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.
Highlights
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal discomfort or pain and changes in bowel habits [1,2]
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
Summary
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal discomfort or pain and changes in bowel habits (constipation and/or diarrhea) [1,2]. The intestinal epithelium serves as a barrier between the body and the microbiota and is an active agent in the mucosal immune response through its expression of pro-inflammatory genes, the secretion of inflammatory cytokines, and the recruitment of inflammatory cells in response to pathogenic bacteria and their products [9]. Human TLRs comprise a large family of 10 proteins [12] expressed on mucosal immune cells such as macrophages, or dendritic cells and at low levels in the intestinal epithelial cells (IECs) [13]and bind specific molecules of diverse commensals and pathogens. 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. The understanding of the precise molecular pathophysiology remains largely unknown
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