Gut virome and its implications in the pathogenesis and therapeutics of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) refers to chronic, recurrent inflammatory intestinal disorders, primarily including Crohn's disease (CD) and Ulcerative colitis (UC). Numerous studies have elucidated the importance of the gut microbiome in IBD. Recently, numerous studies have focused on the gut virome, an intriguing and enigmatic aspect of the gut microbiome. Alterations in the composition of phages, eukaryotic viruses, and human endogenous retroviruses that occur in IBD suggest potential involvement of the gut virome in IBD. Nevertheless, the mechanisms by which it maintains intestinal homeostasis and interacts with diseases are only beginning to be understood. Here, we thoroughly reviewed the composition of the gut virome in both healthy individuals and IBD patients, emphasizing the key viruses implicated in the onset and progression of IBD. Furthermore, the complex connections between the gut virome and the intestinal barrier, immunity, and gut microbiome were dissected to advance the interpretation of IBD pathogenesis. The updated discussion of the evidence regarding the gut virome will advance our knowledge in gut virome and chronic gastrointestinal diseases. Targeting the gut virome is a promising avenue for IBD treatment in future.

Keywords: Crohn’s disease (CD); Eukaryotic gut virome; Fecal virome transplantation; Gut virome-host interactions; Inflammatory bowel disease (IBD); Phage; Ulcerative colitis (UC).

Fig. 1

A Composition of gut virome in health: phages (Siphoviridae, Herelleviridae, Podoviridae, Microviridae, Myoviridae, Inoviridae, Ackermannviridae and unassigned), Eukaryotic viruses (Anelloviridae, Astroviridae, Genomoviridae, Polyomaviridae, Circoviridae, Alphaflexiviridae, Papillomaviridae, Asfarviridae, Picornaviridae, Geminiviridae, Virgaviridae, Iridoviridae, Herpesviridae, Parvoviridae, Caliciviridae, Cruliviridae, Reoviridae, Poxviridae, Adenoviridae), Archaeal viruses. (based on the GVD database). B Changes of gut virome in IBD: IBD (Caudovirales, Faecalibacterium prausnitzii phages, Picornaviridae, Enterovirus B and Anelloviridae increase, while Microviridae decrease), CD (Anelloviridae, Cycloviridae and Hepeviridae increase, while Podoviridae, phages infecting probiotics of Firmicutes phylum and phages infecting pathogenic bacteria decrease), UC (crAss-like phage, Siphoviridae, Podoviridae, Orthohepadnaviridae, Virgaviridae, Anelloviridae, Circoviridae, and Picobirnaviridae increase) [–22]

Fig. 2

Relationship between gut phages and intestinal health and inflammation. A Mechanisms by which phages defend against bacterial invasion and maintain gut homeostasis in health. (1) Adherision: phages form a biological barrier by binding Hoc protein to MUC2 in intestinal mucus, enhancing mucus production and preventing bacterial invasion. (2) Cascading effect: phages lyse pathogenic bacteria, releasing metabolites and progeny phages, thereby influencing the survival dynamics of neighboring bacterial species. (3) Red Queen hypothesis: phages and bacteria co-evolve, with phages selectively lysing specific bacterial strains while adapted phages survive and propagate. (4) Lysogenic bacteria: some phages integrate their genome into bacterial hosts, forming lysogenic bacteria; under stable conditions, this state persists, but external triggers may induce bacterial lysis. (5) Phage-humoral immunity: phages penetrate the gut lamina propria and enter circulation, activating innate and adaptive immunity; B cells differentiate into plasma cells, generating antibodies that neutralize phages, maintaining gut homeostasis. B Mechanisms by which phages contribute to gut inflammation. (1) Changes in the number and diversity of phages and bacteria during intestinal inflammation. (2) Phages activate dendritic cells, initiating T cell–mediated inflammation

Fig. 3

Disruption of gut eukaryotic virome. A The disruption of gut eukaryotic virome influences gut homeostasis and leads to gut inflammation. B Balanced gut eukaryotic virome maintains the gut homeostasis. MNV can interact with bacteriome to act in intestinal microecology. CMV and MNV are proved to stimulate IFN-I signals to promote anti-inflammatory response, intestinal morphology, and function. RVA and NoV can also evoke protective adaptive immune response through TLR3 and TLR7. C Impaired gut eukaryotic virome triggered inflammation. Firstly, NoV is associated with IL-25/L-17 signal pathways, and it can increase the secretion of inflammatory cytokines relying on the virus entry in macrophages. Secondly, based on Atg16L1 mutation or IL-10, MNV can disrupt epithelial permeability, bacteriome and aggravate inflammation, with the binding to epithelium driven by bacteria. Thirdly, HBx possessed by Orthohepadnavirus play a role in the damage of the epithelial barrier and affect the gut immune system. Additionally, interaction of rotavirus and adenovirus with integrins, or activation of the CAR may participate in the pathogenesis of IBD. Finally, once the intestinal barrier is damaged, “bystanders” such as CMV further induce immune abnormality and pathologies