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

Background

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.

Objective

To determine whether structurally distinct dietary fibers differentially modulate colon tumor development and characterize the underlying gut microbiome and metabolic mechanisms.

Design

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; 7.5 mg/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.

Results

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 SCFAs 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.

Conclusion

Inulin supplementation preconditions the gut microbiome toward functional vulnerability, characterized by disrupted fermentation throughput and reprogrammed amino acid metabolism, that is amplified by carcinogen exposure into a tumor-promoting ecosystem, providing a mechanistic basis for the disproportionately higher tumor prevalence in inulin-fed animals.

Significance of this study

What is already known on this subject?

• Dietary fiber intake is broadly associated with reduced colorectal cancer (CRC) risk, but this protective effect is not uniform, with purified fiber supplements showing inconsistent or opposing effects.

• Inulin, a highly fermentable fructan widely used as a prebiotic supplement and a food additive, selectively expands beneficial gut microbiota and is generally regarded as promoting gut health.

• How structurally distinct dietary fibers differentially shape the gut microbiome-metabolome axis to influence colorectal carcinogenic susceptibility remains poorly understood.

What are the new findings?

• Powdered 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 extracts from inulin-fed mice directly promoted HT29 colorectal cancer cell proliferation compared with 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 universal 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.