DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk
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
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
View: Text | PDF
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

×

Figure 6

IL17C induction observed in a subset of patients with IBD is a marker for abnormal epithelial stimulation by gram-negative bacteria.

Options: View larger image (or click on image) Download as PowerPoint
IL17C induction observed in a subset of patients with IBD is a marker fo...
(A) Positive associations of plasma IL-17C concentration with self-reported health history of study participants considering GI, skin, lung, and chronic infectious disease categories. Shown is the average difference in standardized plasma IL-17C for presence versus absence of a condition. We evaluated the nominal significance of effects using the Welch 2-sample test adjusted for age, sex, body mass index, season, and ancestry. See Supplemental Table 11 for detailed results. (B) Expression of IL17C in ileal mucosal biopsies from patients with CD (n = 174) and non-IBD controls (n = 42) from the RISK cohort. Error bars represent medians with IQR. Two-tailed Mann-Whitney. **P = 0.0027. (C) Gene set enrichment analysis using correlation with IL17C expression (rIL17C) as the rank metric to identify IL17C-correlated KEGG pathways in the mucosal biopsies of CD patients (FDR < 0.05). See Supplemental Tables 13 and 14 for additional information. (D) Overrepresentation of IL17C-coexpression signature (rIL17C > 0.5) in disease-associated gene sets from the GLAD4U database (59) (FDR < 0.05; Supplemental Table 15). (E) Multivariate association analysis using the expression of IL17C and proinflammatory cytokines (TNF, IL1B) in ileal CD biopsies (n = 135) as predictors and genus-level microbial abundance data of the mucosal microbiome as a response. Positive coefficients indicate a positive correlation between gene expression and compositional abundance of a bacterial genus (see Supplemental Tables 16 and 17 for input data and detailed results).