Dietary fiber-type-specific gut microbiome preconditioning drives differential susceptibility to sporadic colon cancer development

Abstract

Dietary fiber intake is broadly associated with reduced colorectal cancer (CRC) risk, yet processed fiber supplements exert inconsistent and occasionally opposing effects on colon tumorigenesis. How structurally distinct dietary fibers differentially shape the gut microbiome-metabolome axis to influence carcinogenic susceptibility remains poorly understood. We compared structurally distinct dietary fibers commonly added to processed foods in an experimental model of sporadic CRC. Four-week-old male mice were maintained on low-fiber control or fiber-supplemented diets (7.5%w/w: cellulose, agar, pectin, or inulin) for 28 weeks and received eight intraperitoneal azoxymethane injections (AOM; 7.5mg/kg). Temporal fecal microbiomes were profiled by 16S-rRNA sequencing, cecal metabolites quantified by 1H-NMR spectroscopy, and microbiome-metabolome interactions assessed by co-occurrence networks. Refined inulin supplementation markedly elevated colon tumor incidence (~70%) compared with all other groups (~10-20%), and cecal extracts from inulin-fed mice promoted HT29 cancer-cell proliferation. Longitudinal microbiome profiling identified 36 inulin-specific microbial signatures converging on two axes: depletion of SCFA-producing and fermentation cross-feeding taxa and reprogramming of amino acid and nitrogen metabolism. Metabolomics confirmed succinate, fumarate, and lactate accumulation alongside propionate and amino acid depletion exclusively under AOM conditions, with no differences in carcinogen-naive animals. Two stable co-occurrence hubs were identified exclusively in AOM-treated animals, structurally integrating both functional axes. These findings demonstrate that inulin supplementation preconditions the gut microbiome toward a latent metabolic vulnerability, disrupted fermentation throughput and reprogrammed amino acid metabolism, that carcinogen exposure amplifies into a tumor-promoting ecosystem, establishing fiber structure as a critical and underappreciated determinant of CRC susceptibility. Keywords: Dietary Fibers, Colorectal Cancer, Inulin, Prebiotics, Metabolome, Short-chain fatty acids.