Patients with Inflammatory Bowel Disease Exhibit Dysregulated Responses to Microbial DNA

Abstract

BackgroundA critical role for the gut epithelium lies in its ability to discriminate between pathogens and commensals and respond appropriately. Dysfunctional interactions between microbes and epithelia are believed to have a role in inflammatory bowel disease (IBD). In this study, we analyzed microbiota and gene expression in IBD patients and examined responses of mucosal biopsies to bacterial DNA.MethodsBiopsies were taken from non-inflamed areas of the colon in healthy controls (HC) and Crohn's disease (CD) and ulcerative colitis (UC) patients in remission. Biopsies were snap-frozen or cultured with DNA from Lactobacillus plantarum (LP) or Salmonella dublin (SD). Gene expression was analyzed under basal conditions and in response to DNA. Gene networks were analyzed using Ingenuity Pathways software. Mucosal-associated microbiota was analyzed using terminal restriction fragment length polymorphism. Frequency of single nucleotide polymorphisms in NOD2 and TLR9 was assessed.ResultsPatients with IBD had altered microbiota, enhanced expression of inflammatory genes, and increased correlations between specific gene expression and microbes. Principle component analysis showed CD and UC patients to cluster independently from healthy controls in both gene expression and microbial analysis. DNA from LP stimulated anti-inflammatory pathways in controls and UC patients, but induced an upregulation of IL17A in CD patients. There were no differences in SNP frequencies of TLR9 or NOD2 in the groups.ConclusionsPatients with Crohn's disease exhibit altered responses to bacterial DNA. These findings suggest that the gut response to bacterial DNA may depend not only on the specific type of bacterial DNA, but also on the host.

Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

“…A recent meta-analysis of IBD genetic studies identified 163 IBD risk loci (4), and many of these risk alleles exhibit infection-related balancing natural selection (4). Consistent with this finding, an overall dysfunction in the human gut microbial community has been described in both longstanding adult-onset IBD (5) and treatment-naive pediatric-onset IBD (6), and patients exhibit altered responses to bacterial DNA (7). Animal models have conclusively shown causality in the requirement for bacterial colonization in the development of intestinal inflammation in genetically susceptible hosts (3).…”

Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation

“…Moreover, recent studies suggest that the normal immune interactions between TLR9 and NOD2 are lost in CD patients [28], [29]. NOD2 is a cytosolic innate immune receptor that mediates pro-inflammatory and antibacterial responses through recognition of bacterial cell wall components.…”

DNA Transfer and Toll-like Receptor Modulation by Helicobacter pylori

“…These studies were particularly focused on how dysregulation of TLR9 signaling could lead to the development of inflammatory bowel disease or colitis (Rachmilewitz et al 2004; Katakura et al 2005; Lee et al 2006; Luther et al 2011; Hotte et al 2012; Jounai et al 2012; O’Hara et al 2012; Owyang et al 2012). …”