Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate

Mina Tsenkova, Madita Brauer, Vitaly Igorevich Pozdeev, Marat Kasakin, Susheel Bhanu Busi, Maryse Schmoetten, Dean Cheung, Marianne Meyers, Fabien Rodriguez, Anthoula Gaigneaux, Eric Koncina, Cedric Gilson, Lisa Schlicker, Diran Herebian, Martine Schmitz, Laura Nies, Ertan Mayatepek, Serge Haan, Carine Beaufort, Thorsten Cramer, Johannes Meiser, Carole L. Linster, Paul Wilmes and Elisabeth Letellier ()
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Mina Tsenkova: University of Luxembourg
Madita Brauer: University of Luxembourg
Vitaly Igorevich Pozdeev: University of Luxembourg
Marat Kasakin: University of Luxembourg
Susheel Bhanu Busi: University of Luxembourg
Maryse Schmoetten: University of Luxembourg
Dean Cheung: University of Luxembourg
Marianne Meyers: University of Luxembourg
Fabien Rodriguez: University of Luxembourg
Anthoula Gaigneaux: University of Luxembourg
Eric Koncina: University of Luxembourg
Cedric Gilson: University of Luxembourg
Lisa Schlicker: University of Luxembourg
Diran Herebian: Heinrich Heine University
Martine Schmitz: University of Luxembourg
Laura Nies: University of Luxembourg
Ertan Mayatepek: Heinrich Heine University
Serge Haan: University of Luxembourg
Carine Beaufort: University of Luxembourg
Thorsten Cramer: RWTH University Hospital Aachen
Johannes Meiser: Luxembourg Institute of Health
Carole L. Linster: University of Luxembourg
Paul Wilmes: University of Luxembourg
Elisabeth Letellier: University of Luxembourg

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrates tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth.

Date: 2025
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DOI: 10.1038/s41467-025-56678-0

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