P-192 Unraveling the Functional Role of Dysbiosis in Crohnʼs Disease

Abstract

Background: The gut microbiota is essential for vital host physiological processes, including digestion of dietary factors and development of the gut immune system. On the other hand, perturbations of the homeostatic relationship between the host and the microbiota can lead to the development of various gastrointestinal disorders, including inflammatory bowel disease (IBD). Although mounting evidence has demonstrated that the microbial community in the gastrointestinal tract of IBD patients is significantly perturbed, a condition termed dysbiosis, it remains unclear whether gut dysbiosis plays a primary role in the disease process or is merely secondary to intestinal inflammation. Methods: Germ-free mice were colonized with stool microbiota isolated from patients with IBD (Crohn's disease [CD] and ulcerative colitis [UC]) and non-IBD control subjects. The microbiome of donor and humanized gnotobiotic (GB) mice was analyzed. Likewise, the luminal metabolome and the host gene expression profile of the humanized GB mice were assessed. Lastly, the colitogenic capacity of the CD-associated microbiota was evaluated by colonization in IL-10-deficient mice. Results: The dysbiotic features of the CD and UC microbiota (e.g., decreased diversity) were recapitulated, at least to some extent, in humanized GB mice. In addition, colonization by the CD-associated microbiota induced pro-inflammatory gene expression in the gut, resembling the immunological signatures found in CD patients. Furthermore, the CD microbiota triggered more severe colitis than the HC microbiota in IL-10-deficient mice. Conclusions: Alterations in the microbial community characteristic for IBD (dysbiosis) can be reproduced in humanized GB mice. Dysbiosis contributes to the pathogenesis of CD by affecting host immune responses.