BackgroundSjögren’s syndrome (SS) is an autoimmune disease characterized by inflammation of the exocrine gland. An imbalance of gut microbiota has been linked to SS. However, the molecular mechanism is unclear. We investigated the effects ofLactobacillus acidophilus(L.acidophilus) and propionate on the development and progression of SS in mouse model.MethodsWe compared the gut microbiomes of young and old mice. We administeredL.acidophilusand propionate up to 24 weeks. The saliva flow rate and the histopathology of the salivary glands were investigated, and the effects of propionate on the STIM1-STING signaling pathway were evaluated in vitro.ResultsLactobacillaceae andLactobacilluswere decreased in aged mice. SS symptoms were ameliorated byL.acidophilus. The abundance of propionate-producing bacterial was increased byL.acidophilus. Propionate ameliorated the development and progression of SS by inhibiting the STIM1-STING signaling pathway.ConclusionsThe findings suggest thatLactobacillus acidophilusand propionate have therapeutic potential for SS.Video AbstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12964-023-01141-0.