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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.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
2
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
3
Department of Medicine and.
4
Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
5
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

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.

KEYWORDS:

Gastroenterology; Immunology; Inflammatory bowel disease

PMID:
30137026
PMCID:
PMC6205411
DOI:
10.1172/JCI120453
[Indexed for MEDLINE]
Free PMC Article

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