Journal Article

Identification of environmental factors that promote intestinal inflammation

Li, Zhaorong, Yeste, Ada, Huang, Chien-Jung, Hewson, Patrick, Cox, Laura M., Fonseca-Castro, Pedro Henrique, Giovannoni, Federico, Hauser, Russ, Lee, Hong-Gyun, Hodgetts, Kevin J., Rone, Joseph M., Rejano-Gordillo, Claudia M., Chao, Chun-Cheih, Li, Lucinda, Piester, Gavin, Faust Akl, Camilo, Sanmarco, Liliana M., Takenaka, Maisa, Bladi, Maha Al, de Lima, Kalil Alves, Plasencia, Agustin, Andersen, Brian M., Quintana, Francisco J., Kenison, Jessica E., Guo, Lydia, Tjon, Emily C., Jaronen, Merja, Rothhammer, Veit, Mascanfroni, Ivan, Linnerbauer, Mathias, Mildner, Alexander, Korzenik, Joshua, Hahn, Mark E., Wang, Yu-Chao, Covacu, Ruxandra, Snapper, Scott B., Wheeler, Michael A., Ekwudo, Millicent, Polonio, Carolina M., Alsuwailm, Moneera, Gutierrez-Vazquez, Cristina, Franks, Diana G., Queva, Hugo

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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