Summary:
Colorectal cancer is one of the most commonly diagnosed cancers worldwide, and lifestyle factors such as diet, play an important role in its development and progression. The ketogenic diet has gained attention for its anti-cancer effects, which include limiting energy supply to rapidly dividing cells and altering cell signalling through ketone bodies. This study, a preclinical experimental study using a humanised gut microbiome mouse model and germ-free mice, examined whether changes in the gut microbiome contribute to these effects in colorectal cancer. Mice colonised with stool from healthy human donors and fed a ketogenic diet showed reduced tumour growth, confirming the cancer-suppressing effects of the diet. When the gut microbiome from ketogenic-fed mice was transplanted into germ-free mice, similar reductions in tumour growth were observed, indicating that the microbiome plays an active role beyond the diet itself. Further analysis showed that the ketogenic diet altered the gut microbiome in a way that increased the production of stearic acid, a long-chain saturated fatty acid generated by certain gut bacteria and known to influence cell survival and immune responses. Bacteria that produce stearic acid were enriched, while those that consume it were reduced, leading to sustained increases in free stearic acid in the gut even after the diet was withdrawn. Supplementation with stearic acid reduced tumour burden, increased cancer cell death, and decreased pro-inflammatory immune cells in the colon. Overall, this study demonstrates that the anti-cancer effects of the ketogenic diet in colorectal cancer are somewhat mediated by changes in the gut microbiome, particularly increased stearic acid production.
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.
Article Publication Date: 20/02/2025
DOI: 10.1038/s41467-025-56678-0
