Defining the mechanism of IFNg-mediated regulation of intestinal epithelium during environmental enteric dysfunction (EED) 4456

Description Environmental enteric dysfunction (EED) is one of the major causes of mortality in children of low to middle income countries (LMICs). EED is associated with infiltration of inflammatory immune cells, villous atrophy and impaired intestinal barrier function leading to malabsorption and growth defects. To understand this disease, we developed a mouse model where mice are fed a malnourished (low protein and low fat) diet and colonized with adherent invasive E. coli. We observed a higher frequency of IFNg producing CD8 T cells and substantial loss of absorptive enterocytes in the small intestine. We hypothesize that microbial dysbiosis induces IFNg producing CD8 T cells which in turn leads to impaired intestinal stem cells (ISCs) functions. We demonstrate that neutralizing IFNg by blockade antibody leads to improved EED symptoms. By Knocking out IFNg from CD8 T cells we show IFNg production by CD8 T cells is critical for EED. We observed translocating bacteria in EED mice as potential activators of CD8 T cells and eliminating them by intravenous (IV) ampicillin treatment leads to improved villous structure and reduced frequency of IFNg producing CD8 T cells suggesting a role for bacterial translocation in EED onset. We are examining the targets of IFNg by eliminating its receptor in the epithelium and mesenchymal cells. These findings underpin a biological circuit; wherein translocating bacteria induces IFNg production by CD8 T cells which in turn regulate the ISCs function. Funding Sources Burroughs Wellcome Fund Topic Categories Immune Mechanisms of Human Disease (HUM)