Small peptide encoded by MALAT1 aggravates colitis via upregulating GIP expression in enterocyte

Inflammatory bowel disease is a chronic and relapsing intestinal disorder that is challenging to cure. Enterocytes secrete various small peptides and are closely associated with IBD pathogenesis, but their mechanistic roles remain unclear. Our study identified a novel small peptide encoded by the long non-coding RNA MALAT1 in gut K cells, which namedendocrine enterocytes peptide (EECP). The expression of EECP is upregulated in colitis, and its specific knockout suppresses dextran sulfate sodium-induced colitis symptoms, including reduced immune cell infiltration and alleviated intestinal destruction. Mechanistically, EECP enhances the secretion of gastric inhibitory polypeptide in gut K cells, which in turn promotes production of pro-inflammatory cytokines in macrophages, thereby exacerbating colitis progression. Further investigation revealed that EECP binds to the transcriptional repressor FOXO1 to regulate gastric inhibitory polypeptide expression. This study uncovers a novel mechanism by which enterocytes modulate colitis development and provides potential therapeutic targets for IBD treatment.