Gut virome: New key players in the pathogenesis of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory illness of the intestine. While the mechanism underlying the pathogenesis of IBD is not fully understood, it is believed that a complex combination of host immunological response, environmental exposure, particularly the gut microbiota, and genetic susceptibility represents the major determinants. The gut virome is a group of viruses found in great frequency in the gastrointestinal tract of humans. The gut virome varies greatly among individuals and is influenced by factors including lifestyle, diet, health and disease conditions, geography, and urbanization. The majority of research has focused on the significance of gut bacteria in the progression of IBD, although viral populations represent an important component of the microbiome. We conducted this review to highlight the viral communities in the gut and their expected roles in the etiopathogenesis of IBD regarding published research to date.

Keywords: Bacteriophage; Eukaryotic viruses; Gut virome; Inflammatory bowel disease; Pathogenesis.

Figure 1

Two major lifecycles of bacteriophage (lytic and lysogenic).

Figure 2

Role of gut microbiome in health condition and inflammatory bowel disease progression. In a healthy state, a balanced microbiome helps maintain homeostasis and the production of beneficial metabolites that build tight junctions and keep gut epithelium barrier integrity. On the other hand, gut microbiome dysbiosis participates in damaging tight junctions as well as dysregulating the gut barrier. This enhances the interaction of pathogens with gut epithelium and increases their penetration to the gut lumen with subsequent stimulation to immunological response and immune cells and overproduction of proinflammatory cytokines and progression of inflammatory bowel disease. PBAs: Primary bile acids; SBAs: Secondary bile acid; SCFAs: Short-chain fatty acids; IBD: Inflammatory bowel disease.

Figure 3

Activation of positive feedback inflammatory response through induction of latent prophage and lysis of bacterial host cell. (1) Intestinal inflammation induces gut mucosa to generate stressors (like reactive oxygen species [ROS] and reactive nitrogen species [RNS]); (2) Production of stressors aggregates the stressor response (SOS) in the bacterial host cell (SOS reaction) and redox imbalance; (3) This imbalance leads to damage of bacterial DNA and induction of latent phage; (4) Switch to lytic cycle with subsequent bacterial cell rupture; (5) Accumulation of pathogen-associated molecular patterns (PAMPs) as lipopolysaccharide (LPS) and DNA, that results from bacterial lysis; (6) PAMPs activate receptors in the gut mucosa and stimulate the production of more stressors.

Figure 4

Modification of local immune response through bacteriophage. An inflamed gut is characterized by microbiome imbalance including virome. An imbalanced virome is distinguished by an expansion of Caudovirales phages and lysogenic lifecycle as well as a decline in the relative abundance of the Microviridae family and crAss-like phage. Additionally, in the presence of a thin mucus lining or broken tight junction, microbial antigens (like viral antigens) can penetrate the intestinal epithelium, activate Toll-like receptor (TLR), upregulate pro-inflammatory cytokines production, and dysregulate anti-inflammatory cytokines production. IL: Interleukin; RNS: Reactive nitrogen species; ROS: Reactive oxygen species; TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor alpha.