Altered Mycobiota Signatures and Enriched Pathogenic Aspergillus rambellii Are Associated With Colorectal Cancer Based on Multicohort Fecal Metagenomic Analyses

Abstract

The enteric mycobiota is a major component of the human gut microbiota, but its role in colorectal cancer (CRC) remains largely elusive. We conducted a meta-analysis to uncover the contribution of the fungal mycobiota to CRC. We retrieved fecal metagenomic data sets from 7 previous publications and established an additional in-house cohort, totaling 1329 metagenomes (454 with CRC, 350 with adenoma, and 525 healthy individuals). Mycobiota composition and microbial interactions were analyzed. Candidate CRC-enriched fungal species (Aspergillus rambellii) was functionally validated invitro and invivo. Multicohort analysis revealed that the enteric mycobiota was altered in CRC. We identified fungi that were associated with patients with CRC or adenoma from multiple cohorts. Signature CRC-associated fungi included 6 enriched (A rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsici) and 1 depleted species (A kawachii). Co-occurrent interactions among CRC-enriched fungi became stronger in CRC compared with adenoma and healthy individuals. Moreover, we reported the transkingdom interactions between enteric fungi and bacteria in CRC progression, of which A rambellii was closely associated with CRC-enriched bacteria Fusobacterium nucleatum. A rambellii promoted CRC cell growth invitro and tumor growth in xenograft mice. We further identified that combined fungal and bacterial biomarkers were more accurate than panels with pure bacterial species to discriminate patients with CRC from healthy individuals (the area under the curve relative change increased by 1.44%-10.60%). This study reveals enteric mycobiota signatures and pathogenic fungi in stages of colorectal tumorigenesis. Fecal fungi can be used, in addition to bacteria, for noninvasive diagnosis of patients with CRC.