activity-based probe, LE28, we report that legumain is activated within colonocytes and macrophages of the murine colon, and that it is upregulated in models of acute experimental colitis. We demonstrated that loss of legumain activity in colonocytes, either through pharmacological inhibition or gene deletion, had no impact on epithelial permeability in vitro. Moreover, legumain inhibition or deletion had no obvious impacts on symptoms or histological features associated with dextran sulfate sodium-induced colitis, suggesting its proteolytic activity is dispensable for colitis initiation. To gain insight into potential functions of legumain within the colon, we performed field asymmetric waveform ion mobility spectrometry-facilitated quantitative proteomics and N-terminomics analyses on naïve and inflamed colon tissue from wild-type and legumain-deficient mice. We identified 16 altered cleavage sites with an asparaginyl endopeptidase signature that may be direct substrates of legumain and a further 16 cleavage sites that may be indirectly mediated by legumain. We also analyzed changes in protein abundance and proteolytic events broadly associated with colitis in the gut, which permitted comparison to recent analyses on mucosal biopsies from patients with inflammatory bowel disease. Collectively, these results shed light on potential functions of legumain and highlight its potential roles in the transition from inflammation to colorectal cancer.
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Affiliation(s)
- Alexander R. Ziegler
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneParkvilleVictoriaAustralia
| | - Bethany M. Anderson
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneParkvilleVictoriaAustralia
| | - Rocco Latorre
- Department of Molecular PathobiologyNew York University College of DentistryNew YorkNew YorkUSA
| | - Rachel M. McQuade
- Department of Anatomy and PhysiologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Antoine Dufour
- Department of Physiology and PharmacologyUniversity of CalgaryCalgaryAlbertaCanada
| | - Brian L. Schmidt
- Department of Oral and Maxillofacial SurgeryNew York University College of Dentistry, Bluestone Center for Clinical ResearchNew YorkNew YorkUSA
| | - Nigel W. Bunnett
- Department of Molecular PathobiologyNew York University College of DentistryNew YorkNew YorkUSA
| | - Nichollas E. Scott
- Department of Microbiology and Immunology, Peter Doherty InstituteThe University of MelbourneParkvilleVictoriaAustralia
| | - Laura E. Edgington‐Mitchell
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneParkvilleVictoriaAustralia
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Cheng X, Ren C, Mei X, Jiang Y, Zhou Y. Gut microbiota and irritable bowel syndrome: status and prospect. Front Med (Lausanne) 2024; 11:1429133. [PMID: 39484201 PMCID: PMC11524842 DOI: 10.3389/fmed.2024.1429133] [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: 05/07/2024] [Accepted: 10/07/2024] [Indexed: 11/03/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a very common gastrointestinal disease that, although not as aggressive as tumors, affects patients' quality of life in different ways. The cause of IBS is still unclear, but more and more studies have shown that the characteristics of the gut microbiota, such as diversity, abundance, and composition, are altered in patients with IBS, compared to the healthy population, which confirms that the gut microbiota plays a crucial role in the development of IBS. This paper aims to identify the commonalities by reviewing a large body of literature. Changes in the characteristics of gut microbiota in patients with different types of IBS are discussed, relevant mechanisms are described, and the treatment modalities of gut microbiota in IBS are summarized. Although there are more clinical trials that have made good progress, more standardized, more generalized, larger-scale, multi-omics clinical studies are what is missing. Overall, gut microbiota plays a crucial role in the development of IBS, and there is even more potential for treating IBS by modulating gut microbiota.
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Affiliation(s)
- Xinyu Cheng
- Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, China
| | - Cheng Ren
- Department of Cardiology, The First people’s Hospital of Zhangjiagang, Affiliated Hospital of Soochow University, Medical Center of Soochow University, Zhangjiagang, Jiangsu, China
| | - Xiaofei Mei
- Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, China
| | - Yufeng Jiang
- Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, China
- Institute for Hypertension, Soochow University, Suzhou, China
| | - Yafeng Zhou
- Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, China
- Institute for Hypertension, Soochow University, Suzhou, China
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Ionescu VA, Gheorghe G, Georgescu TF, Bacalbasa N, Gheorghe F, Diaconu CC. The Latest Data Concerning the Etiology and Pathogenesis of Irritable Bowel Syndrome. J Clin Med 2024; 13:5124. [PMID: 39274340 PMCID: PMC11395839 DOI: 10.3390/jcm13175124] [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: 07/26/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/16/2024] Open
Abstract
Globally, irritable bowel syndrome (IBS) is present in approximately 10% of the population. While this condition does not pose a risk of complications, it has a substantial impact on the patient's quality of life. Moreover, this disease has a significant financial impact on healthcare systems. This includes the direct costs associated with the diagnosis and treatment of these patients, as well as the indirect costs that arise from work absenteeism and reduced productivity. In light of these data, recent research has focused on elucidating the pathophysiological basis of this condition in order to improve the quality of life for affected individuals. Despite extensive research to date, we still do not fully understand the precise mechanisms underlying IBS. Numerous studies have demonstrated the involvement of the gut-brain axis, visceral hypersensitivity, gastrointestinal dysmotility, gut microbiota dysbiosis, food allergies and intolerances, low-grade mucosal inflammation, genetic factors, and psychosocial factors. The acquisition of new data is crucial for the advancement of optimal therapeutic approaches aimed at enhancing the general health of these patients while simultaneously reducing the financial burden associated with this ailment.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Teodor Florin Georgescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- General Surgery Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Nicolae Bacalbasa
- Department of Visceral Surgery, Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | | | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Academy of Romanian Scientists, 050085 Bucharest, Romania
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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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Zhao Y, Zhan J, Sun C, Zhu S, Zhai Y, Dai Y, Wang X, Gao X. Sishen Wan enhances intestinal barrier function via regulating endoplasmic reticulum stress to improve mice with diarrheal irritable bowel syndrome. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155541. [PMID: 38579640 DOI: 10.1016/j.phymed.2024.155541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/25/2024] [Accepted: 03/15/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND Diarrheal irritable bowel syndrome (IBS-D), characterized primarily by the presence of diarrhea and abdominal pain, is a clinical manifestation resulting from a multitude of causative factors. Furthermore, Sishen Wan (SSW) has demonstrated efficacy in treating IBS-D. Nevertheless, its mechanism of action remains unclear. METHODS A model of IBS-D was induced by a diet containing 45 % lactose and chronic unpredictable mild stress. Additionally, the impact of SSW was assessed by measuring body weight, visceral sensitivity, defecation parameters, intestinal transport velocity, intestinal neurotransmitter levels, immunohistochemistry, and transmission electron microscopy analysis. Immunofluorescent staining was used to detect the expression of Mucin 2 (MUC2) and Occludin in the colon. Western blotting was used to detect changes in proteins related to tight junction (TJ), autophagy, and endoplasmic reticulum (ER) stress in the colon. Finally, 16S rRNA amplicon sequencing was used to monitor the alteration of gut microbiota after SSW treatment. RESULTS Our study revealed that SSW administration resulted in reduced visceral sensitivity, improved defecation parameters, decreased intestinal transport velocity, and reduced intestinal permeability in IBS-D mice. Furthermore, SSW promotes the secretion of colonic mucus by enhancing autophagy and inhibiting ER stress. SSW treatment caused remodeling of the gut microbiome by increasing the abundance of Blautia, Muribaculum and Ruminococcus torques group. CONCLUSION SSW can improve intestinal barrier function by promoting autophagy and inhibiting ER stress, thus exerting a therapeutic effect on IBS-D.
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Affiliation(s)
- Yucui Zhao
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiaguo Zhan
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Congying Sun
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shixiao Zhu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yue Zhai
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yongna Dai
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Xiaoying Wang
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Xiumei Gao
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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7
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Xu M, Li M, Benz F, Merchant M, McClain CJ, Song M. Ileum Proteomics Identifies Distinct Pathways Associated with Different Dietary Doses of Copper-Fructose Interactions: Implications for the Gut-Liver Axis and MASLD. Nutrients 2024; 16:2083. [PMID: 38999831 PMCID: PMC11242941 DOI: 10.3390/nu16132083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/23/2024] [Accepted: 06/27/2024] [Indexed: 07/14/2024] Open
Abstract
The interactions of different dietary doses of copper with fructose contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) via the gut-liver axis. The underlying mechanisms remain elusive. The aim of this study was to identify the specific pathways leading to gut barrier dysfunction in the ileum using a proteomics approach in a rat model. Male weanling Sprague Dawley rats were fed diets with adequate copper (CuA), marginal copper (CuM), or supplemented copper (CuS) in the absence or presence of fructose supplementation (CuAF, CuMF, and CuSF) for 4 weeks. Ileum protein was extracted and analyzed with an LC-MS. A total of 2847 differentially expressed proteins (DEPs) were identified and submitted to functional enrichment analysis. As a result, the ileum proteome and signaling pathways that were differentially altered were revealed. Of note, the CuAF is characterized by the enrichment of oxidative phosphorylation and ribosome as analyzed with the KEGG; the CuMF is characterized by an enriched arachidonic acid metabolism pathway; and focal adhesion, the regulation of the actin cytoskeleton, and tight junction were significantly enriched by the CuSF. In conclusion, our proteomics analysis identified the specific pathways in the ileum related to the different dietary doses of copper-fructose interactions, suggesting that distinct mechanisms in the gut are involved in the development of MASLD.
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Affiliation(s)
- Manman Xu
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; (M.X.); (C.J.M.)
| | - Ming Li
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA; (M.L.); (M.M.)
- Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Frederick Benz
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Michael Merchant
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA; (M.L.); (M.M.)
- Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
- University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Craig J. McClain
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; (M.X.); (C.J.M.)
- Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
- University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Robley Rex Louisville VAMC, Louisville, KY 40206, USA
| | - Ming Song
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; (M.X.); (C.J.M.)
- Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
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8
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Vakili O, Adibi Sedeh P, Pourfarzam M. Metabolic biomarkers in irritable bowel syndrome diagnosis. Clin Chim Acta 2024; 560:119753. [PMID: 38821336 DOI: 10.1016/j.cca.2024.119753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder characterized by altered bowel habits and abdominal discomfort during defecation. It significantly impacts life quality and work productivity for those affected. Global data suggests a slightly higher prevalence in females than in males. Today, unambiguous diagnosis of IBS remains challenging due to the absence of a specific biochemical, histopathological, or radiological test. Current diagnosis relies heavily on thorough symptom evaluation. Efforts by the Rome committees have established standardized diagnostic criteria (Rome I-IV), improving consistency and clinical applicability. Recent studies in this framework, seem to have successfully employed metabolomics techniques to identify distinct metabolite profiles in breath and stool samples of IBS patients, differentiating them from healthy controls and those with other functional GI disorders, such as inflammatory bowel disease (IBD). Building on this success, researchers are investigating the presence of similar metabolites in easily accessible biofluids such as urine, potentially offering a less invasive diagnostic approach. Accordingly, this review focuses on key metabolites specifically detected in IBS patients' biological specimens, with a focus on urinary metabolites, using various methods, particularly mass spectrometry (MS)-based techniques, including gas chromatography-MS (GC-MS), liquid chromatography-tandem MS (LC-MS/MS), and capillary electrophoresis-MS (CE-MS) metabolomics assays. These findings may make provision for a new set of non-invasive biomarkers for IBS diagnosis and management.
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Affiliation(s)
- Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Peyman Adibi Sedeh
- Gastroenterology and Hepatology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Morteza Pourfarzam
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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9
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Cai Y, Deng W, Yang Q, Pan G, Liang Z, Yang X, Li S, Xiao X. High-fat diet-induced obesity causes intestinal Th17/Treg imbalance that impairs the intestinal barrier and aggravates anxiety-like behavior in mice. Int Immunopharmacol 2024; 130:111783. [PMID: 38514921 DOI: 10.1016/j.intimp.2024.111783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/20/2024] [Accepted: 02/27/2024] [Indexed: 03/23/2024]
Abstract
The prevalence of autism spectrum disorders (ASD) has been steadily increasing, and growing evidence suggests a link between high-fat diet (HFD), obesity, and ASD; however, the mechanism underlying this association remains elusive. Herein, BTBR T + tf/J (BTBR) inbred mice (a mouse ASD model) and C57Bl/6J (C57) mice were fed an HFD and normal diet (ND) for 8 weeks (groups: C57 + ND, C57 + HFD, BTBR + ND, and BTBR + HFD). Subsequently, mice underwent behavioral assessments, followed by intestinal tissues harvesting to detect expression of intestinal barrier proteins and inflammatory factors and immune cell numbers, and a correlation analysis. HFD-fed BTBR mice developed obesity, elevated blood sugar, significantly aggravated anxiety-like behaviors, impaired intestinal barrier function, intestinal inflammation with elevated CD4+IL17+ T (Th17) cells and reduced CD4+Foxp3+ T (Treg) cells, exhibiting reduced expression of proteins related to AMPK regulatory pathway (AMPK, p-AMPK, SIRT1). Correlation analysis revealed that the degree of behavioral anxiety, the degree of intestinal barrier damage, the severity of intestinal inflammation, and the degree of immune cell imbalance positively correlated with each other. Accordingly, HFD-induced obesity may cause intestinal Th17/Treg imbalance via the AMPK-SIRT1 pathway, leading to an inflammatory environment in the intestine, impairing intestinal barrier function, and ultimately aggravating anxiety-like behaviors in mice.
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Affiliation(s)
- Yao Cai
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
| | - Wenlin Deng
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
| | - Qiuping Yang
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
| | - Guixian Pan
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
| | - Zao Liang
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
| | - Ximei Yang
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
| | - Sitao Li
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China.
| | - Xin Xiao
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China.
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10
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Hou JJ, Ding L, Yang T, Yang YF, Jin YP, Zhang XP, Ma AH, Qin YH. The proteolytic activity in inflammatory bowel disease: insight from gut microbiota. Microb Pathog 2024; 188:106560. [PMID: 38272327 DOI: 10.1016/j.micpath.2024.106560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/20/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease caused by the destruction of the intestinal mucosal epithelium that affects a growing number of people worldwide. Although the etiology of IBD is complex and still elucidated, the role of dysbiosis and dysregulated proteolysis is well recognized. Various studies observed altered composition and diversity of gut microbiota, as well as increased proteolytic activity (PA) in serum, plasma, colonic mucosa, and fecal supernatant of IBD compared to healthy individuals. The imbalance of intestinal microecology and intestinal protein hydrolysis were gradually considered to be closely related to IBD. Notably, the pivotal role of intestinal microbiota in maintaining proteolytic balance received increasing attention. In summary, we have speculated a mesmerizing story, regarding the hidden role of PA and microbiota-derived PA hidden in IBD. Most importantly, we provided the diagnosis and therapeutic targets for IBD as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.
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Affiliation(s)
- Jun-Jie Hou
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Liang Ding
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Tao Yang
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Yan-Fei Yang
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Yue-Ping Jin
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Xiao-Ping Zhang
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - A-Huo Ma
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Yue-Hua Qin
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China.
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11
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Maghsood AH, Kayedimajd S, Motavallihaghi S, Abedian R, Kordi S, Davoodi L, Faizi F, Soleymani E. Irritable Bowel Syndrome Associated with Blastocystis hominis or Without Relationship to It? A Case-Control Study and Minireview. Acta Parasitol 2024; 69:639-647. [PMID: 38300499 DOI: 10.1007/s11686-023-00787-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/21/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND Blastocystis hominis (B. hominis) is a protozoan parasite that has a worldwide distribution. Some studies have suggested a link between B. hominis and the development of irritable bowel syndrome (IBS). The objective of this study was to determine the prevalence of B. hominis in patients with IBS compared to healthy individuals. MATERIAL AND METHODS A total of 65 stool samples from patients with IBS and 65 samples from healthy individuals in northern Iran were examined. The samples were tested using various methods including direct smear, formalin ether sedimentation and culture to detect the presence of B. hominis. Additionally, polymerase chain reaction (PCR) was performed on all culture-positive isolates to confirm the results and identify the genotype. RESULTS B. hominis was detected in 15.38% of IBS patients and 9.2% of the healthy group. The culture in RPMI1640 was found to be better than the formalin ether and direct smear methods. Positive samples were confirmed using the molecular method. No significant difference was observed in the order of B. hominis infection between the two groups. CONCLUSIONS The results of our study indicate that no significant difference was observed in the order of B. hominis infection between IBS patients and healthy groups. Therefore, further study is necessary to determine the potential pathogenic effects of this parasite and its role in causing IBS.
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Affiliation(s)
- Amir Hossein Maghsood
- Department of Medical Mycology and Parasitology, School of Medicine, Hamadan University of Medical Science, Hamadan, Iran
| | | | - Seyedmousa Motavallihaghi
- Department of Medical Mycology and Parasitology, School of Medicine, Hamadan University of Medical Science, Hamadan, Iran
| | - Rohallah Abedian
- Department of Infectious Diseases, Antimicrobial Resistance Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shirafkan Kordi
- Department of Infectious Diseases, Antimicrobial Resistance Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Lotfollah Davoodi
- Department of Infectious Diseases, Antimicrobial Resistance Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fariba Faizi
- Department of Medical Mycology and Parasitology, School of Medicine, Hamadan University of Medical Science, Hamadan, Iran
| | - Eissa Soleymani
- Department of Medical Mycology and Parasitology, School of Medicine, Hamadan University of Medical Science, Hamadan, Iran.
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12
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Landini L, Dadson P, Gallo F, Honka MJ, Cena H. Microbiota in anorexia nervosa: potential for treatment. Nutr Res Rev 2023; 36:372-391. [PMID: 35875979 DOI: 10.1017/s0954422422000130] [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: 11/07/2022]
Abstract
Anorexia nervosa (AN) is characterised by the restriction of energy intake in relation to energy needs and a significantly lowered body weight than normally expected, coupled with an intense fear of gaining weight. Treatment of AN is currently based on psychological and refeeding approaches, but their efficacy remains limited since 40% of patients after 10 years of medical care still present symptoms of AN. The intestine hosts a large community of microorganisms, called the "microbiota", which live in symbiosis with the human host. The gut microbiota of a healthy human is dominated by bacteria from two phyla: Firmicutes and, majorly, Bacteroidetes. However, the proportion in their representation differs on an individual basis and depends on many external factors including medical treatment, geographical location and hereditary, immunological and lifestyle factors. Drastic changes in dietary intake may profoundly impact the composition of the gut microbiota, and the resulting dysbiosis may play a part in the onset and/or maintenance of comorbidities associated with AN, such as gastrointestinal disorders, anxiety and depression, as well as appetite dysregulation. Furthermore, studies have reported the presence of atypical intestinal microbial composition in patients with AN compared with healthy normal-weight controls. This review addresses the current knowledge about the role of the gut microbiota in the pathogenesis and treatment of AN. The review also focuses on the bidirectional interaction between the gastrointestinal tract and the central nervous system (microbiota-gut-brain axis), considering the potential use of the gut microbiota manipulation in the prevention and treatment of AN.
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Affiliation(s)
- Linda Landini
- S.S.D. Dietetics and Clinical Nutrition ASL 4 Chiavarese Liguria-Sestri Levante Hospital, Sestri Levante, Italy
| | - Prince Dadson
- Turku PET Centre, University of Turku, Turku, Finland
| | - Fabrizio Gallo
- S.S.D. Dietetics and Clinical Nutrition ASL 4 Chiavarese Liguria-Sestri Levante Hospital, Sestri Levante, Italy
| | | | - Hellas Cena
- Dietetics and Clinical Nutrition Laboratory, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, Pavia, Italy
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13
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Soussou S, Jablaoui A, Mariaule V, Kriaa A, Boudaya H, Wysocka M, Amouri A, Gargouri A, Lesner A, Maguin E, Rhimi M. Serine proteases and metalloproteases are highly increased in irritable bowel syndrome Tunisian patients. Sci Rep 2023; 13:17571. [PMID: 37845280 PMCID: PMC10579243 DOI: 10.1038/s41598-023-44454-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/09/2023] [Indexed: 10/18/2023] Open
Abstract
Serine proteases are involved in many biological processes and are associated with irritable bowel syndrome (IBS) pathology. An increase in serine protease activity has been widely reported in IBS patients. While most of the studies focused on host proteases, the contribution of microbial proteases are poorly studied. In the present study, we report the analysis of proteolytic activities in fecal samples from the first Tunisian cohort of IBS-M patients and healthy individuals. We demonstrated, for the first time, that metalloproteases activities were fourfold higher in fecal samples of IBS patients compared to controls. Of interest, the functional characterization of serine protease activities revealed a 50-fold increase in trypsin-like activities and a threefold in both elastase- and cathepsin G-like activities. Remarkably, we also showed a fourfold increase in proteinase 3-like activity in the case of IBS. This study also provides insight into the alteration of gut microbiota and its potential role in proteolytic modulation in IBS. Our results stressed the impact of the disequilibrium of serine proteases, metalloproteases and gut microbiota in IBS and the need of the further characterization of these targets to set out new therapeutic approaches.
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Affiliation(s)
- Souha Soussou
- Microbiota Interaction With Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, 78350, Jouy-en-Josas, France
- Laboratory of Molecular Biology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Amin Jablaoui
- Microbiota Interaction With Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, 78350, Jouy-en-Josas, France
| | - Vincent Mariaule
- Microbiota Interaction With Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, 78350, Jouy-en-Josas, France
| | - Aicha Kriaa
- Microbiota Interaction With Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, 78350, Jouy-en-Josas, France
| | - Houda Boudaya
- Laboratory of Molecular Biology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | | | - Ali Amouri
- Department of Gastroenterology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Ali Gargouri
- Laboratory of Molecular Biology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Adam Lesner
- Faculty of Chemistry, University of Gdansk, Gdańsk, Poland
| | - Emmanuelle Maguin
- Microbiota Interaction With Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, 78350, Jouy-en-Josas, France
| | - Moez Rhimi
- Microbiota Interaction With Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, 78350, Jouy-en-Josas, France.
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14
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Lee I, Tantisirivat P, Edgington-Mitchell LE. Chemical Tools to Image the Activity of PAR-Cleaving Proteases. ACS BIO & MED CHEM AU 2023; 3:295-304. [PMID: 37599791 PMCID: PMC10436261 DOI: 10.1021/acsbiomedchemau.3c00019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/18/2023] [Accepted: 05/19/2023] [Indexed: 08/22/2023]
Abstract
Protease-activated receptors (PARs) comprise a family of four G protein-coupled receptors (GPCRs) that have broad functions in health and disease. Unlike most GPCRs, PARs are uniquely activated by proteolytic cleavage of their extracellular N termini. To fully understand PAR activation and function in vivo, it is critical to also study the proteases that activate them. As proteases are heavily regulated at the post-translational level, measures of total protease abundance have limited utility. Measures of protease activity are instead required to inform their function. This review will introduce several classes of chemical probes that have been developed to measure the activation of PAR-cleaving proteases. Their strengths, weaknesses, and applications will be discussed, especially as applied to image protease activity at the whole organism, tissue, and cellular level.
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Affiliation(s)
- Irene
Y. Lee
- Department
of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology
Institute, The University of Melbourne, Parkville, Victoria 3052 Australia
| | - Piyapa Tantisirivat
- Department
of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology
Institute, The University of Melbourne, Parkville, Victoria 3052 Australia
| | - Laura E. Edgington-Mitchell
- Department
of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology
Institute, The University of Melbourne, Parkville, Victoria 3052 Australia
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15
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Vanuytsel T, Bercik P, Boeckxstaens G. Understanding neuroimmune interactions in disorders of gut-brain interaction: from functional to immune-mediated disorders. Gut 2023; 72:787-798. [PMID: 36657961 PMCID: PMC10086308 DOI: 10.1136/gutjnl-2020-320633] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023]
Abstract
Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.
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Affiliation(s)
- Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium.,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Premysl Bercik
- Faculty of Health Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Guy Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium .,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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16
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Colomier E, Algera JP, Van den Houte K, Simrén M, Tack J. Mechanisms underlying food-related symptoms in disorders of gut-brain interaction: Course ahead in research and clinical practice. Best Pract Res Clin Gastroenterol 2023; 62-63:101824. [PMID: 37094907 DOI: 10.1016/j.bpg.2023.101824] [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] [Received: 01/19/2023] [Accepted: 02/02/2023] [Indexed: 04/26/2023]
Abstract
A subgroup of patients with a disorder of gut-brain interaction (DGBI) report symptoms such as abdominal pain, gas-related symptoms, dyspeptic symptoms and loose stool or urgency after meal intake. Therefore, the effect of several dietary therapies including fibre-rich or restrictive diets have already been studied in patients with irritable bowel syndrome, functional abdominal bloating or distention, and functional dyspepsia. However, there is a paucity of studies in the literature on the mechanisms underlying food-related symptoms. Therefore, this review focuses on these potential mechanisms and explains the role of nutrient sensing and tasting, physical considerations, malabsorption or allergy-like reaction to food and its interaction with microbiota. In addition, it emphasizes the importance of future research and clinical practice regarding food-related symptoms in patients with a DGBI.
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Affiliation(s)
- Esther Colomier
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Joost P Algera
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Karen Van den Houte
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Center for Functional GI and Motility Disorders, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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17
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Duan H, Zhang X, Figeys D. An emerging field: Post-translational modification in microbiome. Proteomics 2023; 23:e2100389. [PMID: 36239139 DOI: 10.1002/pmic.202100389] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/11/2022]
Abstract
Post-translational modifications (PTMs) play an essential role in most biological processes. PTMs on human proteins have been extensively studied. Studies on bacterial PTMs are emerging, which demonstrate that bacterial PTMs are different from human PTMs in their types, mechanisms and functions. Few PTM studies have been done on the microbiome. Here, we reviewed several studied PTMs in bacteria including phosphorylation, acetylation, succinylation, glycosylation, and proteases. We discussed the enzymes responsible for each PTM and their functions. We also summarized the current methods used to study microbiome PTMs and the observations demonstrating the roles of PTM in the microbe-microbe interactions within the microbiome and their interactions with the environment or host. Although new methods and tools for PTM studies are still needed, the existing technologies have made great progress enabling a deeper understanding of the functional regulation of the microbiome. Large-scale application of these microbiome-wide PTM studies will provide a better understanding of the microbiome and its roles in the development of human diseases.
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Affiliation(s)
- Haonan Duan
- School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada
| | - Xu Zhang
- Center for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, Canada
| | - Daniel Figeys
- School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada
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18
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De Palma G, Reed DE, Bercik P. Diet-microbial cross-talk underlying increased visceral perception. Gut Microbes 2023; 15:2166780. [PMID: 36656562 PMCID: PMC9858425 DOI: 10.1080/19490976.2023.2166780] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Visceral hypersensitivity, a fundamental mechanism of chronic visceral pain disorders, can result from both central or peripheral factors, or their combination. As an important regulator of normal gut function, the gut microbiota has been implicated as a key peripheral factor in the pathophysiology of visceral hypersensitivity. Patients with chronic gastrointestinal disorders, such as irritable bowel syndrome, often present with abdominal pain secondary to adverse reactions to dietary components. As both long- and short-term diets are major determinants of gut microbiota configuration that can result in changes in microbial metabolic output, it is becoming increasingly recognized that diet-microbiota interactions play an important role in the genesis of visceral sensitivity. Changes in pain signaling may occur via diet-induced changes in secretion of mediators by both the microbiota and/or host cells. This review will examine the peripheral influence of diet-microbiota interactions underlying increased visceral sensitivity.
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Affiliation(s)
- Giada De Palma
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - David E. Reed
- GI Diseases Research Unit, Queens University, Kingston, Ontario, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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19
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Tian S, Zhang H, Chen S, Wu P, Chen M. Global research progress of visceral hypersensitivity and irritable bowel syndrome: bibliometrics and visualized analysis. Front Pharmacol 2023; 14:1175057. [PMID: 37201020 PMCID: PMC10185792 DOI: 10.3389/fphar.2023.1175057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/18/2023] [Indexed: 05/20/2023] Open
Abstract
Background: Irritable bowel syndrome (IBS) is a group of functional intestinal disorders characterized by abdominal pain, bloating, and changes in bowel habits, and/or stool characteristics. Recent studies have shown that there has been a significant advancement in the study of visceral hypersensitivity in IBS. Through the use of bibliometrics, this study aims to provide a comprehensive overview of the knowledge structure and research hotpots of visceral hypersensitivity in IBS. Methods: Publications related to visceral hypersensitivity in IBS from 2012 to 2022 were searched on the web of science core collection (WoSCC) database. CiteSpace.6.1. R2 and Vosviewer 1.6.17 were used to perform bibliometric analysis. Results: A total of 974 articles led by China and the United States from 52 countries were included. Over the past decade, the number of articles on visceral hypersensitivity and IBS has steadily increased year by year. China, the United States, and Belgium are the main countries in this field. Univ Oklahoma, Univ Gothenburg, and Zhejiang University are the main research institutions. Simren, Magnus, Greenwood-van meerveld, Beverley, and Tack, Jan are the most published authors in this research field. The research on the causes, genes, and pathways involved in visceral hypersensitivity in IBS and the mechanism of IBS are the main topics and hotspots in this field. This study also found that gut microbiota may be related to the occurrence of visceral hypersensitivity, and probiotics may be a new method for the treatment of visceral hypersensitivity and pain, which may become a new direction for research in this field. Conclusion: This is the first bibliometric study to comprehensively summarize the research trends and developments of visceral hypersensitivity in IBS. This information provides the research frontier and hot topics in this field in recent years, which will provide a reference for scholars studying this field.
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Affiliation(s)
- Siyu Tian
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Hang Zhang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Siqi Chen
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Pengning Wu
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Min Chen
- Department of Colorectal Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Min Chen,
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20
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Tuck CJ, Abu Omar A, De Palma G, Osman S, Jiménez-Vargas NN, Yu Y, Bennet SM, Lopez-Lopez C, Jaramillo-Polanco JO, Baker CC, Bennett AS, Guzman-Rodriguez M, Tsang Q, Alward T, Rolland S, Morissette C, Verdu EF, Bercik P, Vanner SJ, Lomax AE, Reed DE. Changes in signalling from faecal neuroactive metabolites following dietary modulation of IBS pain. Gut 2022; 72:gutjnl-2022-327260. [PMID: 36591617 DOI: 10.1136/gutjnl-2022-327260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 11/23/2022] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Dietary therapies for irritable bowel syndrome (IBS) have received increasing interest but predicting which patients will benefit remains a challenge due to a lack of mechanistic insight. We recently found evidence of a role for the microbiota in dietary modulation of pain signalling in a humanised mouse model of IBS. This randomised cross-over study aimed to test the hypothesis that pain relief following reduced consumption of fermentable carbohydrates is the result of changes in luminal neuroactive metabolites. DESIGN IBS (Rome IV) participants underwent four trial periods: two non-intervention periods, followed by a diet low (LFD) and high in fermentable carbohydrates for 3 weeks each. At the end of each period, participants completed questionnaires and provided stool. The effects of faecal supernatants (FS) collected before (IBS FS) and after a LFD (LFD FS) on nociceptive afferent neurons were assessed in mice using patch-clamp and ex vivo colonic afferent nerve recording techniques. RESULTS Total IBS symptom severity score and abdominal pain were reduced by the LFD (N=25; p<0.01). Excitability of neurons was increased in response to IBS FS, but this effect was reduced (p<0.01) with LFD FS from pain-responders. IBS FS from pain-responders increased mechanosensitivity of nociceptive afferent nerve axons (p<0.001), an effect lost following LFD FS administration (p=NS) or when IBS FS was administered in the presence of antagonists of histamine receptors or protease inhibitors. CONCLUSIONS In a subset of IBS patients with improvement in abdominal pain following a LFD, there is a decrease in pronociceptive signalling from FS, suggesting that changes in luminal mediators may contribute to symptom response.
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Affiliation(s)
- Caroline J Tuck
- Department of Sport, Exercise and Nutrition Sciences, La Trobe University, Melbourne, Victoria, Australia
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Amal Abu Omar
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Physiology, Jordan University of Science and Technology, Irbid, Jordan
| | - Giada De Palma
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Samira Osman
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | | | - Yang Yu
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Sean Mp Bennet
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Cintya Lopez-Lopez
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | | | - Corey C Baker
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Aidan Sw Bennett
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | | | - Quentin Tsang
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Taylor Alward
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Sebastien Rolland
- Department of Medicine, Hopital Maisonneuve-Rosemont, Montreal, Québec, Canada
| | - Celine Morissette
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Elena F Verdu
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Stephen J Vanner
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - David E Reed
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
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21
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Gut Non-Bacterial Microbiota: Emerging Link to Irritable Bowel Syndrome. Toxins (Basel) 2022; 14:toxins14090596. [PMID: 36136534 PMCID: PMC9503233 DOI: 10.3390/toxins14090596] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/18/2022] [Accepted: 08/25/2022] [Indexed: 11/20/2022] Open
Abstract
As a common functional gastrointestinal disorder, irritable bowel syndrome (IBS) significantly affects personal health and imposes a substantial economic burden on society, but the current understanding of its occurrence and treatment is still inadequate. Emerging evidence suggests that IBS is associated with gut microbial dysbiosis, but most studies focus on the bacteria and neglect other communities of the microbiota, including fungi, viruses, archaea, and other parasitic microorganisms. This review summarizes the latest findings that link the nonbacterial microbiota with IBS. IBS patients show less fungal and viral diversity but some alterations in mycobiome, virome, and archaeome, such as an increased abundance of Candida albicans. Moreover, fungi and methanogens can aid in diagnosis. Fungi are related to distinct IBS symptoms and induce immune responses, intestinal barrier disruption, and visceral hypersensitivity via specific receptors, cells, and metabolites. Novel therapeutic methods for IBS include fungicides, inhibitors targeting fungal pathogenic pathways, probiotic fungi, prebiotics, and fecal microbiota transplantation. Additionally, viruses, methanogens, and parasitic microorganisms are also involved in the pathophysiology and treatment. Therefore, the gut nonbacterial microbiota is involved in the pathogenesis of IBS, which provides a novel perspective on the noninvasive diagnosis and precise treatment of this disease.
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22
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Hasler WL, Grabauskas G, Singh P, Owyang C. Mast cell mediation of visceral sensation and permeability in irritable bowel syndrome. Neurogastroenterol Motil 2022; 34:e14339. [PMID: 35315179 PMCID: PMC9286860 DOI: 10.1111/nmo.14339] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/09/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022]
Abstract
Abnormalities of mast cell structure or function may play prominent roles in irritable bowel syndrome (IBS) symptom genesis. Mast cells show close apposition to sensory nerves and release bioactive substances in response to varied stimuli including infection, stress, and other neuroendocrine factors. Most studies focus on patients who develop IBS after enteric infection or who report diarrhea-predominant symptoms. Three topics underlying IBS pathogenesis have been emphasized in recent investigations. Visceral hypersensitivity to luminal stimulation is found in most IBS patients and may contribute to abdominal pain. Mast cell dysfunction also may disrupt epithelial barrier function which alters mucosal permeability potentially leading to altered bowel function and pain. Mast cell products including histamine, proteases, prostaglandins, and cytokines may participate in hypersensitivity and permeability defects, especially with diarrhea-predominant IBS. Recent experimental evidence indicates that the pronociceptive effects of histamine and proteases are mediated by the generation of prostaglandins in the mast cell. Enteric microbiome interactions including increased mucosal bacterial translocation may activate mast cells to elicit inflammatory responses underlying some of these pathogenic effects. Therapies to alter mast cell activity (mast cell stabilizers) or function (histamine antagonists) have shown modest benefits in IBS. Future investigations will seek to define patient subsets with greater potential to respond to therapies that address visceral hypersensitivity, epithelial permeability defects, and microbiome alterations secondary to mast cell dysfunction in IBS.
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Affiliation(s)
- William L. Hasler
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Gintautas Grabauskas
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Prashant Singh
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Chung Owyang
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
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23
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Van den Houte K, Bercik P, Simren M, Tack J, Vanner S. Mechanisms Underlying Food-Triggered Symptoms in Disorders of Gut-Brain Interactions. Am J Gastroenterol 2022; 117:937-946. [PMID: 35506862 PMCID: PMC9169752 DOI: 10.14309/ajg.0000000000001812] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022]
Abstract
There has been a dramatic increase in clinical studies examining the relationship between disorders of gut-brain interactions and symptoms evoked by food ingestion in the upper and lower gastrointestinal tract, but study design is challenging to verify valid endpoints. Consequently, mechanistic studies demonstrating biological relevance, biomarkers and novel therapeutic targets are greatly needed. This review highlights emerging mechanisms related to nutrient sensing and tasting, maldigestion, physical effects with underlying visceral hypersensitivity, allergy and immune mechanisms, food-microbiota interactions and gut-brain signaling, with a focus on patients with functional dyspepsia and irritable bowel syndrome. Many patients suffering from disorders of gut-brain interactions exhibit these mechanism(s) but which ones and which specific properties may vary widely from patient to patient. Thus, in addition to identifying these mechanisms and the need for further studies, biomarkers and novel therapeutic targets are identified that could enable enriched patient groups to be studied in future clinical trials examining the role of food in the generation of gut and non-gut symptoms.
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Affiliation(s)
- Karen Van den Houte
- Translational Research Center for Gastrointestinal Diseases, University of Leuven, Leuven, Belgium
| | - Premysl Bercik
- Department of Medicine, Farncombe Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Magnus Simren
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jan Tack
- Translational Research Center for Gastrointestinal Diseases, University of Leuven, Leuven, Belgium
| | - Stephen Vanner
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada
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24
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Edwinson AL, Yang L, Peters S, Hanning N, Jeraldo P, Jagtap P, Simpson JB, Yang TY, Kumar P, Mehta S, Nair A, Breen-Lyles M, Chikkamenahalli L, Graham RP, De Winter B, Patel R, Dasari S, Kashyap P, Griffin T, Chen J, Farrugia G, Redinbo MR, Grover M. Gut microbial β-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome. Nat Microbiol 2022; 7:680-694. [PMID: 35484230 PMCID: PMC9081267 DOI: 10.1038/s41564-022-01103-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 03/09/2022] [Indexed: 12/13/2022]
Abstract
Intestinal proteases mediate digestion and immune signaling, while increased gut proteolytic activity disrupts the intestinal barrier and generates visceral hypersensitivity, which in common in irritable bowel syndrome (IBS). However, the mechanisms controlling protease function are unclear. Here we show that members of the gut microbiota suppress intestinal proteolytic activity through production of unconjugated bilirubin. This occurs via microbial β-glucuronidase-mediated conversion of bilirubin conjugates. Metagenomic analysis of fecal samples from patients with post-infection IBS (n=52) revealed an altered gut microbiota composition, in particular a reduction in Alistipes taxa, and high gut proteolytic activity driven by specific host serine proteases compared to controls. Germ-free mice showed 10-fold higher proteolytic activity compared with conventional mice. Colonization with microbiota from high proteolytic activity IBS patients failed to suppress proteolytic activity in germ-free mice, but suppression of proteolytic activity was achieved with colonization using microbiota from healthy donors. High proteolytic activity mice had higher intestinal permeability, a higher relative abundance of Bacteroides and a reduction in Alistipes taxa compared with low proteolytic activity mice. High proteolytic activity IBS patients had lower fecal β-glucuronidase activity and end-products of bilirubin deconjugation. Mice treated with unconjugated bilirubin and β-glucuronidase overexpressing E. coli, which significantly reduced proteolytic activity, while inhibitors of microbial β-glucuronidases increased proteolytic activity. Together, these data define a disease-relevant mechanism of host-microbial interaction that maintains protease homeostasis in the gut.
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Affiliation(s)
- Adam L Edwinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Lu Yang
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Stephanie Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Nikita Hanning
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.,Laboratory of Experimental Medicine and Pediatrics and Infla-Med, research center of excellence, University of Antwerp, Antwerp, Belgium
| | | | - Pratik Jagtap
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Joshua B Simpson
- Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA
| | - Tzu-Yi Yang
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Praveen Kumar
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Subina Mehta
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Asha Nair
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | | | | | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Benedicte De Winter
- Laboratory of Experimental Medicine and Pediatrics and Infla-Med, research center of excellence, University of Antwerp, Antwerp, Belgium.,Division of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium
| | - Robin Patel
- Division of Clinical Microbiology, Mayo Clinic, Rochester, MN, USA
| | - Surendra Dasari
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Purna Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Timothy Griffin
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Jun Chen
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Matthew R Redinbo
- Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA.,Departments of Biochemistry and Biophysics, and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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25
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Zhao L, Ren P, Wang M, Wang J, He X, Gu J, Lu Y, Wu Y, Liu J, Wang L, Li H. Changes in intestinal barrier protein expression and intestinal flora in a rat model of visceral hypersensitivity. Neurogastroenterol Motil 2022; 34:e14299. [PMID: 34821442 DOI: 10.1111/nmo.14299] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 08/30/2021] [Accepted: 11/10/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Destruction of the intestinal mucosal barrier and visceral hypersensitivity are main pathogenesis of irritable bowel syndrome (IBS). The study aimed to establish a rat model of visceral hypersensitivity and explore mechanisms involved the changes of the intestinal barrier protein expression and intestinal flora. METHODS A rat model of visceral hypersensitivity was established and evaluated using abdominal withdrawal reflex (AWR) scores, colonic paracellular permeability, and gastrointestinal motility. The expression of tight junction proteins, aquaporin proteins (AQPs), phosphorylated ERK, and proteinase-activated receptor-2 (PAR-2) was determined. The intestinal microflora was evaluated by high-throughput sequencing of the 16S rRNA gene. KEY RESULTS In model rats, AWR score and fecal water content were significantly increased, gastrointestinal motilities were disorder and characterized by an inhibition of gastric motility and an enhancement of small intestinal and colonic movement. The expressions of colonic occludin, ZO-1, AQP3, and AQP8 were decreased but claudin-2 and claudin-4 were markedly increased. Imbalance of intestinal flora appeared and showed an obvious decrease of Lactobacillus and an increase of Clostridiales_bacterium. Additionally, the total serine protease activity in feces, the expressions of PAR2 and phosphorylated ERK in the colon tissues were increased significantly. CONCLUSION AND INFERENCES The model rats of visceral hypersensitivity possess the decreased expression of occludin, ZO-1, AQP3, AQP8, and the increased expression of claudin-2 and claudin-4, meanwhile develop an imbalance of intestinal flora which probably increase serine protease activity, thereby activating the PAR2/ERK signaling and causing the intestinal barrier disorder.
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Affiliation(s)
- Li Zhao
- Department of Physiology, College of Basic Medicine, Lanzhou University, Lanzhou, China
| | - Peipei Ren
- Affiliated Hospital, Gansu University of Chinese Medicine, Lanzhou, China
| | - Miaolei Wang
- Affiliated Hospital, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jingjing Wang
- Department of Physiology, College of Basic Medicine, Lanzhou University, Lanzhou, China
| | - Xueyun He
- Department of Physiology, College of Basic Medicine, Lanzhou University, Lanzhou, China
| | - Jingyan Gu
- Department of Physiology, College of Basic Medicine, Lanzhou University, Lanzhou, China
| | - Yanyu Lu
- Function Laboratory in College of Basic Medicine, Lanzhou University, Lanzhou, Gansu Province, China
| | - Yana Wu
- Affiliated Hospital, Gansu University of Chinese Medicine, Lanzhou, China
| | - Junhong Liu
- Affiliated Hospital, Gansu University of Chinese Medicine, Lanzhou, China
| | - Longde Wang
- Affiliated Hospital, Gansu University of Chinese Medicine, Lanzhou, China
| | - Hongfang Li
- Department of Physiology, College of Basic Medicine, Lanzhou University, Lanzhou, China.,Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, China
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26
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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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27
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Jacenik D, Fichna J, Małecka-Wojciesko E, Mokrowiecka A. Protease-Activated Receptors - Key Regulators of Inflammatory Bowel Diseases Progression. J Inflamm Res 2022; 14:7487-7497. [PMID: 35002281 PMCID: PMC8721023 DOI: 10.2147/jir.s335502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis and course of inflammatory bowel diseases are related to both immune system disorders and dysfunction of colon permeability. Moreover, co-existing diseases in patients with Crohn's disease and ulcerative colitis are identified. Currently, there are some therapeutic strategies that affect the function of cytokine/s causing inflammation in the intestinal wall. However, additional approaches which target other components of inflammatory bowel diseases pathogenesis are still needed. Accumulating evidence suggests that proteases and protease-activated receptors seem to be responsible for colitis progression. Experimental and observational studies showed alteration of protease-activated receptors expression in the colon of patients with Crohn's disease and ulcerative colitis. Furthermore, it was suggested that the expression of protease-activated receptors correlated with inflammatory bowel diseases activity. Moreover, regulation of protease-activated receptors seems to be responsible for the modulation of colitis and clinical manifestation of inflammatory bowel diseases. In this review, we present the current state of knowledge about the contribution of protease-activated receptors to Crohn's disease and ulcerative colitis and its implications for diagnosis and treatment.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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28
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Annaházi A, Schemann M. Contribution of the Enteric Nervous System to Autoimmune Diseases and Irritable Bowel Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:1-8. [PMID: 36587141 DOI: 10.1007/978-3-031-05843-1_1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Anti-neuronal autoantibodies can lead to subacute gastrointestinal dysmotility, presenting with various symptoms typical of intestinal pseudoobstruction, achalasia, gastroparesis, or slow intestinal transit, among others. Such autoantibodies may be produced in response to a remote tumor and accelerate the diagnosis of malignancy, but in other cases they appear without an identifiable underlying cause. One example is the type I anti-neuronal nuclear antibody (ANNA-1 otherwise known as anti-Hu), which is usually linked to small cell-lung carcinoma. Anti-Hu can directly activate enteric neurons and visceral sensory nerve fibers and has a cytotoxic effect. Various other anti-neuronal antibodies have been described, targeting different ion channels or receptors on nerve cells of the central or the enteric nervous system. Autoimmune processes targeting enteric neurons may also play a role in more common disorders such as esophageal achalasia, celiac disease, or multiple sclerosis. Furthermore, anti-enteric neuronal antibodies have been found more abundant in the common functional gastrointestinal disorder, irritable bowel syndrome (IBS), than in controls. The pathogenesis of IBS is very complex, involving the release of various mediators from immune cells in the gut wall. Products of mast cells, such as histamine and tryptase, excite visceral afferents and enteric neurons, which may contribute to symptoms like abdominal pain and disturbed motility. Elevated serine- and cysteine-protease activity in stool of IBS-D and IBS-C patients, respectively, can be a factor leading to leaky gut and visceral hypersensitivity. More knowledge on these mediators in IBS may facilitate the development of novel diagnostic methods or therapies.
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Affiliation(s)
- Anita Annaházi
- Human Biology, Technical University of Munich, Freising, Germany
| | - Michael Schemann
- Human Biology, Technical University of Munich, Freising, Germany.
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29
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Louwies T, Meerveld BGV. Abdominal Pain. COMPREHENSIVE PHARMACOLOGY 2022:132-163. [DOI: 10.1016/b978-0-12-820472-6.00037-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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30
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Layer P, Andresen V, Allescher H, Bischoff SC, Claßen M, Elsenbruch S, Freitag M, Frieling T, Gebhard M, Goebel-Stengel M, Häuser W, Holtmann G, Keller J, Kreis ME, Kruis W, Langhorst J, Jansen PL, Madisch A, Mönnikes H, Müller-Lissner S, Niesler B, Pehl C, Pohl D, Raithel M, Röhrig-Herzog G, Schemann M, Schmiedel S, Schwille-Kiuntke J, Storr M, Preiß JC, Andus T, Buderus S, Ehlert U, Engel M, Enninger A, Fischbach W, Gillessen A, Gschossmann J, Gundling F, Haag S, Helwig U, Hollerbach S, Karaus M, Katschinski M, Krammer H, Kuhlbusch-Zicklam R, Matthes H, Menge D, Miehlke S, Posovszky MC, Schaefert R, Schmidt-Choudhury A, Schwandner O, Schweinlin A, Seidl H, Stengel A, Tesarz J, van der Voort I, Voderholzer W, von Boyen G, von Schönfeld J, Wedel T. Update S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) – Juni 2021 – AWMF-Registriernummer: 021/016. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:1323-1415. [PMID: 34891206 DOI: 10.1055/a-1591-4794] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- P Layer
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - V Andresen
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - H Allescher
- Zentrum für Innere Medizin, Gastroent., Hepatologie u. Stoffwechsel, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Deutschland
| | - S C Bischoff
- Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Deutschland
| | - M Claßen
- Klinik für Kinder- und Jugendmedizin, Klinikum Links der Weser, Bremen, Deutschland
| | - S Elsenbruch
- Klinik für Neurologie, Translational Pain Research Unit, Universitätsklinikum Essen, Essen, Deutschland.,Abteilung für Medizinische Psychologie und Medizinische Soziologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - M Freitag
- Abteilung Allgemeinmedizin Department für Versorgungsforschung, Universität Oldenburg, Oldenburg, Deutschland
| | - T Frieling
- Medizinische Klinik II, Helios Klinikum Krefeld, Krefeld, Deutschland
| | - M Gebhard
- Gemeinschaftspraxis Pathologie-Hamburg, Hamburg, Deutschland
| | - M Goebel-Stengel
- Innere Medizin II, Helios Klinik Rottweil, Rottweil, und Innere Medizin VI, Psychosomat. Medizin u. Psychotherapie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - W Häuser
- Innere Medizin I mit Schwerpunkt Gastroenterologie, Klinikum Saarbrücken, Saarbrücken, Deutschland
| | - G Holtmann
- Faculty of Medicine & Faculty of Health & Behavioural Sciences, Princess Alexandra Hospital, Brisbane, Australien
| | - J Keller
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - M E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Deutschland
| | - P Lynen Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin, Deutschland
| | - A Madisch
- Klinik für Gastroenterologie, interventionelle Endoskopie und Diabetologie, Klinikum Siloah, Klinikum Region Hannover, Hannover, Deutschland
| | - H Mönnikes
- Klinik für Innere Medizin, Martin-Luther-Krankenhaus, Berlin, Deutschland
| | | | - B Niesler
- Abteilung Molekulare Humangenetik Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Pehl
- Medizinische Klinik, Krankenhaus Vilsbiburg, Vilsbiburg, Deutschland
| | - D Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - M Raithel
- Medizinische Klinik II m.S. Gastroenterologie und Onkologie, Waldkrankenhaus St. Marien, Erlangen, Deutschland
| | | | - M Schemann
- Lehrstuhl für Humanbiologie, TU München, Deutschland
| | - S Schmiedel
- I. Medizinische Klinik und Poliklinik Gastroenterologie, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - J Schwille-Kiuntke
- Abteilung für Psychosomatische Medizin und Psychotherapie, Medizinische Universitätsklinik Tübingen, Tübingen, Deutschland.,Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - M Storr
- Zentrum für Endoskopie, Gesundheitszentrum Starnberger See, Starnberg, Deutschland
| | - J C Preiß
- Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Hepatologie, Vivantes Klinikum Neukölln, Berlin, Deutschland
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Barbara G, Barbaro MR, Fuschi D, Palombo M, Falangone F, Cremon C, Marasco G, Stanghellini V. Corrigendum: Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier. Front Nutr 2021; 8:790387. [PMID: 34790692 PMCID: PMC8591313 DOI: 10.3389/fnut.2021.790387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/18/2022] Open
Affiliation(s)
- Giovanni Barbara
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Maria Raffaella Barbaro
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Daniele Fuschi
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Marta Palombo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesca Falangone
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Sapienza, Rome, Italy
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Marasco
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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32
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Kriaa A, Jablaoui A, Rhimi S, Soussou S, Mkaouar H, Mariaule V, Gruba N, Gargouri A, Maguin E, Lesner A, Rhimi M. SP-1, a Serine Protease from the Gut Microbiota, Influences Colitis and Drives Intestinal Dysbiosis in Mice. Cells 2021; 10:2658. [PMID: 34685638 PMCID: PMC8534766 DOI: 10.3390/cells10102658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/22/2021] [Accepted: 10/01/2021] [Indexed: 11/20/2022] Open
Abstract
Increased protease activity has been linked to the pathogenesis of IBD. While most studies have been focusing on host proteases in gut inflammation, it remains unclear how to address the potential contribution of their bacterial counterparts. In the present study, we report a functional characterization of a newly identified serine protease, SP-1, from the human gut microbiota. The serine protease repertoire of gut Clostridium was first explored, and the specificity of SP-1 was analyzed using a combinatorial chemistry method. Combining in vitro analyses and a mouse model of colitis, we show that oral administration of recombinant bacteria secreting SP-1 (i) compromises the epithelial barrier, (ii) alters the microbial community, and (ii) exacerbates colitis. These findings suggest that gut microbial protease activity may constitute a valuable contributor to IBD and could, therefore, represent a promising target for the treatment of the disease.
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Affiliation(s)
- Aicha Kriaa
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Amin Jablaoui
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Soufien Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Souha Soussou
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Héla Mkaouar
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Vincent Mariaule
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Natalia Gruba
- Faculty of Chemistry, University of Gdansk, Uniwersytet Gdanski, Chemistry, Wita Stwosza 63, PL80-308 Gdansk, Poland; (N.G.); (A.L.)
| | - Ali Gargouri
- Laboratory of Molecular Biotechnology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax Bp ‘1177’ 3018, Tunisia;
| | - Emmanuelle Maguin
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
| | - Adam Lesner
- Faculty of Chemistry, University of Gdansk, Uniwersytet Gdanski, Chemistry, Wita Stwosza 63, PL80-308 Gdansk, Poland; (N.G.); (A.L.)
| | - Moez Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute-UMR1319, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (A.K.); (A.J.); (S.R.); (S.S.); (H.M.); (V.M.); (E.M.)
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33
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De bruyn M, Ceuleers H, Hanning N, Berg M, De Man JG, Hulpiau P, Hermans C, Stenman UH, Koistinen H, Lambeir AM, De Winter BY, De Meester I. Proteolytic Cleavage of Bioactive Peptides and Protease-Activated Receptors in Acute and Post-Colitis. Int J Mol Sci 2021; 22:10711. [PMID: 34639054 PMCID: PMC8509398 DOI: 10.3390/ijms221910711] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 12/16/2022] Open
Abstract
The protease activity in inflammatory bowel disease (IBD) and irritable bowel syndrome has been studied extensively using synthetic fluorogenic substrates targeting specific sets of proteases. We explored activities in colonic tissue from a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model by investigating the cleavage of bioactive peptides. Pure trypsin- and elastase-like proteases on the one hand and colonic tissue from rats with TNBS-induced colitis in the acute or post-inflammatory phase on the other, were incubated with relevant peptides to identify their cleavage pattern by mass spectrometry. An increased cleavage of several peptides was observed in the colon from acute colitis rats. The tethered ligand (TL) sequences of peptides mimicking the N-terminus of protease-activated receptors (PAR) 1 and 4 were significantly unmasked by acute colitis samples and these cleavages were positively correlated with thrombin activity. Increased cleavage of β-endorphin and disarming of the TL-sequence of the PAR3-based peptide were observed in acute colitis and linked to chymotrypsin-like activity. Increased processing of the enkephalins points to the involvement of proteases with specificities different from trypsin- or chymotrypsin-like enzymes. In conclusion, our results suggest thrombin, chymotrypsin-like proteases and a set of proteases with different specificities as potential therapeutic targets in IBD.
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Affiliation(s)
- Michelle De bruyn
- Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (A.-M.L.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
| | - Hannah Ceuleers
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium
| | - Nikita Hanning
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium
| | - Maya Berg
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
| | - Joris G. De Man
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium
| | - Paco Hulpiau
- Bioinformatics Knowledge Center (BiKC), Howest University of Applied Sciences, 8000 Bruges, Belgium; (P.H.); (C.H.)
| | - Cedric Hermans
- Bioinformatics Knowledge Center (BiKC), Howest University of Applied Sciences, 8000 Bruges, Belgium; (P.H.); (C.H.)
| | - Ulf-Håkan Stenman
- Department of Clinical Chemistry and Haematology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; (U.-H.S.); (H.K.)
| | - Hannu Koistinen
- Department of Clinical Chemistry and Haematology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; (U.-H.S.); (H.K.)
| | - Anne-Marie Lambeir
- Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (A.-M.L.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
| | - Benedicte Y. De Winter
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Ingrid De Meester
- Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (A.-M.L.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (H.C.); (N.H.); (M.B.); (J.G.D.M.); (B.Y.D.W.)
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Barbara G, Barbaro MR, Fuschi D, Palombo M, Falangone F, Cremon C, Marasco G, Stanghellini V. Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier. Front Nutr 2021; 8:718356. [PMID: 34589512 PMCID: PMC8475765 DOI: 10.3389/fnut.2021.718356] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/12/2021] [Indexed: 12/19/2022] Open
Abstract
The intestinal epithelial barrier (IEB) is one of the largest interfaces between the environment and the internal milieu of the body. It is essential to limit the passage of harmful antigens and microorganisms and, on the other side, to assure the absorption of nutrients and water. The maintenance of this delicate equilibrium is tightly regulated as it is essential for human homeostasis. Luminal solutes and ions can pass across the IEB via two main routes: the transcellular pathway or the paracellular pathway. Tight junctions (TJs) are a multi-protein complex responsible for the regulation of paracellular permeability. TJs control the passage of antigens through the IEB and have a key role in maintaining barrier integrity. Several factors, including cytokines, gut microbiota, and dietary components are known to regulate intestinal TJs. Gut microbiota participates in several human functions including the modulation of epithelial cells and immune system through the release of several metabolites, such as short-chain fatty acids (SCFAs). Mediators released by immune cells can induce epithelial cell damage and TJs dysfunction. The subsequent disruption of the IEB allows the passage of antigens into the mucosa leading to further inflammation. Growing evidence indicates that dysbiosis, immune activation, and IEB dysfunction have a role in several diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and gluten-related conditions. Here we summarize the interplay between the IEB and gut microbiota and mucosal immune system and their involvement in IBS, IBD, and gluten-related disorders.
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Affiliation(s)
- Giovanni Barbara
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Maria Raffaella Barbaro
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Daniele Fuschi
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Marta Palombo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesca Falangone
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Sapienza, Rome, Italy
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Marasco
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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35
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Ferrier L, Eutamène H, Siegwald L, Marquard AM, Tondereau V, Chevalier J, Jacot GE, Favre L, Theodorou V, Vicario M, Rytz A, Bergonzelli G, Garcia-Rodenas CL. Human milk oligosaccharides alleviate stress-induced visceral hypersensitivity and associated microbiota dysbiosis. J Nutr Biochem 2021; 99:108865. [PMID: 34582967 DOI: 10.1016/j.jnutbio.2021.108865] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 06/11/2021] [Accepted: 09/01/2021] [Indexed: 02/08/2023]
Abstract
Pain-related functional gastrointestinal disorders (FGIDs) are characterized by visceral hypersensitivity (VHS) associated with alterations in the microbiota-gut-brain axis. Since human milk oligosaccharides (HMOs) modulate microbiota, gut and brain, we investigated whether HMOs impact VHS, and explored the role of gut microbiota. To induce VHS, C57BL/6JRj mice received hourly water avoidance stress (WAS) sessions for 10 d, or antibiotics (ATB) for 12 d. Challenged and unchallenged (Sham) animals were fed AIN93M diet (Cont) or AIN93M containing 1% of a 6-HMO mix (HMO6). VHS was assessed by monitoring the visceromotor response to colorectal distension. Fecal microbiome was analyzed by shotgun metagenomics. The effect of HMO6 sub-blends on VHS and nociceptive pathways was further tested using the WAS model. In mice fed Cont, WAS and ATB increased the visceromotor response to distension. HMO6 decreased WAS-mediated electromyographic rise at most distension volumes and overall Area Under Curve (AUC=6.12±0.50 in WAS/HMO6 vs. 9.46±0.50 in WAS/Cont; P<.0001). In contrast, VHS in ATB animals was not improved by HMO6. In WAS, HMO6 promoted most microbiota taxa and several functional pathways associated with low VHS and decreased those associated with high VHS. Among the sub-blends, 2'FL+DFL and LNT+6'SL reduced visceromotor response close to Sham/Cont values and modulated serotoninergic and CGRPα-related pathways. This research further substantiates the capacity of HMOs to modulate the microbiota-gut-brain communication and identifies mitigation of abdominal pain as a new HMO benefit. Ultimately, our findings suggest the value of specific HMO blends to alleviate pain associated FGIDs such as infantile colic or Irritable Bowel Syndrome.
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Affiliation(s)
- Laurent Ferrier
- Nestlé Institute of Health Sciences, Nestle Research, Lausanne, Switzerland
| | - Hélène Eutamène
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Léa Siegwald
- Nestlé Institute of Health Sciences, Nestle Research, Lausanne, Switzerland
| | | | - Valerie Tondereau
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Julien Chevalier
- Nestlé Institute of Health Sciences, Nestle Research, Lausanne, Switzerland
| | - Guillaume E Jacot
- Nestlé Institute of Health Sciences, Nestle Research, Lausanne, Switzerland
| | - Laurent Favre
- Project Management, Nestle Research, Lausanne, Switzerland
| | - Vassilia Theodorou
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Maria Vicario
- Nestlé Institute of Health Sciences, Nestle Research, Lausanne, Switzerland
| | - Andreas Rytz
- Clinical Research Unit, Nestle Research, Lausanne, Switzerland
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36
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Brizuela M, Castro J, Harrington AM, Brierley SM. Pruritogenic mechanisms and gut sensation: putting the "irritant" into irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2021; 320:G1131-G1141. [PMID: 33949199 DOI: 10.1152/ajpgi.00331.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic abdominal pain is a common clinical condition experienced by patients with irritable bowel syndrome (IBS). A general lack of suitable treatment options for the management of visceral pain is the major contributing factor to the debilitating nature of the disease. Understanding the underlying causes of chronic visceral pain is pivotal to identifying new effective therapies for IBS. This review provides the current evidence, demonstrating that mediators and receptors that induce itch in the skin also act as "gut irritants" in the gastrointestinal tract. Activation of these receptors triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system leading to visceral hypersensitivity and visceral pain. Accumulating evidence points to significant roles of irritant mediators and their receptors in visceral hypersensitivity and thus constitutes potential targets for the development of more effective therapeutic options for IBS.
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Affiliation(s)
- Mariana Brizuela
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Joel Castro
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Andrea M Harrington
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Stuart M Brierley
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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Hanning N, De bruyn M, Ceuleers H, Boogaerts T, Berg M, Smet A, De Schepper HU, Joossens J, van Nuijs ALN, De Man JG, Augustyns K, De Meester I, De Winter BY. Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats. Pharmaceutics 2021; 13:pharmaceutics13060811. [PMID: 34072320 PMCID: PMC8229129 DOI: 10.3390/pharmaceutics13060811] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Dysregulation of the protease–antiprotease balance in the gastrointestinal tract has been suggested as a mechanism underlying visceral hypersensitivity in conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). We aimed to study the potential therapeutic role of an intracolonically administered serine protease inhibitor for the treatment of abdominal pain in a post-inflammatory rat model for IBS. An enema containing 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male Sprague–Dawley rats, whereas controls received a saline solution. Colonoscopies were performed to confirm colitis and follow-up mucosal healing. In the post-inflammatory phase, the serine protease inhibitor UAMC-00050 (0.1–5 mg/kg) or its vehicle alone (5% DMSO in H2O) was administered in the colon. Thirty minutes later, visceral mechanosensitivity to colorectal distensions was quantified by visceromotor responses (VMRs) and local effects on colonic compliance and inflammatory parameters were assessed. Specific proteolytic activities in fecal and colonic samples were measured using fluorogenic substrates. Pharmacokinetic parameters were evaluated using bioanalytical measurements with liquid chromatography–tandem mass spectrometry. Post-inflammatory rats had increased trypsin-like activity in colonic tissue and elevated elastase-like activity in fecal samples compared to controls. Treatment with UAMC-00050 decreased trypsin-like activity in colonic tissue of post-colitis animals. Pharmacokinetic experiments revealed that UAMC-00050 acted locally, being taken up in the bloodstream only minimally after administration. Local administration of UAMC-00050 normalized visceral hypersensitivity. These results support the role of serine proteases in the pathophysiology of visceral pain and the potential of locally administered serine protease inhibitors as clinically relevant therapeutics for the treatment of IBS patients with abdominal pain.
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Affiliation(s)
- Nikita Hanning
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium; (N.H.); (H.C.); (A.S.); (H.U.D.S.); (J.G.D.M.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
| | - Michelle De bruyn
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
- Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium
| | - Hannah Ceuleers
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium; (N.H.); (H.C.); (A.S.); (H.U.D.S.); (J.G.D.M.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
| | - Tim Boogaerts
- Toxicological Centre, University of Antwerp, 2610 Wilrijk, Belgium; (T.B.); (A.L.N.v.N.)
| | - Maya Berg
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
| | - Annemieke Smet
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium; (N.H.); (H.C.); (A.S.); (H.U.D.S.); (J.G.D.M.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
| | - Heiko U. De Schepper
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium; (N.H.); (H.C.); (A.S.); (H.U.D.S.); (J.G.D.M.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Jurgen Joossens
- Laboratory of Medicinal Chemistry, University of Antwerp, 2610 Wilrijk, Belgium;
| | | | - Joris G. De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium; (N.H.); (H.C.); (A.S.); (H.U.D.S.); (J.G.D.M.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
| | - Koen Augustyns
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
- Laboratory of Medicinal Chemistry, University of Antwerp, 2610 Wilrijk, Belgium;
| | - Ingrid De Meester
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
- Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium
| | - Benedicte Y. De Winter
- Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium; (N.H.); (H.C.); (A.S.); (H.U.D.S.); (J.G.D.M.)
- Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium; (M.D.b.); (M.B.); (K.A.); (I.D.M.)
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
- Correspondence: ; Tel.: +32-3-2652710
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Hou JJ, Wang X, Li Y, Su S, Wang YM, Wang BM. The relationship between gut microbiota and proteolytic activity in irritable bowel syndrome. Microb Pathog 2021; 157:104995. [PMID: 34048892 DOI: 10.1016/j.micpath.2021.104995] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 02/08/2023]
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease that affects 3.8-9.2% of the world population. It affects the physiology and psychology of patients and increases the burden on families, the healthcare system, society, and economic development. Presently, a large number of studies have shown that compared to healthy individuals, the composition and diversity of gut microbiota in IBS patients have changed, and the proteolytic activity (PA) in fecal supernatant and colonic mucosa of IBS patients has also increased. These findings indicate that the imbalance of intestinal microecology and intestinal protein hydrolysis is closely related to IBS. Furthermore, the intestinal flora is a key substance that regulates the PA and is associated with IBS. The current review described the intestinal microecology and intestinal proteolytic activity of patients with IBS and also discussed the effect of intestinal flora on PA. In summary, this study proposed a pivotal role of gut microbiota and PA in IBS, respectively, and provided an in-depth insight into the diagnosis and treatment targets of IBS as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.
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Affiliation(s)
- Jun-Jie Hou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Xin Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Ying Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Shuai Su
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Yu-Ming Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, PR China.
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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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Basson AR, Ahmed S, Almutairi R, Seo B, Cominelli F. Regulation of Intestinal Inflammation by Soybean and Soy-Derived Compounds. Foods 2021; 10:foods10040774. [PMID: 33916612 PMCID: PMC8066255 DOI: 10.3390/foods10040774] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 02/06/2023] Open
Abstract
Environmental factors, particularly diet, are considered central to the pathogenesis of the inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis. In particular, the Westernization of diet, characterized by high intake of animal protein, saturated fat, and refined carbohydrates, has been shown to contribute to the development and progression of IBD. During the last decade, soybean, as well as soy-derived bioactive compounds (e.g., isoflavones, phytosterols, Bowman-Birk inhibitors) have been increasingly investigated because of their anti-inflammatory properties in animal models of IBD. Herein we provide a scoping review of the most studied disease mechanisms associated with disease induction and progression in IBD rodent models after feeding of either the whole food or a bioactive present in soybean.
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Affiliation(s)
- Abigail Raffner Basson
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
- Correspondence:
| | - Saleh Ahmed
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
| | - Rawan Almutairi
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Brian Seo
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
| | - Fabio Cominelli
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
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Hagan M, Hayee BH, Rodriguez-Mateos A. (Poly)phenols in Inflammatory Bowel Disease and Irritable Bowel Syndrome: A Review. Molecules 2021; 26:1843. [PMID: 33805938 PMCID: PMC8036772 DOI: 10.3390/molecules26071843] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 12/12/2022] Open
Abstract
(Poly)phenols (PPs) may have a therapeutic benefit in gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). The aim of this review is to summarise the evidence-base in this regard. Observational evidence does not give a clear indication that PP intake has a preventative role for IBD or IBS, while interventional studies suggest these compounds may confer symptomatic and health-related quality of life improvements in known patients. There are inconsistent results for effects on markers of inflammation, but there are promising reports of endoscopic improvement. Work on the effects of PPs on intestinal permeability and oxidative stress is limited and therefore conclusions cannot be formed. Future work on the use of PPs in IBD and IBS will strengthen the understanding of clinical and mechanistic effects.
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Affiliation(s)
- Marilyn Hagan
- Department of Nutrition and Dietetics, Royal Papworth Hospital NHS Foundation Trust, Cambridge CB2 0AY, UK;
| | - Bu' Hussain Hayee
- Department of Gastroenterology, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
| | - Ana Rodriguez-Mateos
- Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
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Nakov R, Snegarova V, Dimitrova-Yurukova D, Velikova T. Biomarkers in Irritable Bowel Syndrome: Biological Rationale and Diagnostic Value. Dig Dis 2021; 40:23-32. [PMID: 33752201 DOI: 10.1159/000516027] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Patients with irritable bowel syndrome (IBS) usually suffer from nonspecific and overlapping signs that hamper the diagnostic process. In line with this, biomarkers specific for IBS could be of great benefit for diagnosing and managing patients. In IBS, the need is for apparent distinguishing features linked to the disease that improve diagnosis, differentiate from other organic diseases, and discriminate between IBS subtypes. SUMMARY Some biomarkers are associated with a possible pathophysiologic mechanism of IBS; others are used for differentiating IBS from non-IBS patients. Implementation of IBS biomarkers in everyday clinical practice is critical for early diagnosis and treatment. However, our knowledge about their efficient use is still scarce. Key Messages: This review discusses the biomarkers implemented for IBS diagnosis and management, such as blood (serum), fecal, immunological, related to the microbiome, microRNAs, and some promising novel biomarkers associated with imaging and psychological features of the disease. We focus on the most commonly studied and validated biomarkers and their biological rationale, diagnostic, and clinical value.
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Affiliation(s)
- Radislav Nakov
- Clinic of Gastroenterology, Tsaritsa Yoanna University Hospital, Medical University of Sofia, Sofia, Bulgaria
| | - Violeta Snegarova
- Department of Hygiene and Epidemiology, Medical University of Varna, Varna, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia University St. Kliment Ohridski, Sofia, Bulgaria
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Hanning N, Edwinson AL, Ceuleers H, Peters SA, De Man JG, Hassett LC, De Winter BY, Grover M. Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol 2021; 14:1756284821993586. [PMID: 33717210 PMCID: PMC7925957 DOI: 10.1177/1756284821993586] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 01/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIM Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life. METHODS A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered. RESULTS We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17-50%), IBS-D (37-62%) and IBS-C (4-25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies). CONCLUSIONS Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.
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Affiliation(s)
- Nikita Hanning
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA,Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | - Adam L. Edwinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Hannah Ceuleers
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | - Stephanie A. Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Joris G. De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | | | - Benedicte Y. De Winter
- Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, Universiteitsplein 1, Antwerp, 2610, Belgium,Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
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Cibert-Goton V, Lam C, Lingaya M, Falcone Y, Wood JN, Bulmer DC, Spiller R. Pain Severity Correlates With Biopsy-Mediated Colonic Afferent Activation But Not Psychological Scores in Patients With IBS-D. Clin Transl Gastroenterol 2021; 12:e00313. [PMID: 33617189 PMCID: PMC7901800 DOI: 10.14309/ctg.0000000000000313] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/07/2021] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Despite heterogeneity, an increased prevalence of psychological comorbidity and an altered pronociceptive gut microenvironment have repeatedly emerged as causative pathophysiology in patients with irritable bowel syndrome (IBS). Our aim was to study these phenomena by comparing gut-related symptoms, psychological scores, and biopsy samples generated from a detailed diarrhea-predominant IBS patient (IBS-D) cohort before their entry into a previously reported clinical trial. METHODS Data were generated from 42 patients with IBS-D who completed a daily 2-week bowel symptom diary, the Hospital Anxiety and Depression score, and the Patient Health Questionnaire-12 Somatic Symptom score and underwent unprepared flexible sigmoidoscopy. Sigmoid mucosal biopsies were separately evaluated using immunohistochemistry and culture supernatants to determine cellularity, mediator levels, and ability to stimulate colonic afferent activity. RESULTS Pain severity scores significantly correlated with the daily duration of pain (r = 0.67, P < 0.00001), urgency (r = 0.57, P < 0.0005), and bloating (r = 0.39, P < 0.05), but not with psychological symptom scores for anxiety, depression, or somatization. Furthermore, pain severity scores from individual patients with IBS-D were significantly correlated (r = 0.40, P < 0.008) with stimulation of colonic afferent activation mediated by their biopsy supernatant, but not with biopsy cell counts nor measured mediator levels. DISCUSSION Peripheral pronociceptive changes in the bowel seem more important than psychological factors in determining pain severity within a tightly phenotyped cohort of patients with IBS-D. No individual mediator was identified as the cause of this pronociceptive change, suggesting that nerve targeting therapeutic approaches may be more successful than mediator-driven approaches for the treatment of pain in IBS-D.
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Affiliation(s)
- Vincent Cibert-Goton
- National Centre for Bowel Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
| | - Ching Lam
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Melanie Lingaya
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Yirga Falcone
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - John N. Wood
- Molecular Nociception Group, Wolfson Institute of Biomedical Sciences, University College London, London, UK;
| | - David C. Bulmer
- National Centre for Bowel Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
- Department of Pharmacology, University of Cambridge, Cambridge, UK.
| | - Robin Spiller
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
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Camilleri M. Human Intestinal Barrier: Effects of Stressors, Diet, Prebiotics, and Probiotics. Clin Transl Gastroenterol 2021; 12:e00308. [PMID: 33492118 PMCID: PMC7838004 DOI: 10.14309/ctg.0000000000000308] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/18/2020] [Indexed: 12/12/2022] Open
Abstract
The objectives of this article are to understand the effects of stressors (nonsteroidal antiinflammatory drug, exercise, and pregnancy) and components in the diet, specifically prebiotics and probiotics, on intestinal barrier function. Stressors generally reduce barrier function, and these effects can be reversed by supplements such as zinc or glutamine that are among the substances that enhance the barrier. Other dietary factors in the diet that improve the barrier are vitamins A and D, tryptophan, cysteine, and fiber; by contrast, ethanol, fructose, and dietary emulsifiers increase permeability. Effects of prebiotics on barrier function are modest; on the other hand, probiotics exert direct and indirect antagonism of pathogens, and there are documented effects of diverse probiotic species, especially combination agents, on barrier function in vitro, in vivo in animal studies, and in human randomized controlled trials conducted in response to stress or disease. Clinical observations of benefits with combination probiotics in inflammatory diseases have simultaneously not appraised effects on intestinal permeability. In summary, probiotics and synbiotics enhance intestinal barrier function in response to stressor or disease states. Future studies should address the changes in barrier function and microbiota concomitant with assessment of clinical outcomes.
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Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, Minnesota
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The Prevalence of Blastocystis Infection in Pediatric Patients with Malignancy: A Single-Center Study in Ahvaz, Iran. ARCHIVES OF PEDIATRIC INFECTIOUS DISEASES 2021. [DOI: 10.5812/pedinfect.104068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Blastocystis spp. is known as one of the few intestinal parasites, prevalent in more than 5% and 30 - 60% of the population in industrialized and developing countries, respectively. In this respect, immunocompromised individuals, such as patients undergoing chemotherapy or those with malignancies, are at risk of the clinical symptoms of Blastocystis infection; however, the given condition is often self-limiting in healthy individuals. Objectives: The current study aimed at evaluating the prevalence of Blastocystis infection in children with malignancies receiving chemo drugs. Methods: The current descriptive, cross-sectional study was conducted on 52 stool specimens collected from patients with cancer admitted to the Oncology Ward of Shahid Baqaei 2 Hospital, Ahvaz, Iran, for six months. A standardized questionnaire was filled out for all cases. Each specimen was also prepared using direct smear, the Lugol iodine staining, and the formalin-ether condensation method. Results: Blastocystis spp. was detected in 21.1% of the cases among them, 11.5% demonstrated gastrointestinal symptoms; therefore, a significant relationship was observed between Blastocystis infection and gastrointestinal symptoms. Conclusion: Patients undergoing chemotherapy should be screened for opportunistic parasitic infections such as Blastocystis to avoid potentially life-threatening outcomes. Besides, further studies are required to identify the subtypes of Blastocystis.
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Motta JP, Rolland C, Edir A, Florence AC, Sagnat D, Bonnart C, Rousset P, Guiraud L, Quaranta-Nicaise M, Mas E, Bonnet D, Verdu EF, McKay DM, Buscail E, Alric L, Vergnolle N, Deraison C. Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation. Mucosal Immunol 2021; 14:667-678. [PMID: 33674762 PMCID: PMC8075934 DOI: 10.1038/s41385-021-00375-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 12/03/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.
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Affiliation(s)
- Jean-Paul Motta
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - Corinne Rolland
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - Anissa Edir
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - Ana-Carolina Florence
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - David Sagnat
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - Chrystelle Bonnart
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - Perrine Rousset
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | - Laura Guiraud
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
| | | | - Emmanuel Mas
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France ,grid.414018.80000 0004 0638 325XUnité de Gastroentérologie, Hépatologie, Nutrition, Diabétologie et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, Toulouse, France
| | - Delphine Bonnet
- grid.411175.70000 0001 1457 2980Pole Digestif, CHU Toulouse, Toulouse, France
| | - Elena F. Verdu
- grid.25073.330000 0004 1936 8227Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON Canada
| | - Derek M. McKay
- grid.22072.350000 0004 1936 7697Department of Physiology and Pharmacology, University of Calgary, Calgary, AB Canada
| | - Etienne Buscail
- grid.411175.70000 0001 1457 2980Pole Digestif, CHU Toulouse, Toulouse, France
| | - Laurent Alric
- grid.411175.70000 0001 1457 2980Pole Digestif, CHU Toulouse, Toulouse, France
| | - Nathalie Vergnolle
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France ,grid.22072.350000 0004 1936 7697Department of Physiology and Pharmacology, University of Calgary, Calgary, AB Canada
| | - Céline Deraison
- grid.503230.7IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France
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Mishima Y, Ishihara S. Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome. Int J Mol Sci 2020; 21:ijms21228664. [PMID: 33212919 PMCID: PMC7698457 DOI: 10.3390/ijms21228664] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term “brain–gut–microbiome axis” has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.
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Abstract
Background: Blastocystis hominis is recognized as a common intestinal parasite. Some studies have reported the effect of phenotypic, serologic, and biochemical indices on the parasites’ pathogenic characteristics. Objectives: This study aimed to introduce B. hominis as a pathogen, trying to change views about this parasite and introduce it as a parasite important in medical sciences. Methods: An open-ended, language-restricted (English) search was conducted in MEDLINE (PubMed), CINAHL, Scopus, and the Cochrane Library databases (from 1990 to 2018) using specific search criteria to identify Blastocystis spp. Results: The search of the literature retrieved 158 published articles on Blastocystis spp. Among these articles, the ones related to the pathogenicity of B. hominis were selected for further investigations. Results obtained in this study showed that the number of articles within five-year periods had an increasing trend. Also, studies of B. hominis have mainly investigated its pathogenic characteristics, accounting for 37.34% of the studies. Conclusions: This study showed comprehensive reasons for proving the pathogenesis of the parasite. It is hoped that further studies would fill the existing gaps regarding this parasite and identify its true identity as a medically important parasite.
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Mast Cell Regulation and Irritable Bowel Syndrome: Effects of Food Components with Potential Nutraceutical Use. Molecules 2020; 25:molecules25184314. [PMID: 32962285 PMCID: PMC7570512 DOI: 10.3390/molecules25184314] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/12/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Mast cells are key actors in inflammatory reactions. Upon activation, they release histamine, heparin and nerve growth factor, among many other mediators that modulate immune response and neuron sensitization. One important feature of mast cells is that their population is usually increased in animal models and biopsies from patients with irritable bowel syndrome (IBS). Therefore, mast cells and mast cell mediators are regarded as key components in IBS pathophysiology. IBS is a common functional gastrointestinal disorder affecting the quality of life of up to 20% of the population worldwide. It is characterized by abdominal pain and altered bowel habits, with heterogeneous phenotypes ranging from constipation to diarrhea, with a mixed subtype and even an unclassified form. Nutrient intake is one of the triggering factors of IBS. In this respect, certain components of the daily food, such as fatty acids, amino acids or plant-derived substances like flavonoids, have been described to modulate mast cells' activity. In this review, we will focus on the effect of these molecules, either stimulatory or inhibitory, on mast cell degranulation, looking for a nutraceutical capable of decreasing IBS symptoms.
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