Exploring the Relationship between the Gut Mucosal Virome and Colorectal Cancer: Characteristics and Correlations

SIMPLE SUMMARY: This study is for the first time to analyze the mucosal virome in patients with colorectal cancer (CRC) compared to healthy controls and show the differences between them. Unlike the changes in fecal virome in CRC (mainly associated with bacteriophages), this study revealed that the difference in the mucosal virome between CRC and HCs was dominated by eukaryotic viruses other than bacteriophages. The enrichment of TTV, one sub-species of Anelloviridae, in CRC tissues suggests that they may play an important oncogenic role in CRC, which will pave the way for innovative therapeutic strategies blocking or reverting CRC pathogenesis in the future. ABSTRACT: The fecal virome has been reported to be associated with CRC. However, little is known about the mucosal virome signature in CRC. This study aimed to determine the viral community within CRC tissues and their contributions to colorectal carcinogenesis. Colonic mucosal biopsies were harvested from patients with CRC (biopsies of both neoplasia and adjacent normal tissue (CRC-A)) and healthy controls (HC). The shot-gun metagenomic sequencing of virus-like particles (VLPs) was performed on the biopsies. Viral community, functional pathways, and their correlations to clinical data were analyzed. Fluorescence in situ hybridizations (FISH) for the localization of viruses in the intestine was performed, as well as quantitative PCR for the detection of Torque teno virus load in human mucosal VLP DNA. A greater number and proportion of core species were found in CRC tissues than in CRC-A and HC tissues. The diversity of the mucosal virome in CRC tissues was significantly increased compared to that in HC and CRC-A tissues. The mucosal virome signature of CRC tissues were significantly different from those of HC and CRC-A tissues at the species level. The abundances of eukaryotic viruses from the Anelloviridae family and its sub-species Torque teno virus (TTV) were significantly higher in CRC patients than in HC. Furthermore, increased levels of TTV in the intestinal lamina propria were found in the CRC group. Multiple viral functions of TTV associated with carcinogenesis were enriched in CRC tissues. We revealed for the first time that the mucosal virobiota signature of CRC is characterized by a higher diversity and more eukaryotic viruses. The enrichment of TTV species in CRC tissues suggests that they may play an oncogenic role in CRC. Targeting eukaryotic viruses in the gut may provide novel strategies for the prevention and treatment of CRC.