The inflammatory bowel diseases (IBD) - comprised of Crohn's disease and ulcerative colitis - are chronic inflammatory diseases with growing prevalence in the Western world. It is believed to arise from a combination of genetic susceptibility and environmental factors that trigger an inappropriate mucosal inflammatory response. A role for the microbiome in the pathogenesis of IBD has been suggested by studies demonstrating alterations in the composition and function of the intestinal microbiome in IBD patients compared to healthy controls. This is consistent with the results of genome-wide association studies, which have found that many IBD-associated genes are involved in mucosal host-microbe interactions, and animal studies demonstrating resistance to colitis in many experimental models in the absence of a microbiome.
The Jacobs Laboratory is investigating whether dysbiosis - i.e. altered composition and function of the intestinal microbiome - precedes the development of IBD. The intestinal microbiome and metabolome were studied in a cohort of high-risk families with pediatric IBD. Dysbiosis was observed in IBD patients in clinical remission and in a subset of their healthy first degree relatives. This microbial state was associated with alterations in bioactive intestinal metabolites that affect immune activity and epithelial function. The significance of dysbiosis in healthy relatives of IBD patients is being further explored using humanized gnotobiotic mice to determine whether dysbiosis confers increased susceptibility to experimental IBD. Dysbiosis in individuals at risk for IBD may arise due to genetic variants that disrupt regulation of the microbiome by the mucosal immune system. This possibility is being studied with a combination of human studies to identify genetic variants associated with microbial composition and knockout/transgenic mice to validate a causal relationship between candidate IBD-associated genes and microbial composition.