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Original research
Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer
  1. Cheng Kong1,2,
  2. Lei Liang1,2,
  3. Guang Liu3,
  4. Lutao Du4,
  5. Yongzhi Yang1,2,
  6. Jianqiang Liu5,
  7. Debing Shi1,2,
  8. Xinxiang Li1,2,
  9. Yanlei Ma1,2
  1. 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
  2. 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
  3. 3 Guangdong Hongyuan Pukang Medical Technology Co., Ltd, Guangdong, China
  4. 4 Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong province, China
  5. 5 Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China
  1. Correspondence to Dr Yanlei Ma, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; yanleima{at}


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.


Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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