Role of Toll Like Receptors in Irritable Bowel Syndrome: Differential Mucosal Immune Activation According to the Disease Subtype

Abstract

BackgroundThe 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 FindingsIn 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.ConclusionsOur 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.

The Colonic Tissue Levels of TLR2, TLR4 and Nitric Oxide in Patients with Irritable Bowel Syndrome

“…In the present study, the authors demonstrated that TLR2 and TLR4 induced the production of TNF-alpha in IBS patients (20). In the most recent study, which was published by Belmonte et al, the authors demonstrated the significant upregulation of TLR2 and TLR4 in the colonic mucosa of IBS patients (21). Interestingly within these trials, only one study performed a subgroup analysis of IBS patients.…”

“…TLR2 and TLR4 appear to recognize several different microbial molecules. It has been shown that some virulence factors, including the presence of fimbriae and enterotoxins activated TLR2 and TLR4 (19)(20)(21)(22)(23). Stress has been shown to increase the motility and sensation of the colon to a greater degree in IBS patients than in healthy individuals without IBS.…”

Effect of deoxynivalenol on the levels of toll-like receptors 2 and 9 and their mRNA expression in enterocytes in the porcine large intestine: a preliminary study

“…It is believed that IBD is caused by abnormal gut microflora, increased intestinal permeability and changes in TLR expression (Kassinen et al 2007, Camilleri and Gorman 2007, Brint et al 2011. Belmonte et al (2012) demonstrated that IBD patients suffering from constipation alternating with diarrhea had higher TLR2 and TLR4 expression in colonic enterocytes. Mice with turned off TLR2 gene were more sensitive to colitis induced by dextran sulfate sodium (DSS) (Cario et al 2010).…”

Pathogenesis of Irritable Bowel Syndrome - Review Regarding Associated Infection and Immune Activation

“…They found increased expression of TLR4, TLR5, single immunoglobulin (Ig) IL-1R-related molecule (SIGIRR), IL-1-receptor-associated kinase-M (IRAK-M) and Toll-interacting protein (Tollip) in colonic tissues obtained from IBS patients, but expression levels of TLR7 and TLR8 were significantly decreased compared to controls. A recent study by Belmonte et al [69] also revealed increased expression of TLR4 and TLR5 in the colonic mucosa of IBS-mixed subtype (IBS-M) patients, along with increased colonic expression of IL1β and IL-8 (table 3). These findings suggest that the innate TLR-mediated immune system may be activated in IBS patients.…”

“…As altered microbial flora influence the intestinal innate immune system, investigations of TLRs are helpful for understanding the pathogenesis of IBS. With regard to this issue, several studies have been presented in recent years [67]. …”