Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

• Published in: Cell Vol. 173; no. 5; pp. 1123 - 1134.e11
• Main Authors: Iyer, Shankar S., Gensollen, Thomas, Gandhi, Amit, Oh, Sungwhan F., Neves, Joana F., Collin, Frederic, Lavin, Richard, Serra, Carme, Glickman, Jonathan, de Silva, Punyanganie S.A., Sartor, R. Balfour, Besra, Gurdyal, Hauser, Russell, Maxwell, Anthony, Llebaria, Amadeu, Blumberg, Richard S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2018
• Subjects: Animals; Antigens, CD1d - genetics; Antigens, CD1d - metabolism; aryl hydrocarbon receptor; CD1d; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Diet; Disease Models, Animal; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; indoleamine 2,3 dioxygenase; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; inflammatory bowel disease; Interleukin-10 - metabolism; intestinal epithelial cell; Intestines - cytology; Intestines - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; microbiota; microcin; mucosal inflammation; Natural Killer T-Cells - immunology; natural killer T cell; oxazole; Oxazoles - pharmacology; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; tryptophan; Tryptophan - metabolism; microbiota; intestinal epithelial cell; natural killer T cell; mucosal inflammation; CD1d; indoleamine 2,3 dioxygenase; microcin; inflammatory bowel disease; tryptophan; oxazole; aryl hydrocarbon receptor
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.04.037

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium. [Display omitted] •Oxazoles derived from diet, industrial sources, and microbes activate IDO1•Environmental oxazoles induce tryptophan-derived metabolites to activate AhR in IECs•AhR activation in IECs limits CD1d-restricted production of IL-10•Oxazole activation of AhR in IECs results in iNKT-mediated intestinal inflammation A class of microbial and environmental compounds triggers inflammation in gut epithelial cells through the action of natural killer T cells and aryl hydrocarbon receptor signaling.