Dysregulated calcium signaling underlies hyposalivation and microbial dysbiosis in Down syndrome

Individuals with Down syndrome (DS) produce less saliva for unknown reasons resulting in chronic periodontal disease with systemic detrimental effects. Using the (Dp(16)1Yey) mouse model of DS we define the molecular mechanisms of hyposalivation and potential links to periodontal disease. We show that Dp(16)1Yey mice produce less saliva and have a higher immune burden in the salivary glands. We demonstrate that store operated calcium entry (SOCE), required for saliva secretion, is deficient in the salivary glands of Dp(16)1Yey mice. SOCE is also reduced in iPSCs from an individual with DS. We show that the oral and gut microbiomes of Dp(16)1Yey mice have abundant succinate-associated microbes and high succinate levels in the serum. We highlight associations between altered Ca²⁺ handling and hyposalivation, dysbiosis, and periodontal disease in DS. The administration of pilocarpine in Dp(16)1Yey mice increased salivation, suggesting that cholinergic agonists might be useful to improve the oral health of individual with DS.