Enteric Viruses and Inflammatory Bowel Disease

Abstract

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.

Keywords: Crohn’s disease; adenovirus; aichi virus; astrovirus; inflammatory bowel disease; norovirus; rotavirus; sapovirus; ulcerative colitis.

Figure 1

Summary of potential mechanisms underlying enteric virus interactions during the course of inflammatory bowel disease (IBD). Inflammatory pathways involved in IBD pathogenesis are shown in red and green stars. (A) Enteric viruses, such as rotavirus and norovirus, may modulate the immune response during IBD and improve the symptoms of IBD through the increased secretion of interferon β (IFN β) [23]. The protective role of interleukin (IL)-10 was confirmed in IL-10^-/- murine models showing enterocolitis after exposition to enteric viruses [24,25,26,27,28,29]. (B) Interactions of the gut bacteriome and virome could also explain IBD pathogenesis, for instance, an asymptomatic murine norovirus (MNV) infection could replace the effects of beneficial commensal bacteria [30]. (C) Recent scientific data revealed that norovirus may bind to tuft cells, which would then play an important role in the IL-25/IL-17 inflammatory pathway, as seen during IBD [31,32,33]. (D) The absence of histo-blood group antigen (HBGA) synthesis in non-secretor subjects carrying polymorphisms of the FUT2 and FUT3 genes could be linked to altered virus–bacteria–cell interactions and involved in the pathogenesis of IBD [18,20,22]. (E) Interactions between enteric viruses and HBGA-like molecules at the surface of commensal or pathogenic bacteria modulated by an “IBD-shaped” microbiota could explain the variations in susceptibility to enteric viruses during IBD [34,35,36]. (F) Binding of enteric viruses to critical receptors involved in leukocyte adhesion and cytokine secretion could also be part of IBD pathogenesis, as exemplified by rotavirus and adenovirus interactions with integrins, or activation of the Coxsackie–Adenovirus Receptor (CAR) [37,38,39,40,41]. (G) Specific interactions between enteric viruses (MNV) and defensin-deficient Paneth cells in patients carrying polymorphisms of the ATG16L gene could lead to the activation of the NOD2 gene and upregulate T-helper 1 (Th1) or T-helper 17 (Th17) inflammatory pathways, as seen in IBD [42,43,44,45,46,47]. (H) Ectopic expression of HBGA in intestinal epithelium undergoing alterations induced by inflammation may modulate the binding potency of enteric viruses [21,48]. (I) Enteric virus entry in macrophages stimulates tumor necrosis factor alpha (TNF-α) and interferon gamma (IFNγ) secretion, which are involved in IBD pro-inflammatory pathways [47,49,50].