Intestinal IL-17R signaling modulates commensal microbiota by regulating expression of Nox1 and Pigr

Abstract

Abstract Despite recent advances in understanding the role of IL-17 in host immunity, its role in regulating enteric immune responses as well as its impact on the commensal microbiome has not been well studied. To further understand this, we have generated intestinal epithelial cell specific IL-17R knockout mice. Our data shows that global and intestinal epithelial cell specific Il17r−/− mice have overgrowth of segmented filamentous bacteria (SFB), suggesting a critical role of IL-17 signaling in SFB colonization. Higher SFB colonization in Il17rafl/fl x villin cre+ mice resulted in expansion of IL-17A and IL-22 producing Th17 cells. The expansion of SFB was also confirmed by 16S rRNA. Furthermore this analysis also showed higher abundance of S24-7 and the Clostridiales family in Il17rafl/fl x villin cre+ mice. RNA sequencing data from the distal small intestine of SFB-colonized Il17ra−/− and Il17rafl/fl x villin cre+ mice revealed substantial reduction of Nox1 (an apical NADPH oxidase) and Pigr genes. Mouse and human primary intestinal organoid culture further confirmed a direct role of IL-17 in regulating Nox1 and Pigr expression. Reduced Nox1 expression correlated with significant reduction in H202 levels in the terminal ileum of Il17rcfl/fl x villin cre+ mice. Furthermore, Nox1−/− and IgA−/− mice showed a higher degree of SFB colonization in the feces and terminal ileum as compared to cohoused control WT mice. We have evidence that Il17rafl/fl x villin cre+ mice are more susceptible to autoimmune inflammation. Collectively, our data indicate IL-17R-dependent intestinal signaling controls commensal bacteria by regulating the expression of Nox1 and Pigr which regulates lumenal H202 and sIgA concentrations respectively.