β-Hydroxybutyrate suppresses colorectal cancer

Oxana Dmitrieva-Posocco, Andrea C. Wong, Patrick Lundgren, Aleksandra M. Golos, Hélène C. Descamps, Lenka Dohnalová, Zvi Cramer, Yuhua Tian, Brian Yueh, Onur Eskiocak, Gabor Egervari, Yemin Lan, Jinping Liu, Jiaxin Fan, Jihee Kim, Bhoomi Madhu, Kai Markus Schneider, Svetlana Khoziainova, Natalia Andreeva, Qiaohong WangNing Li, Emma E. Furth, Will Bailis, Judith R. Kelsen, Kathryn E. Hamilton, Klaus H. Kaestner, Shelley L. Berger, Jonathan A. Epstein, Rajan Jain, Mingyao Li, Semir Beyaz, Christopher J. Lengner, Bryson W. Katona, Sergei I. Grivennikov, Christoph A. Thaiss, Maayan Levy

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.

Original languageEnglish
Pages (from-to)160-165
Number of pages6
JournalNature
Volume605
Issue number7908
DOIs
StatePublished - May 5 2022

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