The response to ketogenic diet in colorectal cancer is mediated by lasting functional alterations of the gut microbiome

Abstract

AbstractColorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a known microbiome modulator. 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 gut microbial function were maintained in the absence of continued selective pressure from the KD. Stearic acid is identified as a putative microbiome-derived anti-cancer metabolite. Taken together, the beneficial effects of the KD are mediated by the gut microbiome and may be dependent on a pre-existing “non-responder” or “responder” gut microbiome profile. These results have important implications for future clinical trials evaluating the effects of the ketogenic diet on human CRC.