Metagenomic Analyses of Multiple Gut Datasets Revealed the Association of Phage Signatures in Colorectal Cancer

Abstract

The association of colorectal cancer (CRC) and the human gut microbiome dysbiosis has been the focus of several studies in the past. Many bacterial taxa have been shown to have differential abundance among CRC patients compared to healthy controls. However, the relationship between CRC and non-bacterial gut microbiome such as the gut virome is under-studied and not well understood. In this study we conducted a comprehensive analysis of the association of viral abundances with CRC using metagenomic shotgun sequencing data of 462 CRC subjects and 449 healthy controls from 7 studies performed in 8 different countries. Despite the high heterogeneity, our results showed that the virome alpha diversity was consistently higher in CRC patients than in healthy controls (p-value <0.001). This finding is in sharp contrast to previous reports of low alpha diversity of prokaryotes in CRC compared to healthy controls. In addition to the previously known association of Podoviridae, Siphoviridae and Myoviridae with CRC, we further demonstrate that Herelleviridae, a newly constructed viral family, is significantly depleted in CRC subjects. Our interkingdom association analysis reveals a less intertwined correlation between the gut virome and bacteriome in CRC compared to healthy controls. Furthermore, we show that the viral abundance profiles can be used to accurately predict CRC disease status (AUROC >0.8) in both within-study and cross-study settings. The combination of training sets resulted in rather generalized and accurate prediction models. Our study clearly shows that subjects with colorectal cancer harbor a distinct human gut virome profile which may have an important role in this disease.

Keywords: CRC prediction; colorectal cancer; gut virome; metagenomics; virus-host association.