ROLE OF GUT MICROBES IN IMMUNE-MEDIATED FOOD SENSITIVITIES
Immune-mediated food sensitivities that include celiac disease and food allergies are increasing worldwide. It is estimated that 1 in 20 Americans suffer from food sensitivities. Elimination of the causative food from the diet is the current standard and only care but always bears the risk of cross contamination with the offending food, which can significantly impact health in adults and especially children. The mechanisms underlying the increased incidence of food sensitivities remain unclear; however, several studies demonstrated that gut microbes, along with other host predisposing factors, dictate the development of immune-mediated food sensitivities. Gut microbes are increasingly considered as key modulators of mucosal immune responses to dietary antigens that protect from immune-mediated food sensitivities. To target microbe-induced immune pathways for intervention it is crucial to understand the functional mechanisms of how microbes modulate immune responses to food antigens. In the past decade, there was a significant advancement in our understanding of how commensal gut bacteria and enteric viral infections modulate mucosal immune responses in the context of food sensitivities. We recently showed that certain enteric viral infections lead to loss of oral tolerance to dietary gluten and the development of celiac disease. The mammalian gut microbiome encompasses bacteria, fungi, archaea and protists that contribute to gut health. We ask the question whether certain gut microbes can prevent inflammatory immune response to dietary antigens in the context of celiac disease and food allergies and, if so, what are the microbial-induced mechanisms of this beneficial immunomodulatory phenomenon?
NOVEL PLAYERS IN INTESTINAL TYPE-2 INFLAMMATION
Enteric helminth and protist infections remain a significant global health problem. Although infections by these parasites are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anemia and malnourishment. Infections are strongly associated with protective type-2 immune mediated intestinal inflammation, observed across species, including mice and humans, and characterized by innate lymphoid cell (ILC2), eosinophil, and mast cell recruitment and tissue injury. Mouse models of infection with intestinal parasites have been established to study the cellular and molecular mechanisms of type-2 immune responses in greater detail: Helminths, such as Nippostrongylus brasiliensis and Heligmosomoides polygyrus, and certain protists of the order Trichomonadida induce acute host type-2 immune defense responses in the small intestine upon infection. Type-2 immune responses are initiated by parasite sensing interleukin-25 (IL-25) producing epithelial tuft cells, resulting in the activation of IL-13 producing ILC2 that in turn signal back on epithelial cells. This feedforward IL-25-ILC2-IL-13 circuit amplifies type-2 immune responses and initiates massive tissue remodeling including tuft- and goblet cell hyperplasia, and mucus production resulting in the containment of intestinal parasites. Despite the recent advancement in our understanding in immune-tissue crosstalk in type-2 mediated inflammation, we lack a complete understanding of the detailed processes underlying parasite-induced type-2 immune responses in the gut; these limits effective treatment options to enteric parasitic infections. To characterize type-2 mediated inflammation in the intestine in greater detail we screened for novel players implicated in intestinal type-2 inflammation. The goal is to study newly identified type-2 inducible genes in the protective type-2 immunity to protists and helminths and their function in intestinal epithelial cells. We therefore generated knock-out mice and small intestinal organoid cultures.
ROLE OF HUMAN GUT COLONIZING PROTIST IN COLITIS
The human gut microbiome has a profound impact on gut immunity in health and disease. Host-microbe interactions play a key role in inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis. Microbial-induced immune pathways are plausible targets for intervention in IBD. Protists are unicellular organisms that commonly inhabit the human gut. Presently, the most well-studied gut-colonizing protists are species that are pathogenic to humans and other mammals. This means that the roles of non-pathogenic commensal protists in gut health and disease remain largely unexplored. In this study, we aim to identify commensal protist-derived metabolites that can promote regulatory immune responses that prevent or ameliorate IBD. To that end, we will apply conceptually and technically innovative approaches to dissect the mechanisms by which protists induce protective immune responses that may prevent overt inflammation and thus suppress IBD severity. This research benefits from the collaborative efforts of experts in experimental and computational biology and will provide a novel and rational approach to prevent or ameliorate IBD by utilizing the tolerogenic potential of protists and their metabolites.