Gut microbiome signatures in colorectal neoplasia: a cross-sectional study across neoplasia stages and subtypes

Background

While colorectal cancer (CRC) has been linked to the gut microbiome, it remains unclear whether specific microbial signatures are detectable in precursor lesions such as adenomatous polyps, serrated lesions or sessile serrated lesions.

Objective

To assess gut microbiome taxonomic and functional associations with colorectal neoplasia presence, severity (non-advanced, advanced and CRC) and subtype and evaluate predictive potential in high-risk neoplasia.

Design

Analysed cross-sectional stool metagenomes (pre-colonoscopy) from 1762 participants (97% White British) undergoing colonoscopy in the multicentre COLO-COHORT study. Neoplasia was classified per British Society of Gastroenterology surveillance guidelines. Linear mixed-effects models and random forest classifiers assessed taxonomic and functional associations, adjusting for dietary, clinical and lifestyle covariates.

Results

Gut microbiome composition differences between individuals with and without neoplasia were statistically significant but minimal (R²=0.0008, p=0.03). A small number of species, including Mediterraneibacter faecis and Pseudoruminococcus massiliensis, and microbial pathways, including amino acid biosynthesis and β-lactam resistance, were modestly linked to neoplasia, particularly early lesions (q value <0.05). Associations were generally weak and attenuated after covariate adjustment. Predictive models combining the microbiome with clinical/demographic features modestly improved high-risk neoplasia classification (area under the curve=0.64 vs 0.58 for clinical/demographic features alone).

Conclusion

This large prospective cross-sectional study found weak and inconsistent associations between the gut microbiome and premalignant colorectal neoplasia, with no robust microbial signatures. Findings suggest that previously reported microbial shifts may emerge later in disease progression, potentially as a consequence rather than a cause of CRC. Longitudinal, multiomic studies disentangling temporal and causal pathways between the gut microbiome and neoplasia are required.