Ketogenic diet suppresses AOM/DSS-induced colorectal cancer through reshaping gut microbiota and modulating the intestinal FXR/NF-κB signaling pathway

Specific dietary patterns are crucial in the incidence and progression of colorectal cancer. Although there is evidence indicating that the ketogenic diet (KD) may inhibit colorectal cancer and potentially act as a therapeutic approach, the mechanisms by which it influences gut microbiota and modifies metabolic pathways remain poorly understood. This study aimed to explore the therapeutic effects of a KD on colorectal cancer in azoxymethane/dextran sulfate sodium model through targeted bile acid metabolomics, transcriptomics, and 16S rDNA gene sequencing analysis. Our results demonstrate that the KD provides both preventive and therapeutic benefits against colorectal cancer by reducing inflammatory responses and restoring intestinal barrier integrity. Additionally, serum metabolomic analysis indicated a reprogramming of bile acid metabolism. Furthermore, 16S rDNA sequencing and targeted bile acid metabolomics revealed that the KD significantly altered gut microbiota composition and bile acid metabolism, leading to a unique serum bile acid profile characterized by increased primary bile acids and decreased secondary bile acids. Moreover, the combination of a KD with antibiotics and fecal microbiota transplantation consistently resulted in higher abundances of Muribaculaceae, Akkermansia, and Lachnospiraceae NK4A136, while levels of Parasutterella decreased following KD intervention. The concentrations of cholic acid and chenodeoxycholic acid, deoxycholic acid, and 12-keto lithocholic acid in colorectal tissues or feces were consistent with those observed in KD-treated subjects. An upregulation of farnesoid X receptor (FXR) expression in colorectal tissues was noted, which modulated NF-κB metabolic pathways and contributed to a reduction in inflammatory responses. Our findings underscore that the KD suppresses colorectal cancer by reshaping gut microbiota and modulating the intestinal FXR/NF-κB signaling pathway.