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Cell. 2018 May 17;173(5):1123-1134.e11. doi: 10.1016/j.cell.2018.04.037.

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

Author information

1
Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
2
Inspiralis, Innovation Centre, Norwich Research Park, Colney Lane, Norwich NR4 7GJ, UK.
3
Center for Clinical and Translational Metagenomics, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4
Laboratory of Medicinal Chemistry, Department of Biomedicinal Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
5
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
6
Departments of Medicine, and Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
7
School of Biosciences, University of Birmingham, Birmingham, UK.
8
Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA.
9
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
10
Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: rblumberg@bwh.harvard.edu.

Abstract

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.

KEYWORDS:

CD1d; aryl hydrocarbon receptor; indoleamine 2,3 dioxygenase; inflammatory bowel disease; intestinal epithelial cell; microbiota; microcin; mucosal inflammation; natural killer T cell; oxazole; tryptophan

PMID:
29775592
PMCID:
PMC6119676
DOI:
10.1016/j.cell.2018.04.037
[Indexed for MEDLINE]
Free PMC Article

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