Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s disease
Ta-Chiang Liu, … , Richard D. Head, Thaddeus S. Stappenbeck
Ta-Chiang Liu, … , Richard D. Head, Thaddeus S. Stappenbeck
Published August 23, 2018
Citation Information: J Clin Invest. 2018;128(11):5110-5122. https://doi.org/10.1172/JCI120453.
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Research Article Gastroenterology Immunology

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

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.

Authors

Ta-Chiang Liu, Justin T. Kern, Kelli L. VanDussen, Shanshan Xiong, Gerard E. Kaiko, Craig B. Wilen, Michael W. Rajala, Roberta Caruso, Michael J. Holtzman, Feng Gao, Dermot P.B. McGovern, Gabriel Nunez, Richard D. Head, Thaddeus S. Stappenbeck

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Figure 2

Atg16l1T300A mice were more susceptible to Paneth cell defects after exposure to cigarette smoking.

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Atg16l1T300A mice were more susceptible to Paneth cell defects after ex...
(A) Schematic illustration of experimental design. Atg16l1T300A (T300A) mice and WT littermates were treated with or without cigarette smoking for 4 weeks, and Paneth cell morphology was assessed. (B) Smoking induced more Paneth cell defects, specifically in Atg16l1T300A mice (overall P < 0.0001). (A and B) WT-nonsmoking, n = 12; WT-smoking, n = 21; T300A-nonsmoking, n = 19; T300A-smoking, n = 25. Results are from 6 independent experiments. Data were analyzed by 2-way ANOVA. (C) Two weeks of cigarette smoking was sufficient to induce Paneth cell defects in Atg16l1T300A mice (P = 0.0054), while no additional Paneth cell defects were seen with longer exposure time, up to 6 weeks (P > 0.9999). Nonexposed, n = 17; 2 weeks, n = 10; 4 weeks, n = 10. (D) After 4 weeks of cessation of cigarette exposure, the percentage of normal Paneth cells of the Atg16l1T300A mice returned to a level comparable to that of unexposed status (P = 0.0027). Baseline, n = 6; 2 weeks, n = 7; 4 weeks, n = 7. (C and D) Data were analyzed by 1-way ANOVA, followed by Mann-Whitney U tests between groups. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (B–D) Data represent mean ± SEM.