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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Crohn Disease / genetics
  • Crohn Disease / metabolism*
  • Crohn Disease / pathology
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation, Missense*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Paneth Cells / metabolism*
  • Paneth Cells / pathology
  • Rosiglitazone / pharmacology
  • Smoking / genetics
  • Smoking / metabolism*

Substances

  • ATG16L1 protein, human
  • Atg16l1 protein, mouse
  • Autophagy-Related Proteins
  • Carrier Proteins
  • PPAR gamma
  • PPARG protein, human
  • Rosiglitazone