iNKT cells have been recognized to play an important role in defining host commensalism in mucosal surfaces and the response to mucosal pathogen exposures. At the same time, iNKT cells are under the influence of the commensal microbiota such that in the germ-free (GF) state iNKT cell quantity is increased in the intestines and lungs and can only be normalized when microbes are present during an early life “window of opportunity” when the host is responsive to microbial signals such as those derived from sphingolipid producing bacteria such Bacteroides fragilis. Interestingly, oxazolone-induced colitis occurs and with increased severity in the GF state. Normalization of responses to oxazolone in fact only occur if microbial commensalism is established in early, but not later life in association with normalization of iNKT levels to that observed under SPF conditions. This suggests that a set-point is established in early life that determines CD1d-restricted iNKT cell responses to environmental factors capable of stimulating iNKT cell-mediated inflammation, as modeled with oxazolone as an agent of exposure.  This is interesting in light of current hypotheses for IBD pathogenesis wherein environmental triggers activate inflammation in a susceptible host. This lead us to hypothesize that oxazolone may be an example of a much larger collection of environmental chemical moieties capable of triggering CD1d-restricted iNKT cell responses. We have thus sought evidence for the existence of oxazolone-related chemicals in the environment and microbiota capable of inducing intestinal inflammation. In so doing, we have identified environmental mimetics of oxazolone that are derived from dietary or microbial sources which are characterized by the presence of a 5-membered oxazole ring and capable of driving CD1d-dependent inflammation through activation of the aryl hydrocarbon receptor pathway within IECs of the colon. As efforts to define and evaluate natural and synthetic compounds from dietary, industrial and agricultural sources, in either homeostatic or disease contexts have generally been elusive, these results have important and broad disease implications.