Cheng, C.-W.Biton, M.Haber, A. L.Gündüz, NurayEng, G.Gaynor, L. T.Tripathi, S.Çalıbaşı-Koçal, G.Rickelt, S.Butty, V. L.Moreno-Serrano, M.Iqbal, A. M.Bauer-Rowe, K. E.Imada, S.Ulutaş, M. S.Mylonas, C.Whary, M. T.Levine, S. S.Başbınar, Y.Hynes, R. O.Mino-Kenudson, M.Deshpande, V.Boyer, L. A.Fox, J. G.Terranova, C.Rai, K.Piwnica-Worms, H.Mihaylova, M. M.Regev, A.Yılmaz, Ö. H.2020-02-192020-02-1920190092-8674http://hdl.handle.net/11693/53420Little is known about how metabolites couple tissue-specific stem cell 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 (βOHB), distinguishes self-renewing Lgr5 + stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5 + ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury. Graphical AbstractEnglishHmgcs2Ketone bodiesBeta-hydroxybutyrateNotchHDACIntestinal stem cellKetogenic dietArticle10.1016/j.cell.2019.07.048