Journal Article

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

Pozdeev, Vitaly Igorevich, Kasakin, Marat, Schmoetten, Maryse, Koncina, Eric, Meiser, Johannes, Tsenkova, Mina, Haan, Serge, Letellier, Elisabeth, Rodriguez, Fabien, Schmitz, Martine, Wilmes, Paul, Cheung, Dean, de Beaufort, Carine, Mayatepek, Ertan, de Nies, Laura, Busi, Susheel Bhanu, Schlicker, Lisa, Linster, Carole L., Meyers, Marianne, Gaigneaux, Anthoula, Gilson, Cedric, Cramer, Thorsten, Brauer, Madita, Herebian, Diran

2025

Overview

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. Attenuating effects of the ketogenic diet on colorectal cancer (CRC) cell growth has been previously described. Here, using a mouse model of CRC with a humanized microbiome, the authors identify a shift toward gut bacterial species that produce stearic acid in ketogenic conditions, resulting in elevated levels of free stearate in the gut lumen, which they then show exhibits tumor-suppressing properties.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 45 / 45/91 / 631/326 / 631/67/327 / 64 / 64/60 / 96 / 96/2 / Acid production / Animal models / Animals / Apoptosis / Bacteria - genetics / Bacteria - metabolism / Cancer / Cell growth / Cell Line, Tumor / Colon - microbiology / Colon - pathology / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - diet therapy / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - microbiology / Colorectal Neoplasms - pathology / Diet / Diet, Ketogenic / Digestive system / Disease Models, Animal / Fecal Microbiota Transplantation / Female / Gastrointestinal Microbiome - physiology / Gastrointestinal tract / Germfree / Gut microbiota / Helper cells / High fat diet / Humanities and Social Sciences / Humans / Immune system / Intestinal microflora / Ketogenesis / Low carbohydrate diet / Lymphocytes T / Male / Mice / Microbiomes / Microbiota / Microorganisms / multidisciplinary / Science / Science (multidisciplinary) / Stearic acid / Stearic Acids - metabolism / Tumors