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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation
Geoffroy Mallaret, Amandine Lashermes, Mathieu Meleine, Ludivine Boudieu, Julie Barbier, Youssef Aissouni, Agathe Gelot, Benoit Chassaing, Andrew T Gewirtz, Denis Ardid, Frederic Antonio Carvalho
Geoffroy Mallaret, Mathieu Meleine, Ludivine Boudieu, Julie Barbier, Youssef Aissouni, Agathe Gelot, Denis Ardid, Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
Amandine Lashermes, Department of Microbiology, Université Paris-Saclay, National Research Institute for Agriculture, Food and the Environment, AgroParisTech, Micalis Institute, Jouy-en-Josas 78350, France
Benoit Chassaing, Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, INSERM U1016, CNRS UMR 8104, Université Paris Cité, Paris 75014, France
Andrew T Gewirtz, Center for Inflammation, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA30033, United States
Frederic Antonio Carvalho, Department of Pharmacology, INSERM 1107 NeuroDOL/University of Clermont Auvergne, Clermont-Ferrand 63000, France
Author contributions: Mallaret G and Lashermes A contributed equally to this article; Study concept and design done by Mallaret G, Lashermes A, Ardid D and Carvalho FA; Acquisition of data done by Mallaret G, Lashermes A, Barbier J, Aissouni Y, Chassaing B; Analysis and interpretation of data done by Mallaret G, Lashermes A, Chassaing B, Gewirtz AT, Ardid D and Carvalho FA; Drafting of the manuscript done by Mallaret G, Lashermes A Meleine M, Boudieu L and Carvalho FA; Obtained funding done by Ardid D and Carvalho FA; Study supervision done by Gewirtz AT, Ardid D and Carvalho FA.
Supported by the Region Auvergne-Rhône-Alpes and FEDER, No. Thématiques émergentes and Pack Ambition Recherche; the French Government IDEX-ISITE Initiative, No. 16-IDEX-0001-CAP 20-25; the Ministère de la Recherche et de la Technologie, INSERM and University of Clermont Auvergne, No. UMR1071.
Institutional animal care and use committee statement: All experiments were performed according to the ethical guidelines set out by the International Association for the Study of Pain, complied with the European Union regulation and were approved by ethics committees: the local committees C2EA-02 of Clermont-Ferrand (approvals CE110-12 and CE111-12).
Conflict-of-interest statement: All authors have nothing to disclose.
Data sharing statement: All sequencing raw data have been deposited in European Nucleotide Archive (ENA) under accession number PRJEB50651.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Frederic Antonio Carvalho, PhD, Academic Research, Department of Pharmacology, INSERM 1107 NeuroDOL/University of Clermont Auvergne, 28 Place Henri Dunant, Clermont-Ferrand 63000, France. frederic.carvalho@inserm.fr
Received: March 15, 2022
Peer-review started: March 15, 2022
First decision: May 29, 2022
Revised: June 9, 2022
Accepted: July 5, 2022
Article in press: July 5, 2022
Published online: August 7, 2022
BACKGROUND
Chronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity (CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors (TLRs), which play a central role in innate immunity.
AIM
To understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes.
METHODS
Maternal separation model (NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension (CRD) coupled with intracolonic pressure variation (IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes. Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin (FliC) on CHS in adult naive wildtype mice was analyzed.
RESULTS
Around 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5 mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance.
CONCLUSION
Altogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5.
Core Tip: Neonatal maternal separation (NMS) model mimic deleterious events in childhood, which can induce a wide range of chronic disorders during adulthood. Herein, around 50% of NMS mice exhibited increased intestinal permeability and colonic hypersensitivity (CHS) associated with intestinal dysbiosis. Only toll-like receptor 5 (TLR5) mRNA expression was increased in colonocytes of NMS mice with CHS and acute intrarectal instillation of flagellin transiently increased intracolonic pressure variations, reflecting transient CHS appearance. Together, those findings suggest a pathophysiological continuum between intestinal permeability, intestinal dysbiosis and CHS, with a previously undescribed role for TLR5 in CHS.
