Nature. 2022 Nov;611(7937):801-809. doi: 10.1038/s41586-022-05308-6. Epub 2022 Oct 20.

Liliana M Sanmarco ^# 1, Chun-Cheih Chao ^# 1, Yu-Chao Wang ^# 2, Jessica E Kenison ^# 1, Zhaorong Li ¹, Joseph M Rone ¹, Claudia M Rejano-Gordillo ¹, Carolina M Polonio ¹, Cristina Gutierrez-Vazquez ¹, Gavin Piester ^1 3, Agustin Plasencia ¹, Lucinda Li ¹, Federico Giovannoni ¹, Hong-Gyun Lee ¹, Camilo Faust Akl ¹, Michael A Wheeler ^1 4, Ivan Mascanfroni ¹, Merja Jaronen ¹, Moneera Alsuwailm ¹, Patrick Hewson ¹, Ada Yeste ¹, Brian M Andersen ^1 5, Diana G Franks ⁶, Chien-Jung Huang ², Millicent Ekwudo ¹, Emily C Tjon ¹, Veit Rothhammer ¹, Maisa Takenaka ¹, Kalil Alves de Lima ¹, Mathias Linnerbauer ¹, Lydia Guo ¹, Ruxandra Covacu ¹, Hugo Queva ¹, Pedro Henrique Fonseca-Castro ¹, Maha Al Bladi ¹, Laura M Cox ¹, Kevin J Hodgetts ¹, Mark E Hahn ⁶, Alexander Mildner ⁷, Joshua Korzenik ⁸, Russ Hauser ⁹, Scott B Snapper ^10 11, Francisco J Quintana ^12 13

Author information

¹Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

²Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.

³Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.

⁴The Broad Institute of Harvard and MIT, Cambridge, MA, USA.

⁵Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

⁶Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA, USA.

⁷Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.

⁸Department of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

⁹Harvard T. H. Chan School of Public Health, Boston, MA, USA.

¹⁰Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.

¹¹Department of Medicine, Harvard Medical School, Boston, MA, USA.

¹²Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.

¹³The Broad Institute of Harvard and MIT, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu.

^#Contributed equally.

Abstract

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 severity². 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.