DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk
Helmut Grasberger, … , Gilbert S. Omenn, John Y. Kao
Helmut Grasberger, … , Gilbert S. Omenn, John Y. Kao
Published March 2, 2021
Citation Information: J Clin Invest. 2021;131(9):e141676. https://doi.org/10.1172/JCI141676.
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Research Article Gastroenterology

DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk

Abstract

A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.

Authors

Helmut Grasberger, Andrew T. Magis, Elisa Sheng, Matthew P. Conomos, Min Zhang, Lea S. Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zaatari, Sho Kitamoto, Nobuhiko Kamada, Ryan W. Stidham, Yasutada Akiba, Jonathan Kaunitz, Yael Haberman, Subra Kugathasan, Lee A. Denson, Gilbert S. Omenn, John Y. Kao

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Figure 4

Il17c induction in the gut epithelium of DUOX2 deficient mice is T cell–independent and mimicked by impairment of the supraepithelial mucus layer.

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Il17c induction in the gut epithelium of DUOX2 deficient mice is T cell–...
(A and B) Il17c mRNA expression in the terminal ileum and colon of Duoxa–/– (n = 26) and WT (n = 22) littermates. Arrows indicate samples with outlier high Il17c expression (Il17chi). Ccl20 (C), Il17a (D), and Il17f (E) expression in the terminal ileum. Two-tailed Mann-Whitney. (F and G) Expression of Il17c in the ileum and colon of intestinal epithelial-specific Duoxa–/– and floxed littermate control mice. We challenged the normal bacterial compartmentalization by chronically feeding the emulsifier CMC (1% wt/vol in drinking water for 8 weeks) that thins the mucus layer (12). n = 6 and n = 17 for floxed control mice without or with CMC treatment, respectively, and n = 5 and n = 20 for intestinal epithelial-specific Duoxa–/– mice without or with CMC treatment, respectively. Kruskal-Wallis and Dunn’s post hoc test. (H and I) Il17c expression is preserved in Rag1–/– mice lacking T cells as a major source of IL-17 family cytokines. n = 11 for Rag1–/–, Duoxafl/fl mice; n = 9 for Rag1–/–, Duoxafl/fl, Vil1-Cre mice. Two-tailed Mann-Whitney. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars in A–I indicate 95% CI of geometric means.