Microbiome Signatures for Colorectal Cancer (CRC) – dealing with confounding variables to find the real message

Review by Prof. Zikai Wang (China)

Study Summary 

While many studies have linked microbiome signatures to risk for or presence of CRC, limitations in microbial methodology and the impact of confounding variables have limited interpretability. This new study, which involved 589 patients with colorectal cancer at various CRC stages, represents a significant advance over the 15 previously published studies (4,439 patients and controls total). They used 16S rRNA quantitative microbiome analysis and rigorous confounder control to identify fecal microbiota signatures in CRC. The study found that transit time, fecal calprotectin, and body mass index were the primary covariates affecting microbiota composition. After controlling for these confounding factors, the association of Anaerococcus vaginalis, Dialister pneumoniae, Parvimonas micra, Pepto streptococcus anaerobius, Porphyromonas asaccharolytica and Prevotella intermedia remained robust, highlighting their target potential. Interestingly the previously reported association of Fusobacterium nucleatum with CRC was not confirmed. Besides, control individuals were enriched for the dysbiotic Bacteroides2 enterotype, emphasizing the uncertainties that surround the definition of healthy controls in cancer microbiome research.

Commentary 

This study used quantitative microbiome profiling based on 16S rRNA amplicon sequencing, combined with rigorous confounder control to identify the fecal microbiota associated with the developmental stages of CRC. Finally, the study indicates the importance of quantitative microbiome profiling and covariate control for biomarker identification in CRC microbiome studies. This study still has limitations, including sample selection bias, potential confounding factors that have not been fully controlled, and dependence on microbiome databases. Multidomain approaches to discover CRC biomarkers and longitudinal prospective studies to better study the dynamics of CRC progression are needed to comprehensively inform cancer detection and treatment. Further research is needed on the association between the microbiome and CRC, and rigorous validation of potential microbial biomarkers is required to ensure their clinical relevance and effectiveness.

Citation

Tito RY, Verbandt S, Aguirre Vazquez M, et al. Microbiome confounders and quantitative profiling challenge predicted microbial targets in colorectal cancer development. Nat Med. 2024;30(5):1339-1348. doi:10.1038/s41591-024-02963-2

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