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 Wang, Ning 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 () and Maayan Levy ()
Additional contact information
Oxana Dmitrieva-Posocco: Perelman School of Medicine, University of Pennsylvania
Andrea C. Wong: Perelman School of Medicine, University of Pennsylvania
Patrick Lundgren: Perelman School of Medicine, University of Pennsylvania
Aleksandra M. Golos: Perelman School of Medicine, University of Pennsylvania
Hélène C. Descamps: Perelman School of Medicine, University of Pennsylvania
Lenka Dohnalová: Perelman School of Medicine, University of Pennsylvania
Zvi Cramer: School of Veterinary Medicine, University of Pennsylvania
Yuhua Tian: School of Veterinary Medicine, University of Pennsylvania
Brian Yueh: Cold Spring Harbor Laboratory
Onur Eskiocak: Cold Spring Harbor Laboratory
Gabor Egervari: Perelman School of Medicine, University of Pennsylvania
Yemin Lan: Perelman School of Medicine, University of Pennsylvania
Jinping Liu: Perelman School of Medicine, University of Pennsylvania
Jiaxin Fan: Perelman School of Medicine, University of Pennsylvania
Jihee Kim: Perelman School of Medicine, University of Pennsylvania
Bhoomi Madhu: Perelman School of Medicine, University of Pennsylvania
Kai Markus Schneider: Perelman School of Medicine, University of Pennsylvania
Svetlana Khoziainova: Perelman School of Medicine, University of Pennsylvania
Natalia Andreeva: Fox Chase Cancer Center
Qiaohong Wang: Perelman School of Medicine, University of Pennsylvania
Ning Li: School of Veterinary Medicine, University of Pennsylvania
Emma E. Furth: University of Pennsylvania Medical Center, Perelman School of Medicine, University of Pennsylvania
Will Bailis: Children’s Hospital of Philadelphia
Judith R. Kelsen: Children’s Hospital of Philadelphia
Kathryn E. Hamilton: Children’s Hospital of Philadelphia
Klaus H. Kaestner: Perelman School of Medicine, University of Pennsylvania
Shelley L. Berger: Perelman School of Medicine, University of Pennsylvania
Jonathan A. Epstein: Perelman School of Medicine, University of Pennsylvania
Rajan Jain: Perelman School of Medicine, University of Pennsylvania
Mingyao Li: Perelman School of Medicine, University of Pennsylvania
Semir Beyaz: Cold Spring Harbor Laboratory
Christopher J. Lengner: School of Veterinary Medicine, University of Pennsylvania
Bryson W. Katona: Perelman School of Medicine, University of Pennsylvania
Sergei I. Grivennikov: Fox Chase Cancer Center
Christoph A. Thaiss: Perelman School of Medicine, University of Pennsylvania
Maayan Levy: Perelman School of Medicine, University of Pennsylvania

Nature, 2022, vol. 605, issue 7908, 160-165

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04649-6

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