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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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 1

CD subjects with ATG16L1T300A genotype (T300A) were more susceptible to cigarette smoking–associated Paneth cell defects.

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CD subjects with ATG16L1T300A genotype (T300A) were more susceptible to ...
(A) In a cohort of CD subjects (n = 186) who underwent ileocolectomy, 126 received postoperative prophylaxis. Within this prophylaxis subset, smokers with type I Paneth cell phenotype (<80% Paneth cells with normal granule morphology) showed the shortest time to disease recurrence (P = 0.0183 by log-rank test). (B) Representative HD5 immunofluorescence. Scale bar: 10 μm. Asterisks indicate abnormal Paneth cells. (C) Cigarette smoking was associated with lower percentage of normal Paneth cells in patients with ATG16L1T300A allele or alleles, while no significant differences in Paneth cell defects were seen between NR patients with or without smoking history (overall P =0.001). NR-nonsmoking, n = 25; NR-smoking, n = 14; T300A-nonsmoking, n = 84; T300A-smoking, n = 62. Data were analyzed by Kruskal-Wallis test followed by Dunn’s multiple comparison tests between groups and represent mean ± SEM. P values for comparisons between groups are shown in Supplemental Table 2. *P < 0.05; **P < 0.01.