Aspartate Alleviates Colonic Epithelial Damage by Regulating Intestinal Stem Cell Proliferation and Differentiation via Mitochondrial Dynamics

Scope Proliferation and differentiation of intestinal stem cells (ISCs) are crucial for functional restoration after injury, which can be regulated by nutritional molecules. Aspartate is implicated in maintaining intestinal barrier after injury, but underlying mechanisms remain elusive. Here, this study seeks to investigate if aspartate alleviates colonic epithelial damage by regulating ISC function, and to elucidate its mechanisms. Methods and results Eight‐week‐old male C57BL/6 mice supplement with or without 1% L‐aspartate are subjected to drinking water or 2.5% DSS to induce colitis. In this study, aspartate administration alleviates the severity of colitis, as indicated by reduced body weight loss, colon shortening, and inhibited pro‐inflammatory cytokine expression in DSS‐challenged mice. Additionally, aspartate promotes colonic epithelial cell proliferation and differentiation after DSS‐induced damage in mice. Pretreatment with aspartate not only enhances ISC proliferation but also induces ISC differentiation toward enterocytes and goblet cells, which prevent TNF‐α‐induced colonoid damage. Mechanistically, aspartate ameliorates DSS/TNF‐α‐induced perturbation of mitochondrial metabolism and maintains mitochondrial dynamics in colonic epithelium and colonoids. Moreover, aspartate‐mediated ISC proliferation and differentiation are primarily dependent on mitochondrial fusion rather than fission. Conclusions The findings indicate that aspartate promotes ISC proliferation and differentiation to alleviate colonic epithelial damage by regulation of mitochondrial metabolism and dynamics.