High-Salt Diet Induces IL-17-Dependent Gut Inflammation and Exacerbates Colitis in Mice

Sarah Leão Fiorini Aguiar, Mariana Camila Gonçalves Miranda, Mauro Andrade Freitas Guimarães, Helton Costa Santiago, Camila Pereira Queiroz, Pricila da Silva Cunha, Denise Carmona Cara, Giselle Foureaux, Anderson José Ferreira, Valbert Nascimento Cardoso, Patrícia Aparecida Barros, Tatiani Uceli Maioli, Ana Maria Caetano Faria

Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase severity of autoimmune diseases. The purpose of the present study was to evaluate the effects of a diet supplemented with NaCl in the colonic mucosa at steady state and during inflammation. We showed that consumption of HSD by mice triggered a gut inflammatory reaction associated with IL-23 production, recruitment of neutrophils, and increased frequency of the IL-17-producing type 3 innate lymphoid cells (ILC3) in the colon. Moreover, gut inflammation was not observed in IL-17-/- mice but it was present, although at lower grade, in RAG-/- mice suggesting that the inflammatory effects of HSD was dependent on IL-17 but only partially on Th17 cells. Expression of SGK1, a kinase involved in sodium homeostasis, increased 90 min after ingestion of 50% NaCl solution and decreased 3 weeks after HSD consumption. Colitis induced by oral administration of either dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid was exacerbated by HSD consumption and this effect was associated with increased frequencies of RORγt+ CD4+ T cells and neutrophils in the colon. Therefore, our results demonstrated that consumption of HSD per se triggered a histologically detectable inflammation in the colon and also exacerbated chemically induced models of colitis in mice by a mechanism dependent on IL-17 production most likely by both ILC3 and Th17 cells.