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J Clin Invest. 2018 Nov 1;128(11):5110-5122. doi: 10.1172/JCI120453. Epub 2018 Oct 15.

Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn's disease.

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Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
Department of Medicine and.
Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.


It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome. We hypothesized that CD susceptibility genes interact with cigarette smoking, a major CD environmental risk factor, to trigger Paneth cell defects. We found that both CD subjects and mice with ATG16L1T300A (T300A; a prevalent CD susceptibility allele) developed Paneth cell defects triggered by tobacco smoke. Transcriptional analysis of full-thickness ileum and Paneth cell-enriched crypt base cells showed the T300A-smoking combination altered distinct pathways, including proapoptosis, metabolic dysregulation, and selective downregulation of the PPARγ pathway. Pharmacologic intervention by either apoptosis inhibitor or PPARγ agonist rosiglitazone prevented smoking-induced crypt apoptosis and Paneth cell defects in T300A mice and mice with conditional Paneth cell-specific knockout of Atg16l1. This study demonstrates how explicit G+E can drive disease-relevant phenotype and provides rational strategies for identifying actionable targets.


Gastroenterology; Immunology; Inflammatory bowel disease

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