RETRACTED ARTICLE:Deficiency in intestinal epithelial Reg4ameliorates intestinal inflammation and alters the colonic bacterial composition

The regenerating islet-derived family member 4 (Reg4) in the gastrointestinal tract is up-regulated during intestinal inflammation. However, the physiological function of Reg4in the inflammation is largely unknown. In the current study, the functional roles and involved mechanisms of intestinal epithelial Reg4in intestinal inflammation were studied in healthy and inflamed states using human intestinal specimens, an intestinal conditional Reg4knockout mouse (Reg4ΔIEC) model and dextran sulfate sodium (DSS)-induced colitis model. We showed that the elevated serum Reg4in pediatric intestinal failure (IF) patients were positively correlated with the serum concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α). In inflamed intestine of IF patients, the crypt base Reg4protein was increased and highly expressed towards the luminal face. The Reg4was indicated as a novel target of activating transcription factor 2 (ATF2) that enhanced Reg4expression during the intestinal inflammation. In vivo, the DSS-induced colitis was significantly ameliorated in Reg4ΔIECmice. Reg4ΔIECmice altered the colonic bacterial composition and reduced the bacteria adhere to the colonic epithelium. In vitro, Reg4was showed to promote the growth of colonic organoids, and that this occurs through a mechanism involving activation of signal transducer and activator of transcription 3 (STAT3). In conclusion, our findings demonstrated intestinal-epithelial Reg4deficiency protects against experimental colitis and mucosal injury via a mechanism involving alteration of bacterial homeostasis and STAT3 activation.