Abstract
Despite recent progress in our understanding of the association betweenthe gut microbiome and colorectal cancer (CRC), multi-kingdom gut microbiomedysbiosis in CRC across cohorts is unexplored. We investigated four-kingdommicrobiota alterations using CRC metagenomic datasets of 1,368 samples from 8distinct geographical cohorts. Integrated analysis identified 20 archaeal, 27bacterial, 20 fungal and 21 viral species for each single-kingdom diagnostic model.However, our data revealed superior diagnostic accuracy for models constructed withmulti-kingdom markers, in particular the addition of fungal species. Specifically,16 multi-kingdom markers including 11 bacterial, 4 fungal and 1 archaeal feature,achieved good performance in diagnosing patients with CRC (area under the receiveroperating characteristic curve (AUROC) = 0.83) and maintainedaccuracy across 3 independent cohorts. Coabundance analysis of the ecologicalnetwork revealed associations between bacterial and fungal species, such asTalaromyces islandicus and Clostridium saccharobutylicum. Using metagenome shotgunsequencing data, the predictive power of the microbial functional potential wasexplored and elevated D-amino acid metabolism and butanoate metabolism were observedin CRC. Interestingly, the diagnostic model based on functional EggNOG genesachieved high accuracy (AUROC = 0.86). Collectively, our findingsuncovered CRC-associated microbiota common across cohorts and demonstrate theapplicability of multi-kingdom and functional markers as CRC diagnostic tools and,potentially, as therapeutic targets for the treatment of CRC.
Highlights
As the second leading cause of cancer-related deaths worldwide, colorectal cancer (CRC) accounts for approximately 900,000 deaths annually[1,2,3,4,5]
To identify reproducible microbial markers for diagnosing patients with CRC, the discovery dataset consisted of samples with broader geographical heterogeneity and genetic background, including 491 individuals with CRC and 494 tumour-free controls across 5 countries (Austria, France, Germany, China and Japan) (Fig. 1a)
We explored the functional alterations at Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology (KO) genes and pathway levels and identified 1,053 differential KO genes, including 612 KO genes with increased abundance in patients with CRC compared to controls (Supplementary Data 10)
Summary
As the second leading cause of cancer-related deaths worldwide, colorectal cancer (CRC) accounts for approximately 900,000 deaths annually[1,2,3,4,5]. Non-bacterial microorganisms including fungi, archaea and viruses, were altered in CRC, adding further complexity to CRC microbiome association studies[2,15]. Several attempts were made to identify the core CRC-associated bacterial microbiome signatures by meta-analysis using published shotgun metagenomic sequencing datasets. These studies provide an unbiased evaluation of CRC-associated bacterial microbiomes across multiple cohorts[12,13,21]. They did not determine the consistency, or potential inconsistency, of a multi-kingdom microbiome across different populations in CRC. Cross-cohort, multi-kingdom studies are urgently needed to provide integrated and robust assessment of CRC and multi-kingdom microbiome association
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