Identification of environmental factors that promote intestinal inflammation

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD) 1 —a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move int...

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Bibliographic Details
Published in:	Nature (London) Vol. 611; no. 7937; pp. 801 - 809
Main Authors:	Sanmarco, Liliana M., Chao, Chun-Cheih, Wang, Yu-Chao, Kenison, Jessica E., Li, Zhaorong, Rone, Joseph M., Rejano-Gordillo, Claudia M., Polonio, Carolina M., Gutierrez-Vazquez, Cristina, Piester, Gavin, Plasencia, Agustin, Li, Lucinda, Giovannoni, Federico, Lee, Hong-Gyun, Faust Akl, Camilo, Wheeler, Michael A., Mascanfroni, Ivan, Jaronen, Merja, Alsuwailm, Moneera, Hewson, Patrick, Yeste, Ada, Andersen, Brian M., Franks, Diana G., Huang, Chien-Jung, Ekwudo, Millicent, Tjon, Emily C., Rothhammer, Veit, Takenaka, Maisa, de Lima, Kalil Alves, Linnerbauer, Mathias, Guo, Lydia, Covacu, Ruxandra, Queva, Hugo, Fonseca-Castro, Pedro Henrique, Bladi, Maha Al, Cox, Laura M., Hodgetts, Kevin J., Hahn, Mark E., Mildner, Alexander, Korzenik, Joshua, Hauser, Russ, Snapper, Scott B., Quintana, Francisco J.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 24-11-2022 Nature Publishing Group
Subjects:	45 45/91 631/250/38 64 64/116 64/60 692/699/1503 Animal models Animals Bioassays Biological activity CCAAT-Enhancer-Binding Protein-beta Colon Databases, Factual Dendritic cells Dendritic Cells - drug effects Dendritic Cells - immunology Dendritic Cells - metabolism Disease Disease Models, Animal Environment Environment models Environmental factors Gastrointestinal system Gastrointestinal tract Genome-wide association studies Genomes Health risks Herbicides Herbicides - adverse effects Humanities and Social Sciences Inflammation Inflammation - chemically induced Inflammation - etiology Inflammation - immunology Inflammation - pathology Inflammatory bowel disease Inflammatory bowel diseases Inflammatory Bowel Diseases - chemically induced Inflammatory Bowel Diseases - etiology Inflammatory Bowel Diseases - immunology Inflammatory Bowel Diseases - pathology Inflammatory diseases Intestine Intestines - drug effects Intestines - immunology Intestines - metabolism Intestines - pathology Large intestine Lymphocytes Lymphocytes T Machine Learning Mice Microbiota multidisciplinary NF-kappa B NF-κB protein Pathogenesis Pathology Receptors, Aryl Hydrocarbon Science Science (multidisciplinary) T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Tumor necrosis factor-TNF Zebrafish
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Summary:	Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD) 1 —a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity 2 . However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR–NF-κB–C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases. The herbicide propyzamide increases inflammation in the small and large intestine, and the AHR–NF-κB–C/EBPβ signalling axis—which operates in T cells and dendritic cells to promote intestinal inflammation—is targeted by propyzamide.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions L.M.S., C.-C.C., J.E.K. and F.J.Q. designed research. L.M.S., C.-C.C., J.E.K., J.M.R., C.M.R.-G., C.M.P., C.G.-V., G.P., A.P., L.L., F.G., H.-G.L., C.F.A., M.A.W., I.M., M.J., M.A., P.H., A.Y., B.M.A., D.G.F., M.E., V.R., M.T., K.A.d.L., M.L., L.G., R.C., H.Q., P.H.F.-C. and M.A.B. performed experiments. L.M.S., C.-C.C., J.E.K., Z.L., E.C.T., V.R., L.M.C., K.J.H, M.E.H., J.K., R.H., S.B.S. and F.J.Q. analysed data. A.M. contributed mice and reagents. Y.-C.W., E.C.T. and C.-J.H. performed machine learning. L.M.S., C.-C.C., J.E.K. and F.J.Q. wrote the paper with input from all of the authors. F.J.Q. directed and supervised the study.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-022-05308-6