Stearoyl-CoA desaturases regulate intestinal stem and progenitor cell metabolism and function in response to nutrient abundance.

Diet composition and nutrient availability play critical roles in intestinal stem and progenitor cell function and proliferation. Here, we show that stearoyl-CoA desaturases (SCDs) are regulated by nutrient abundance and link intracellular lipid metabolism to intestinal homeostasis. Pharmacological inhibition or genetic deletion of Scd1 and Scd2 in intestinal mouse organoids disrupted lipid desaturation, induced endoplasmic reticulum (ER) stress, and impaired stem and progenitor cell proliferation, effects largely mitigated by oleic acid supplementation. Intestine-specific deletion of Scd1 and Scd2 reduced the number of LGR5+ stem cells in vivo and was accompanied by metabolic rewiring and expansion of transient amplifying cells. Loss of Scd1 and Scd2 also reduced epithelial regeneration capacity following irradiation and exacerbated tissue damage and inflammation in a DSS-induced colitis model. Together, these findings reveal important SCD dependencies and metabolic adaptations in intestinal stem and progenitor cells that are necessary for epithelial regeneration and repair following injury.