Work

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

Year: 2026

Type: preprint

Abstract: 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. Graphical abstract Significance of this study What is already known on this subject? Dietary fiber from whole foods is consistently associated with a reduced risk of colorectal cancer (CRC). Inulin, a highly fermentable fructan used widely as both a prebiotic supplement and a food additive, selectively expands putatively beneficial gut taxa and is generally regarded as promoting gut health. Structurally distinct dietary fibers differentially shape the gut microbiome–metabolome axis. What are the new findings? Refined inulin supplementation dramatically elevated colorectal tumor prevalence (∼70%) compared with all other fiber-supplemented and control groups (∼10–20%) under AOM-induced carcinogenic conditions. Longitudinal microbiome profiling identified 36 inulin-specific microbial signatures converging on two primary axes: depletion of SCFA-producing and cross-feeding taxa, and reprogramming of amino acid and nitrogen metabolism. Cecal metabolomics confirmed succinate, fumarate, and lactate accumulation alongside propionate and amino acid depletion, exclusively under AOM conditions, establishing carcinogen-dependent amplification of a diet-preconditioned metabolic vulnerability. Cecal content extracts from inulin-fed mice increased the proliferation of human HT-29 colorectal cancer cells compared with extracts from cellulose-fed mice, providing functional evidence that the inulin-conditioned luminal environment supports tumor growth. Stable microbiome-metabolome co-occurrence hubs were identified exclusively in AOM-treated animals, absent in carcinogen-naive counterparts, demonstrating that carcinogen exposure consolidates inulin-driven community restructuring into a structurally defined tumor-promoting ecosystem. How might it impact on clinical practice in the foreseeable future? Under carcinogenic conditions, inulin-driven gut microbiome restructuring reveals a broader dysbiotic context of depleted protective fermentation capacity and oncometabolite accumulation, challenging its framing as a prebiotic benefit. Given the increasing use of isolated inulin in processed foods and as a dietary supplement, alongside the rising incidence of early-onset colorectal cancer, prospective human studies examining the association between inulin intake and colorectal cancer risk are warranted. Dietary fiber type specificity should be considered in clinical recommendations and supplement guidance for individuals at elevated colorectal cancer risk.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.21.753221