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.