Abstract
BackgroundInflammatory bowel diseases (IBDs) appear to be modulated by the interaction of pathogen-associated molecular patterns (PAMPs) derived from intestinal bacteria with their respective innate immune receptors, including Toll-like receptors (TLRs). We aimed to establish if intestinal concentrations of proinflammatory bacterial ligands of TLR2, TLR4, or TLR5 may be altered in murine IBD models, and to characterize which of the major bacterial groups may contribute to each signal.Methodology/Principal FindingsPAMPs specific for TLR2 (lipopeptide equivalents), TLR4 (lipopolysaccharide equivalents), and TLR5 (flagellin equivalents) in human and murine fecal and intestinal samples were quantified using HEK-293 cells transfected with respective TLRs and calibrated with defined standard PAMPs. The induction of colitis in mice by dextran-sodium-sulphate treatment significantly increased colonic lipopeptide (fourfold) and LPS equivalent (550-fold) concentrations, while flagellin equivalent concentrations remained similar. The induction of ileitis by oral infection with Toxoplasma gondii dramatically increased ileal concentrations of lipopeptide (370-fold), LPS (3,300-fold), and flagellin equivalents (38-fold), all P<0.01. Analysis of representative strains of the major bacterial groups of the human intestine revealed that enterobacterial species are likely to be more significant contributors of soluble TLR2 and TLR4 stimulants to the intestinal milieu than Bacteroides species or Gram-positive Firmicutes.Conclusions/SignificanceWe conclude that the induction of colitis or ileitis in mice is associated with significant disease-specific alterations to the PAMP profile of the gut microbiota.
Highlights
Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn’s disease, are widely believed to be driven by inappropriate responses to the intestinal microbiota [1]
As very little information is currently available regarding which bacterial groups may contribute to the soluble and bacteria-associated pathogen-associated molecular patterns (PAMPs) pools in the intestine, or of how PAMP concentrations in the intestinal contents may be altered during the course of IBDs, we aimed to quantify the relative biological activities of PAMPs specific for TLR2, TLR4 and TLR5 in human and murine faecal and intestinal samples, and to establish whether the concentrations of these agents may be altered in two murine models of IBDs, T. gondii-induced ileitis and DSS-induced colitis
Intestinal PAMP Profile Is Markedly Altered During T. gondii-Induced Ileitis
Summary
Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn’s disease, are widely believed to be driven by inappropriate responses to the intestinal microbiota [1]. Among the mechanisms by which bacteria may promote inflammatory signalling, recent evidence suggests that pathogen-associated molecular patterns (PAMPs) derived from intestinal bacteria may modulate IBDs via stimulation of their respective innate immune receptors, including Toll-like receptors (TLRs) [2]. PAMP-recognition by intestinal epithelial cells has been shown to lead to the promotion of barrier enhancement, epithelial repair and the secretion of anti-microbial peptides, rather than overt inflammatory reponses [4,5,6] Mechanisms such as these enable the healthy gut mucosa to remain largely uninflammed despite chronic lumenal exposure to large quantities of potentially pro-inflammatory PAMPs derived from the host commensal microbiota. We aimed to establish if intestinal concentrations of proinflammatory bacterial ligands of TLR2, TLR4, or TLR5 may be altered in murine IBD models, and to characterize which of the major bacterial groups may contribute to each signal
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