Journal
NATURE
Volume 605, Issue 7908, Pages 160-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04649-6
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Funding
- University of Pennsylvania Molecular Pathology and Imaging Core, Department of Medicine, Gastroenterology Division
- PennCHOP Microbiome Program
- Children's Hospital of Philadelphia Gastrointestinal Epithelium Modelling Program
- NIH [R01-CA-218133, R01-CA-227629, P30-CA-006927]
- Burroughs Wellcome Fund [T32-AI-055400-19, T32-AI-141393]
- BSF US-Israel Foundation
- Boehringer Ingelheim Fonds MD fellowship
- DFG Fellowship DFG [SCHN 1626/1-1]
- NIH Director's New Innovator Award [DP2-AG-067511]
- Agilent Early Career Professor Award
- Edward Mallinckrodt Jr Foundation
- IDSA Foundation
- Thyssen Foundation
- Penn Institute for Immunology, Penn Center for Molecular Studies in Digestive and Liver Diseases [P30-DK-050306, P30-AR-069589]
- Penn Diabetes Research Center [P30-DK-019525]
- Penn Institute on Aging
- American Cancer Society Scholar Award
- Searle Scholar program
- Abramson Cancer Center, Penn Institute for Immunology, Penn Center for Molecular Studies in Digestive and Liver Diseases, Penn Center for Precision Medicine, Penn Institute on Aging [P30-ES-013508]
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The study identifies a metabolite signalling pathway that can be used as a strategy for preventing and treating colorectal cancer. Ketogenic diets and the ketone body BHB show a strong inhibitory effect on tumor growth by reducing cell proliferation. The findings suggest that BHB-triggered pathway could play a crucial role in regulating intestinal tumorigenesis.
Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed(1). 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 beta-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.
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