Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2024; 30(16): 2258-2271
Published online Apr 28, 2024. doi: 10.3748/wjg.v30.i16.2258
Chitin-glucan improves important pathophysiological features of irritable bowel syndrome
Caroline Valibouze, Caroline Dubuquoy, Philippe Chavatte, Michaël Genin, Veronique Maquet, Salvatore Modica, Pierre Desreumaux, Christel Rousseaux
Caroline Valibouze, Department of Digestive Surgery and Transplantation, Lille University, Lille 59037, France
Caroline Dubuquoy, Christel Rousseaux, Intestinal Biotech Development, Faculté de Médicine, Lille 59045, France
Philippe Chavatte, U1286-INFINITE-Institute for Translational Research in Inflammation, Université de Lille, Lille 59000, France
Michaël Genin, ULR 2694-METRICS, Évaluation des Technologies de santé et des Pratiques Médicales, University of Lille, Lille 59000, France
Veronique Maquet, Salvatore Modica, KitoZyme SA, Institution Société Anonyme, Zone 2, Parc des Hauts Sarts, Rue de Milmort, Herstal 4040, Belgium
Pierre Desreumaux, Hepato-Gastroenterology Department, Lille University Hospital, Lille 59037, France
Author contributions: Valibouze C, Dubuquoy C, Rousseaux C, and Chavatte P acquired the data; Genin M supervised the statistical analyses; Valibouze C, Desreumaux P, and Rousseaux C drafted the manuscript; and all the authors interpreted the data and critically reviewed the manuscript; Intestinal Biotech Development supervised study coordination, data collection, and analysis; Chitin glucan was obtained from Kitozyme (SA).
Supported by the Service Public de Wallonie (SPW-EER, convention 8588, Belgium).
Institutional animal care and use committee statement: All the studies were approved by the Local Investigational Ethics Review Board (Approval Nord-Pas-de-Calais CEEA No. 75, Lille, France; protocol reference No. 352012 and No. 19-2009R); and French Government Agreement (Approval No. APAFIS#7542-20 17030609233680).
Conflict-of-interest statement: Desreumaux reports personal fees from Abbvie, personal fees from Abbott, personal fees from Amgen, personal fees from Biocodex, personal fees from Biofortis, personal fees from Biogen, personal fees from Biokuris, personal fees from Dr Falk, personal fees from Ferring, personal fees from Galapagos, personal fees from Fresenius, personal fees from Janssen, personal fees from Intestinal Biotech Development, personal fees from Kitozyme, personal fees from Lesaffre, personal fees from MSD, personal fees from Norgine, personal fees from Pfizer, personal fees from Sandoz, personal fees from Shire, personal fees from Takeda, personal fees from Tillotts, and personal fees from UCB outside the submitted work; Dr. Desreumaux has issued a patent (WO2009103884) issued; Christel Rousseaux is Chief Executive Officer at Intestinal Biotech Development; Veronique Maquet is a Product Development Manager at Kitozyme; Salvatore Modica is Chief Operating Officer at Biokuris, a spin-off company of Kitozyme; The other authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors 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: Christel Rousseaux, PhD, Researcher, Intestinal Biotech Development, Faculté de Médicine, Pole Recherche Amphi JK, Bd du Pr Jules Leclercq, Lille 59045, France. crousseaux@ibd-biotech.com
Received: January 25, 2024
Peer-review started: January 25, 2024
First decision: February 1, 2024
Revised: February 21, 2024
Accepted: March 28, 2024
Article in press: March 28, 2024
Published online: April 28, 2024
Processing time: 91 Days and 11.7 Hours
Abstract
BACKGROUND

Irritable bowel syndrome (IBS) is one of the most frequent and debilitating conditions leading to gastroenterological referrals. However, recommended treatments remain limited, yielding only limited therapeutic gains. Chitin-glucan (CG) is a novel dietary prebiotic classically used in humans at a dosage of 1.5-3.0 g/d and is considered a safe food ingredient by the European Food Safety Authority. To provide an alternative approach to managing patients with IBS, we performed preclinical molecular, cellular, and animal studies to evaluate the role of chitin-glucan in the main pathophysiological mechanisms involved in IBS.

AIM

To evaluate the roles of CG in visceral analgesia, intestinal inflammation, barrier function, and to develop computational molecular models.

METHODS

Visceral pain was recorded through colorectal distension (CRD) in a model of long-lasting colon hypersensitivity induced by an intra-rectal administration of TNBS [15 milligrams (mg)/kilogram (kg)] in 33 Sprague-Dawley rats. Intracolonic pressure was regularly assessed during the 9 wk-experiment (weeks 0, 3, 5, and 7) in animals receiving CG (n = 14) at a human equivalent dose (HED) of 1.5 g/d or 3.0 g/d and compared to negative control (tap water, n = 11) and positive control (phloroglucinol at 1.5 g/d HED, n = 8) groups. The anti-inflammatory effect of CG was evaluated using clinical and histological scores in 30 C57bl6 male mice with colitis induced by dextran sodium sulfate (DSS) administered in their drinking water during 14 d. HT-29 cells under basal conditions and after stimulation with lipopolysaccharide (LPS) were treated with CG to evaluate changes in pathways related to analgesia (µ-opioid receptor (MOR), cannabinoid receptor 2 (CB2), peroxisome proliferator-activated receptor alpha, inflammation [interleukin (IL)-10, IL-1b, and IL-8] and barrier function [mucin 2-5AC, claudin-2, zonula occludens (ZO)-1, ZO-2] using the real-time PCR method. Molecular modelling of CG, LPS, lipoteichoic acid (LTA), and phospholipomannan (PLM) was developed, and the ability of CG to chelate microbial pathogenic lipids was evaluated by docking and molecular dynamics simulations. Data were expressed as the mean ± SEM.

RESULTS

Daily CG orally-administered to rats or mice was well tolerated without including diarrhea, visceral hypersensitivity, or inflammation, as evaluated at histological and molecular levels. In a model of CRD, CG at a dosage of 3 g/d HED significantly decreased visceral pain perception by 14% after 2 wk of administration (P < 0.01) and reduced inflammation intensity by 50%, resulting in complete regeneration of the colonic mucosa in mice with DSS-induced colitis. To better reproduce the characteristics of visceral pain in patients with IBS, we then measured the therapeutic impact of CG in rats with TNBS-induced inflammation to long-lasting visceral hypersensitivity. CG at a dosage of 1.5 g/d HED decreased visceral pain perception by 20% five weeks after colitis induction (P < 0.01). When the CG dosage was increased to 3.0 g/d HED, this analgesic effect surpassed that of the spasmolytic agent phloroglucinol, manifesting more rapidly within 3 wk and leading to a 50% inhibition of pain perception (P < 0.0001). The underlying molecular mechanisms contributing to these analgesic and anti-inflammatory effects of CG involved, at least in part, a significant induction of MOR, CB2 receptor, and IL-10, as well as a significant decrease in pro-inflammatory cytokines IL-1b and IL-8. CG also significantly upregulated barrier-related genes including muc5AC, claudin-2, and ZO-2. Molecular modelling of CG revealed a new property of the molecule as a chelator of microbial pathogenic lipids, sequestering gram-negative LPS and gram-positive LTA bacterial toxins, as well as PLM in fungi at the lowesr energy conformations.

CONCLUSION

CG decreased visceral perception and intestinal inflammation through master gene regulation and direct binding of microbial products, suggesting that CG may constitute a new therapeutic strategy for patients with IBS or IBS-like symptoms.

Keywords: Chitin-glucan; Irritable bowel syndrome; Abdominal pain; Inflammation; Intestinal barrier; Molecular modelling; Microbial cell walls chelation

Core Tip: Currently available irritable bowel syndrome (IBS) treatments are often inadequate. Chitin-glucan is a novel, well-tolerated, non-digestible prebiotic considered a safe food ingredient by the European Food Safety Authority. This study suggests new capacities of chitin-glucan to target most pathophysiological mechanisms of IBS and its therapeutic potential as a promising new generation of prebiotics for patients with IBS or IBS-like symptoms.