Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype

PLoS One. 2012;7(8):e42777. doi: 10.1371/journal.pone.0042777. Epub 2012 Aug 17.

Abstract

Background: The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose pathogenesis is not completely understood. Its high prevalence and the considerable effects on quality of life make IBS a disease with high social cost. Recent studies suggest that low grade mucosal immune activation, increased intestinal permeability and the altered host-microbiota interactions that modulate innate immune response, contribute to the pathophysiology of IBS. However, the understanding of the precise molecular pathophysiology remains largely unknown.

Methodology and findings: In this study our objective was to evaluate the TLR expression as a key player in the innate immune response, in the colonic mucosa of IBS patients classified into the three main subtypes (with constipation, with diarrhea or mixed). TLR2 and TLR4 mRNA expression was assessed by real time RT-PCR while TLRs protein expression in intestinal epithelial cells was specifically assessed by flow cytometry and immunofluorescence. Mucosal inflammatory cytokine production was investigated by the multiplex technology. Here we report that the IBS-Mixed subgroup displayed a significant up-regulation of TLR2 and TLR4 in the colonic mucosa. Furthermore, these expressions were localized in the epithelial cells, opening new perspectives for a potential role of epithelial cells in host-immune interactions in IBS. In addition, the increased TLR expression in IBS-M patients elicited intracellular signaling pathways resulting in increased expression of the mucosal proinflammatory cytokines IL-8 and IL1β.

Conclusions: Our results provide the first evidence of differential expression of TLR in IBS patients according to the disease subtype. These results offer further support that microflora plays a central role in the complex pathophysiology of IBS providing novel pharmacological targets for this chronic gastrointestinal disorder according to bowel habits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Colon / immunology
  • Colon / metabolism*
  • Colon / pathology
  • Cytokines / metabolism
  • Female
  • Gene Expression
  • Humans
  • Inflammation Mediators / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Irritable Bowel Syndrome / immunology
  • Irritable Bowel Syndrome / metabolism*
  • Irritable Bowel Syndrome / pathology
  • Lipopolysaccharide Receptors / metabolism
  • Male
  • Middle Aged
  • PPAR gamma / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Up-Regulation

Substances

  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharide Receptors
  • PPAR gamma
  • RNA, Messenger
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4

Grant support

The study was supported by the Institut National de la Santé et de la Recherche Médicale Unit U1073, University of Rouen, France and Ministry of Sciences and Technology of Buenos Aires, Argentina. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.