The Gut Virome as a Trigger for IBD: From Metagenomics to Pathogenesis

The human intestine is progressively colonized after birth by several microbial strains that change during lifespan according to anatomical, dietary and nutritional statuses. Alterations in the gut microbiota composition (dysbiosis) are well-recognized contributors to the pathogenesis of gastrointestinal disorders, such as inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). In fact, bacteria, fungi, archaea, and viruses, all populating the human intestine, were found to control gut homeostasis, with a continuous pathogen-host interplay that results in both local (mucosal and luminal) and systemic (metabolic and nutritional) effects.

Although bacteria have always gained the greatest attention in gastrointestinal disorders, the viral component of the human gut microbiome, termed the "gut virome", is understudied. The viral community of the microbiota is mainly composed of prokaryotic-infecting viruses (bacteriophages), thus rendering the gut a dynamic community structure, characterized by continuous "predator-prey interactions" that cause either horizontal gene transfer (viruses to bacteria) or modification in the bacterial composition of the microbiota, impacting on both health and disease.

Besides bacteriophages, the gut virome hosts also DNA- and RNA-based eukaryotic-targeting viruses able to directly transfer their genetic information to host cells, and demonstrated to be associated with the pathogenesis of both UC and CD. Furthermore, eukaryotic viruses have been shown to contribute to intestinal dysbiosis in mice carrying mutations in the IBD-associated Il10 or Atg16L1 genes, suggesting that the gut virome might cooperate with genetic factors, ultimately leading to chronic intestinal inflammation.

Variations in gut virome composition have been shown to occur also in pathogenic conditions. In fact, by targeted deep-sequencing analysis of stools from patients with CD and UC, Norman and colleagues demonstrated not only that the virome composition was disease- and cohort-specific, but also that its variations contributed to intestinal dysbiosis. However, this study is incomplete, since it exploits metagenomic analysis of DNA sequences only, thus ignoring RNA viruses, such as Norovirus and Astrovirus, previously suggested as potential precipitators or triggers of intestinal inflammation.

Therefore, although a consistent number of studies described the viral composition of the intestinal microbiota in human stools, mainly focusing on bacteriophages, the whole eukaryotic virome that colonizes intestinal mucosa of IBD patients and which intestinal cell population is mainly affected still need to be defined. So far, the occurrence of gut viral infections has been evaluated only in cohorts of IBD patients with long-lasting chronic intestinal inflammation. However, in these studies, either immunosuppressants or disease-induced stressing conditions may have led to the activation of latent viral infections such as those from Hepatitis B and C (HBV and HCV), Cytomegalovirus (CMV) and Epstein-Bar virus (EBV). For example, a recent metagenomic analysis on colonic mucosae revealed Herpesviridae as the most enriched viral community in IBD patients. Nonetheless, since in these works most of the enrolled patients were under pharmacological treatments and not early diagnosed, the identification of any putative viral entity responsible for the onset of IBD might not have been accurate.