Dysregulated Gastrointestinal Innate Immune Function in Human Type 1 Diabetes

The host-environment dialogue is thought to be a critical mediator in the initiation and progression of autoinflammatory and autoimmune disease, including Type 1 Diabetes (T1D), though the exact mechanisms of (mis)communications taking place largely remain elusive. Therefore, we aim to decipher the global intestinal immune environment in T1D, focusing on the innate immune function of intestinal epithelial cells (IEC) and local immune cell milieu. Using fresh human duodenal tissue, we evaluated the soluble mediator profiles of and immune cell populations within the gastrointestinal environment. Our data indicate a whole organ T1D-associated 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. We also evaluated IEC-specific innate immune responsiveness using primary IEC culture, where T1D-derived cultures demonstrated a lack of tolerogenic responses concomitant with induction of inflammatory responses 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 or consequence of disease remains to be defined.