Celiac disease (CeD) is a complex immune mediated disorder that is triggered by abnormal immune responses to the dietary protein gluten, which is found in grains like wheat, barley, and rye. Normally, immune tolerance to dietary proteins prevents inflammatory immune responses from developing. However, in those with CeD, the presence of HLA susceptibility genes plus unknown environmental or immune triggers lead to a pro-inflammatory Th1 response towards gluten proteins. While gluten exposure and genetic risk are both required for CeD, only a proportion of genetically susceptible individuals will go on to develop the disease, highlighting a critical role of environmental modifiers. Epidemiological studies have suggested a link between infections or a dysbiotic microbiota and CeD, but mechanistic studies and experimental data to support these associations are lacking. Moreover, the events that lead to the loss of tolerance to these innocuous dietary proteins in the gut, like gluten, are not well understood.

A new study published in Science by Bouziat and colleagues show that reovirus, which are mild or clinically silent viruses that infect humans frequently over the course of a lifetime, can break tolerance to dietary proteins and may constitute an environmental modifier for CeD development. The collection of viruses within the body, known as the virome, is an often forgotten member of the human microbiome. This study helps to highlight the complexity of the gut microbiota and the effects its various components (bacteria, viruses, fungi) have on host immunity. These exciting results also provide evidence that supports the epidemiological link between infections and CeD development.

In a series of elegant experiments, the authors infected mice with two different strains of reovirus. While both strains infected the intestine, induced protective immunity, and were cleared, they differentially modulated immune responses to dietary proteins in the gut. The reovirus strain T1L induced more extensive transcriptional changes in the mesenteric lymph nodes, the site where immune responses to dietary antigens are induced. Interestingly, this was associated with an increase in pro-inflammatory dendritic cells that uptake food antigens, and it promoted an inflammatory Th1 response while inhibiting a tolerogenic, regulatory response. Using a series of in vivo and in vitro experiments with knock-out mice, the authors further showed that the pro-inflammatory Th1 phenotype to dietary antigen induced by T1L was dependent on interferon regulatory factor 1 (IRF1), a transcription factor involved in Th1 regulation. Moreover, in an animal model expressing the CeD susceptibility gene, T1L infection led to a pro-inflammatory dendritic cell phenotype and the loss of tolerance to gluten peptides upon feeding. These exciting findings suggest that reovirus could interact with the host to promote an inflammatory environment at the site where oral tolerance is induced, setting the stage for the generation of inflammatory immune responses to dietary antigens instead of tolerogenic responses.

Viruses have been suggested to play a role in CeD development in humans, and Bouziat et al. also showed a trend for higher reovirus antibody titres in patients with CeD compared to controls. The implications of this are critical, as the events leading to CeD and other food allergies are not well understood, and this provides a target for further investigation. The findings also raise the possibility of other gut microbial (viral or bacterial) modulators of oral tolerance. Indeed, an altered microbial composition has been described in CeD patients, with increases in opportunistic pathogens (see here and here). Increases in bacterial virulent factors have been reported in CeD patients and the presence of the pathobiont E. coli can increase susceptibility to gluten-induced pathology in mice expressing the CeD susceptibility gene. More recently, Caminero and colleagues reported the presence of the opportunistic pathogen P. aeruginosa in CeD patients. The study found that proteases from P. aeruginosa could participate in gluten metabolism in vivo, leading to the production of gluten peptides with greater immunogenicity. It may be that multiple members of the gut microbiota, including bacteria or viruses, could potentially (independently, through different pathways) play a role in loss of tolerance to gluten or other food antigens.

Together these findings highlight the complex scenario surrounding the factors involved in CeD development. The study by Bouziat et al. shows one scenario where subclinical viral infections can lead to the loss of tolerance to dietary antigens like gluten. Importantly, it suggests that members of the gut microbiota can influence immune responses to innocuous proteins in the gut. This scenario may also apply to other microbial members or to other food sensitivities or autoimmune diseases. Deepening our understanding of the events leading to adverse reactions to innocuous antigens will allow for the development of preventative strategies. This is particularly important given the recent increase in prevalence of autoimmune disease, food sensitivities, and food allergies.




Bouziat R, Hinterleitner R, Brown JJ, et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science. 2017; 356(6333): 44-50. doi: 10.1126/science.aah5298