The intestinal microbiome in inflammatory bowel disease and its response to therapy

Abstract

Inflammatory bowel diseases, consisting of both Crohn’s disease (CD) and ulcerative colitis (UC), occur when a susceptible host mounts a chronic aberrant immune response to its commensal microbial community resulting in chronic inflammation. CD and UC may exhibit similar clinical manifestations that oscillate between active disease and remission, but these diseases are distinct, and are characterized by specific pathophysiology. The incidence and prevalence of IBD has been increasing over time, with the highest rates occurring in Europe and North America. Although many genome-wide association studies (GWAS) on CD and UC have found loci associated with these diseases, studies conducted on monozygotic twins show low concordance rates, suggesting environmental causes play an important role in the onset of IBD. Current therapies for treatment of IBD focus on suppressing the immune response, but remission rates remain low and relapses occur often. There is a dire need for new treatment options that involve suppressing the immune system stimuli – the commensal gut microbiota. The commensal microbiota triggers the mucosal immune system to drive chronic inflammation in IBD, and studies have shown that patients display a gut dysbiosis compared to healthy individuals. Modulation of the disease through modulation of the gut microbiome, has recently gained interest as a potential treatment option. Little is known about how the microbial community in IBD patients will respond to therapies that attempt to modulate the community. Thus, the overall goal of this thesis was to characterize the IBD microbiome in relation to disease status, severity, and response to therapy. Together these results, (a) provide an in-depth characterization of the intestinal microbiome in IBD, (b) demonstrate the response of the gut microbiome in UC patients to FMT, providing insight into the successful mechanism, and (c) provide evidence for inflammation related differences in CD giving insight into the mechanism of pathogenesis. These results not only further our understanding regarding dysbiosis in IBD, but also can be used to modify our current treatment protocols to increase efficacy.