Diabetic liver-enriched secretory dipeptidyl peptidase 4 (DPP4) fuels gut inflammation via attenuation of autophagy

The recurrent pathological inflammation of the gut is a major concern in diabetic patients. With the failure of anti-inflammatory or diabetic drugs to limit relapse of colon inflammation demands the unearthing of mechanistic details underlying higher incidences of colitis in diabetic patients. Here we report the enrichment of DPP4 in the livers and blood samples of diabetic humans and mice models of diabesity that is in parallel to the development of colitis. Overexpression of DPP4 exacerbates or hepatic silencing of DPP4 impairs experimental colitis induced by DSS and STM. Mechanistically, we identified liver DPP4 attenuates gut-autophagic response to trigger enteric cell apoptosis, reduced mucin secretion, and compromised gut barrier leading to high infiltration of immune cells secreting inflammatory cytokines establishing pathological gut inflammation. Thus, liver-DPP4-mediated gut autophagy inhibition is a key pathway in diabesitic colitis.