Approved June 2024
Viruses have been implicated in celiac disease development [1-5]. While several hypotheses have been postulated to explain this clinical association, recent studies have provided some mechanistic insight. Common viruses, including reovirus [6] and norovirus [7], can transiently disrupt oral tolerance- an active process whereby the immune system is unresponsive to orally ingested antigens, including food components. In celiac disease, loss of oral tolerance to gluten precedes the development of enteropathy. This mechanism of virus-induced loss of tolerance depends not on the type of virus, but on the ability of the virus to modulate the inflammatory potential of dendritic cells, key cells involved in mounting antigen-specific immune responses. During infection, the induction of interferon regulatory factor 1 (IRF-1) in dendritic cells within the mesenteric lymph nodes is critical for the virus-induced loss of tolerance to dietary proteins like gluten [6,7]. These findings help shed some light on potential environmental factors, including viruses and other microorganisms such as bacteria or protists that could participate in triggering celiac disease, and that could be targeted in preventative approaches.
A recent study by Medina Sanchez and colleagues demonstrated that this process isn’t quite this simple, and the presence or absence of other microorganisms within the gut can influence whether a virus induces a pro-inflammatory signature in dendritic cells that ultimately disrupts tolerance to gluten [8]. This discovery was made when researchers noticed that mice that were maintained “in-house” did not develop virus-mediated inflammatory responses to dietary proteins, whereas mice from an outside vendor did. Further investigation revealed that the “in-house” mice were colonized with a previously uncharacterized commensal protist from the Parabasalia class. Historically regarded as a separate kingdom, protists are diverse unicellular eukaryotic microbes whose role in the gut microbiome is underappreciated. Colonization with this specific protist, recently named Tritrichomonas arnold, altered the transcriptional profile of dendritic cells, suppressing the virus-mediated induction of IRF-1 in dendritic cells. This protection against virus-mediated loss of tolerance to gluten was mediated through unidentified metabolites from T. arnold and was independent of its induction of a T helper type 2 response and antiviral host responses.
Currently, the only available treatment for celiac disease is a lifelong gluten-free diet, so there is an interest among patients for new and alternative approaches [9]. The mechanism by which commensal microbes could favor oral tolerance therefore has several important clinical implications for celiac disease management and preventing the loss of gluten tolerance. First, these findings suggest that inducing a type-2 response does not necessarily suppress a Th1 immune response to dietary antigens, and a therapeutic strategy taking this type of approach in celiac disease is unlikely to succeed. Indeed, infection of celiac disease patients with the parasitic type-2-inducing hookworm failed to restore tolerance in a recent clinical trial [10].
The finding that the class Parabasalia (to which T. arnold belongs) is underrepresented in patients with celiac disease (7.7%) compared to healthy volunteers (34.8%) [8], provides some clinical relevance to the results obtained in mice, and also suggests that a lack of these protective protists could be an environmental factor contributing to celiac disease development. Strategies that could promote colonization of select protists, or delivery of still yet to be identified metabolites could be future preventative approaches in genetically at-risk individuals. However, little is known about commensal protists within the human gut, particularly how they colonize, the factors that influence colonization, and their crosstalk with viruses. Dietary soluble fiber was needed to sustain T. arnold colonization in mice. Interestingly, inadequate fiber intake is common in celiac disease patients consuming a gluten-free diet [11]. But whether this contributes to variations in protist colonization or immune responses to gluten has yet to be determined.
Restoring tolerance to gluten for individuals with celiac disease is the ultimate goal, and the only therapeutic option that would likely be a standalone therapy. Indeed, there are several approaches currently in clinical trials, and in preclinical development [12]. Most of these approaches are antigen-specific therapies that utilize bioengineering to target liver antigen-presenting cells that are poised to maintain tolerance [13]. How a tolerance-promoting protist would fit into this landscape of therapies is still unclear. Several critical knowledge gaps remain that are key for the therapeutic potential of protists. First and foremost is whether T. arnold and its metabolites can reestablish tolerance to gluten. We also need a better understanding of the metabolites that mediate this protective effect, as well as the effects of T. arnold on other tolerogenic dendritic cell or antigen-presenting cell subsets. Finally, whether other human commensal protists have similar tolerance-inducing properties in a complex human microbial ecosystem that has localized bacterial niches along the small intestine, is unknown [14]. These studies raise the hypothesis that inter-kingdom interactions within the small intestine may provide a balance of tolerance, or its breakdown, in a genetically predisposed host.
Nevertheless, these results demonstrate a previously unrealized crosstalk between viruses, protists, and the immune system, that will hopefully provide novel opportunities to prevent or reverse inflammatory reactions to gluten.
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