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

Jalanka, Jonna; Lam, Ching; Bennett, Andrew; Hartikainen, Anna; Crispie, Fiona; Finnegan, Laura A; Cotter, Paul D; Spiller, Robin

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.

Citation

Jalanka, J., Lam, C., Bennett, A., Hartikainen, A., Crispie, F., Finnegan, L. A., …Spiller, R. (2021). 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. Journal of Neurogastroenterology and Motility, 27(2), 279-291. https://doi.org/10.5056/JNM20205

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2020
• Online Publication Date: Apr 30, 2021
• Publication Date: Apr 30, 2021
• Deposit Date: Sep 9, 2021
• Publicly Available Date: Sep 9, 2021
• Journal: Journal of Neurogastroenterology and Motility
• Print ISSN: 2093-0879
• Electronic ISSN: 2093-0887
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 2
• Pages: 279-291
• DOI: https://doi.org/10.5056/JNM20205
• Keywords: Gene expression; Irritable bowel syndrome; Mesalazine; Microbiota; Toll-like receptor 4
• Public URL: https://nottingham-repository.worktribe.com/output/5504805
• Publisher URL: https://www.jnmjournal.org/journal/view.html?doi=10.5056/jnm20205
• Additional Information: J Neurogastroenterol Motil: http://www.jnmjournal.org/journal/view.html?doi=10.5056/jnm20205; Received: 2020-09-09; Revised: 2020-10-23; Accepted: 2020-11-09; Published: 2021-04-30; Copyright: © 2021 The Korean Society of Neurogastroenterology and Motility; License: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.