Western lifestyle with high salt consumption leads to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper (TH)17 cells, which may also contribute to hypertension. Induction of TH17 cells depends on the gut microbiota, yet the effect of salt on the gut microbiome is unknown. In mouse model systems, we show that high salt intake affects the gut microbiome, particularly by depleting Lactobacillus murinus. Consequently, L. murinus treatment prevents salt-induced aggravation of actively-induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension, by modulating TH17 cells. In line with these findings, moderate high salt challenge in a pilot study in humans reduces intestinal survival of Lactobacillus spp. along with increased TH17 cells and blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.