Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22

Abstract A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5 + intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5 + ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5 + ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5 + ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8αβ + T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8 + T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.