Identification of environmental factors that promote intestinal inflammation

Liliana M. Sanmarco, Chun-Cheih Chao, Yu-Chao Wang, Jessica E. Kenison, Zhaorong Li, Joseph M. Rone, Claudia M. Rejano-Gordillo, Carolina M. Polonio, Cristina Gutierrez-Vazquez, Gavin Piester, Agustin Plasencia, Lucinda Li, Federico Giovannoni, Hong-Gyun Lee, Camilo Faust Akl, Michael A. Wheeler, Ivan Mascanfroni, Merja Jaronen, Moneera Alsuwailm, Patrick Hewson, Ada Yeste, Brian M. Andersen, Diana G. Franks, Chien-Jung Huang, Millicent Ekwudo, Emily C. Tjon, Veit Rothhammer, Maisa Takenaka, Kalil Alves Lima, Mathias Linnerbauer, Lydia Guo, Ruxandra Covacu, Hugo Queva, Pedro Henrique Fonseca-Castro, Maha Al Bladi, Laura M. Cox, Kevin J. Hodgetts, Mark E. Hahn, Alexander Mildner, Joshua Korzenik, Russ Hauser, Scott B. Snapper and Francisco J. Quintana ()
Additional contact information
Liliana M. Sanmarco: Brigham and Women’s Hospital, Harvard Medical School
Chun-Cheih Chao: Brigham and Women’s Hospital, Harvard Medical School
Yu-Chao Wang: National Yang Ming Chiao Tung University
Jessica E. Kenison: Brigham and Women’s Hospital, Harvard Medical School
Zhaorong Li: Brigham and Women’s Hospital, Harvard Medical School
Joseph M. Rone: Brigham and Women’s Hospital, Harvard Medical School
Claudia M. Rejano-Gordillo: Brigham and Women’s Hospital, Harvard Medical School
Carolina M. Polonio: Brigham and Women’s Hospital, Harvard Medical School
Cristina Gutierrez-Vazquez: Brigham and Women’s Hospital, Harvard Medical School
Gavin Piester: Brigham and Women’s Hospital, Harvard Medical School
Agustin Plasencia: Brigham and Women’s Hospital, Harvard Medical School
Lucinda Li: Brigham and Women’s Hospital, Harvard Medical School
Federico Giovannoni: Brigham and Women’s Hospital, Harvard Medical School
Hong-Gyun Lee: Brigham and Women’s Hospital, Harvard Medical School
Camilo Faust Akl: Brigham and Women’s Hospital, Harvard Medical School
Michael A. Wheeler: Brigham and Women’s Hospital, Harvard Medical School
Ivan Mascanfroni: Brigham and Women’s Hospital, Harvard Medical School
Merja Jaronen: Brigham and Women’s Hospital, Harvard Medical School
Moneera Alsuwailm: Brigham and Women’s Hospital, Harvard Medical School
Patrick Hewson: Brigham and Women’s Hospital, Harvard Medical School
Ada Yeste: Brigham and Women’s Hospital, Harvard Medical School
Brian M. Andersen: Brigham and Women’s Hospital, Harvard Medical School
Diana G. Franks: Woods Hole Oceanographic Institution
Chien-Jung Huang: National Yang Ming Chiao Tung University
Millicent Ekwudo: Brigham and Women’s Hospital, Harvard Medical School
Emily C. Tjon: Brigham and Women’s Hospital, Harvard Medical School
Veit Rothhammer: Brigham and Women’s Hospital, Harvard Medical School
Maisa Takenaka: Brigham and Women’s Hospital, Harvard Medical School
Kalil Alves Lima: Brigham and Women’s Hospital, Harvard Medical School
Mathias Linnerbauer: Brigham and Women’s Hospital, Harvard Medical School
Lydia Guo: Brigham and Women’s Hospital, Harvard Medical School
Ruxandra Covacu: Brigham and Women’s Hospital, Harvard Medical School
Hugo Queva: Brigham and Women’s Hospital, Harvard Medical School
Pedro Henrique Fonseca-Castro: Brigham and Women’s Hospital, Harvard Medical School
Maha Al Bladi: Brigham and Women’s Hospital, Harvard Medical School
Laura M. Cox: Brigham and Women’s Hospital, Harvard Medical School
Kevin J. Hodgetts: Brigham and Women’s Hospital, Harvard Medical School
Mark E. Hahn: Woods Hole Oceanographic Institution
Alexander Mildner: Max-Delbrück-Center for Molecular Medicine (MDC)
Joshua Korzenik: Brigham and Women’s Hospital, Harvard Medical School
Russ Hauser: Harvard T. H. Chan School of Public Health
Scott B. Snapper: Boston Children’s Hospital
Francisco J. Quintana: Brigham and Women’s Hospital, Harvard Medical School

Nature, 2022, vol. 611, issue 7937, 801-809

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05308-6

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