High Soluble Fiber Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites in Mice

BACKGROUND & AIMS: Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice. METHODS: Apcmin/ thorn mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high -fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high -guar gum diet, high -cellulose diet, or diets with different inulin dose. Germfree mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively. RESULTS: Mixed high -fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apcmin/ thorn mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high -fiber diet, while transplanting stools from mice fed with mixed highfiber diet accelerated tumor growth in AOM-treated germfree mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apcmin/ thorn mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifido- bacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ -free mice. CONCLUSION: High -dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dosedependent manner by dysregulating gut microbiota and metabolites in mice.