Role of Nod2 in preventing intestinal disease downstream of microbial imbalances

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Genetic and epidemiological evidence have implicated aberrant host-microbe interactions in the development of Crohn's disease, a major type of inflammatory bowel disease (IBD) that frequently affects the small intestine. Commensal bacteria are thought to be critical because an imbalance in the composition of bacteria in the intestine, referred to as dysbiosis, is a hallmark of the disease. The mechanism of dysbiosis requires further elucidation. Another correlation that is mechanistically poorly understood is the inverse relationship between disease incidence and helminth infections. A major challenge has been linking these observations with genetic susceptibility. Mutations in the bacterial sensor Nod2 are among the strongest risk factors for Crohn's disease, and understanding the function of this gene in relation to imbalances in intestinal microbes is likely key to gaining insight into this complex disease etiology. We have found that Nod2-/- mice display multiple abnormalities in the small intestine including inflammatory gene expression in the epithelium, goblet cell dysfunction, and excess interferon- production by intra-epithelial lymphocytes, and piroxicam-induced pathologies. All of these intestinal abnormalities, which are detected to various degrees in patients, were dependent on dysbiosis represented by the specific expansion of a common member of the intestinal bacterial community, Bacteroides vulgatus. Remarkably, infection of Nod2-/- mice with the helminth Trichuris muris reversed B. vulgatus colonization and ameliorated these abnormalities. Therefore, Nod2 prevents inflammatory dysbiosis, which can be reversed by helminth infection. The goal of this proposal is to elucidate the mechanism by which Nod2-deficiency leads to this dysbiosis represented by B. vulgatus expansion and downstream inflammatory pathologies, and determine how this imbalance is reversed by T. muris. These experiments will not only elucidate the basic function of Nod2 in small intestinal immunity, but will likely shed light on why certain microbial factors and interventions apply to some individuals but not others.