Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet

Little is known about how metabolites couple tissue stem function with physiology. Here we show that in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2)—the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (ßOHB)—distinguishes the self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes ßOHB levels in Lgr5+ ISCs and skews their differentiation towards secretory cell fates, which can be rescued by exogenous ßOHB and class I histone deacetylases (HDACs) inhibitor treatment. Mechanistically, ßOHB acts by inhibiting HDACs to reinforce Notch signaling in ISCs, thereby instructing self-renewal and lineage decisions. Notably, while a low glucose ketogenic diet elevates ISC function and post-injury regeneration through ßOHB-mediated Notch signaling, a glucose supplemented diet has the opposite effects. These findings reveal how control of ßOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.