Intestinal epithelial cell mediated miscommunication in type 1 diabetes: a tipping point for disease? (MUC2P.933)

Abstract

Abstract The host-environment dialogue at the intestinal interface has been strongly implicated in the development of inflammatory diseases. We are interested in understanding the role of this dialogue in autoinflammatory and autoimmune diseases such as type 1 diabetes (T1D). Although the gastrointestinal tract, a dynamic and highly regulated immunologic organ, has been demonstrated to be impaired in T1D, the mechanisms of any (mis)communications taking place remain unknown. Here we describe the global intestinal inflammatory environment and the phenotype of intestinal lymphocytes in human T1D. In addition, we evaluated the intestinal epithelial cell (IEC) innate immune responses using primary cell culture. Our data indicate a whole organ reduction in tolerogenic mediators concomitant with elevated IEC-induced pro-inflammatory mediators. Significant alterations in intestinal leukocyte populations were observed, whereby increased frequencies of pathogenic T cells and alterations in tolerogenic DCs were noted. Finally, T1D-derived primary IEC cultures demonstrated a lack of tolerogenic responses concomitant with induction of inflammatory response to microbial ligand stimulation as compared to non-T1D derived cultures. Together these data suggest a loss of gastrointestinal homeostasis in T1D potentially as a result of a dysfunctional IEC-mediated host-environment dialogue, though whether this is a cause of consequence of disease remains to be defined.