Researchers at NYU College of Dentistry have identified biological changes that may help explain oral health issues associated with Down syndrome, according to a study published in Cell Reports. The research describes a molecular mechanism involving defective calcium signaling that may contribute to reduced saliva production, along with additional factors that may be associated with periodontal disease.
“Understanding the processes responsible for low saliva in Down syndrome and developing therapies to restore salivation could have a transformative impact on the oral and overall health of people with Down syndrome,” said Rodrigo Lacruz, professor of molecular pathobiology at NYU College of Dentistry and the study’s senior author.
According to the researchers, approximately 60% to 90% of individuals with Down syndrome younger than age 35 have periodontal disease, a prevalence that exceeds that of people without Down syndrome, including those with other intellectual disabilities.
“Of the diverse health challenges that individuals with Down syndrome face, their higher risk of oral disease remains largely unexplored,” said Ga-Yeon Son, a senior research scientist in the Department of Molecular Pathobiology at NYU College of Dentistry and the study’s first author. “While dietary and oral hygiene factors may contribute to dental issues in some with Down syndrome, we observed changes in saliva, calcium signaling, and the microbiome, all of which could contribute to poor oral health.”
The researchers noted that previous studies have shown people with Down syndrome often experience hyposalivation, which can alter the oral microbiome and increase infection-causing bacteria associated with periodontal disease and dental caries. They also noted that periodontal disease increases the risk of other health issues, including Alzheimer's disease, which occurs in most people with Down syndrome as they age.
To investigate the biology underlying these findings, the researchers studied a widely used mouse model of Down syndrome. They found that the mice produced substantially less saliva than controls, while the saliva was more acidic and contained elevated levels of certain immune markers. The researchers also found decreased store-operated calcium entry, a calcium signaling process required for saliva secretion, in the animals' salivary glands.
“This dysfunction in calcium signaling is likely responsible for hyposalivation in Down syndrome,” said Lacruz. “Decreased saliva flow can have systemic consequences, advancing periodontal disease and impacting the microbial ecosystem."
Additional analyses identified elevated inflammatory markers in gingival tissue, increased inflammation in the salivary glands, and decreased mitochondrial function.
“Altered mitochondrial function has been widely reported in individuals with Down syndrome. What is particularly compelling about these studies is that they provide evidence of a pathway through which changes in mitochondrial function and calcium handling in salivary glands may be having a system-wide impact on the health of individuals with Down syndrome,” said Beverly Rothermel, a study author and professor at UT Southwestern Medical Center.
The investigators also identified autoantibodies in the mice that are used to diagnose Sjögren’s disease, an autoimmune condition characterized by reduced saliva production. Additional testing suggested that individuals with Down syndrome may have an increased risk for Sjögren’s disease.
Beyond the oral cavity, the researchers examined blood samples and the gut microbiome in the mouse model. They found elevated blood levels of succinate, a metabolic byproduct associated with inflammation and periodontal disease, as well as succinate-producing bacteria in both the gut and oral microbiome.
“This systemic alteration of succinate and changes to the oral and gut microbiome appear to be influencing the biology of Down syndrome,” said study author Deepak Saxena, professor of molecular pathobiology and director of research innovation and entrepreneurship at NYU College of Dentistry. “While more research is needed to understand how these differences influence one another—and ultimately drive hyposalivation and gum disease—the findings provide clues about the unique oral health challenges in this population.”
According to the researchers, strategies to improve oral health in individuals with Down syndrome could include enhanced oral hygiene measures, such as more frequent dental visits and improved diet and toothbrushing practices in group homes, in addition to investigating biological approaches that target hyposalivation.
The researchers also evaluated pilocarpine, a medication used to stimulate saliva and tear production in people with conditions such as Sjögren’s disease or after radiation therapy for head and neck cancer. In the mouse model, pilocarpine increased salivation.
“Targeting hyposalivation to boost saliva production could potentially improve some of the systemic disruptions that individuals with Down syndrome experience. This is our next research focus,” said Lacruz.
The study's additional authors are Guilherme H. S. Bomfim, Fangxi Xu, Scott C. Thomas, Kristen Rosenberg, Tommy Kim, Eleni Rice, Enkhnaran Budjab, Rebecca Jones, Yin-Hu Wang, Erna Mitaishvili, Stefan Feske, Drew R. Jones, and Edwin Rosado-Olivieri of NYU. The research was supported by the National Institute of Dental and Craniofacial Research, the National Institute of Allergy and Infectious Diseases, and NYU Academic Enhancement Funds.
