Objective The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC.
Design We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results.
Results Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome–metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls.
Conclusion Our large-sample multiomics data suggest that altered microbiome–metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.
- COLORECTAL CANCER
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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CK, LL, GL, LD and YY contributed equally.
Contributors YM is responsible for the overall content as the guarantor. CK, LL, GL, LD, YY and YM designed the experiments. LL, LD, YY, JL, XL, DS and YM provided the clinical samples and performed the experiments. CK, YY and GL analysed the data. CK, GL and YM wrote the manuscript. All authors edited the manuscript.
Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 81920108026, 81871964), the National Ten Thousand Plan Young Top Talents (for YM), the Shanghai Science and Technology Development Fund (No.19410713300), the Program of Shanghai Academic Research Leader (No. 20XD1421200), the CSCO-Roche Tumor Research Fund (No. Y-2019Roche-079) and the Fudan University Excellence 2025 Talent Cultivation Plan (for YM). The authors take this opportunity to thank all of the participating patients and healthy volunteers for supporting this study by donating the precious samples used in this research.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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