High-salt diet promotes atopic dermatitis by partially enhancing intestinal SGK1/ENaC signaling and destroying gut Lactobacillus-maintained systemic type 1 interferon

Objective Systemic type 1 interferon (IFN1), which is regulated by intestinal homeostasis, shows potential in inhibiting the immunoglobulin E (IgE) production and Th2 response in vivo . This study aimed to determine the effect of a high-salt diet (HSD) on systemic IFN1, gut microbiota and tight junction protein zonula occludens-1 (ZO-1), intestinal serum- and glucocorticoid-inducible kinase-1 (SGK1), and epithelial sodium ion channels (ENaCs) in atopic dermatitis (AD) mice. Methods MC903 was applied topically to establish AD in wild-type C57BL/6 mice; in mice with IFN1 receptor-1 ( ifnar1 ) knockout, sgk1 conditional knockout (cKO) in intestinal epithelial cells (IECs), or stimulator of interferon genes ( sting ) cKO in dendritic cells (DCs); and in BDCA2 -DTR mice with plasmacytoid DC (pDC) deletion. Results HSD significantly promoted AD accompanied by higher levels of serum IgE, IL-4/IL-13, ileum SGK1, phosphorylated SGK1, βENaC and γENaC, and skin sodium, but lower levels of serum IFN1, ileum ZO-1, gut Lactobacillus_murinus , and Lactobacillus_reuteri . Lactobacillus gavage alleviated AD, reduced serum IgE and IL-4/IL-13, and increased serum IFN1 and ileum ZO-1 in AD mice on HSD, which were largely counteracted by ifnar1 knockout, pDC deletion, or sting cKO in DCs, but not in IECs. cKO of sgk1 in IECs alleviated AD, slightly reduced the serum IgE and IL-4/IL-13, and significantly reduced the ileum βENaC and γENaC and the skin sodium in mice on HSD without changing the gut microbiota, ileum ZO-1, and serum IFN1 levels. Conclusion HSD promotes AD by partially impairing the systemic IFN1 production that is orchestrated by STING signaling in DCs by reducing the gut Lactobacillus and by partially increasing the sodium accumulation in skin lesions via driving the ileum SGK1 phosphorylation and βENaC and γENaC expression. Further research is necessary to assess the effect of Lactobacillus supplementation on clinical AD patients with an HSD habit.