Faulty calcium signaling may drive dry mouth in Down syndrome, raising gum disease risk
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Researchers at NYU College of Dentistry have uncovered what may be biologically driving oral health issues unique to Down syndrome. Their study, published in Cell Reports, describes a molecular mechanism—a defect in calcium signaling—behind low saliva production, along with other factors that may contribute to gum 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.
A challenge to oral health
Down syndrome is a common genetic disorder that results in intellectual differences and physical issues, including an increased risk for hearing loss and heart disease. It's less well known that most people with Down syndrome have gum disease—around 60%–90% of individuals younger than 35, a rate that far 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."
Studies increasingly show that people with Down syndrome produce less saliva, a condition known as hyposalivation. Hyposalivation can alter the oral microbiome—the balance of microbes in the mouth—and increase infection-causing bacteria that promote gum disease and tooth decay. This greater risk of gum disease, in turn, increases the risk of other health issues, including Alzheimer's disease, which occurs in most people with Down syndrome as they age.
Altered signals, microbiome
To gain a deeper understanding of oral health biology in Down syndrome, the researchers studied a widely used mouse model of the genetic disorder. They found several changes to the mice's saliva that mirror what studies show in people with Down syndrome: The mice produced much less saliva, but the saliva was more acidic and contained elevated levels of certain immune markers.
Notably, store-operated calcium entry—a calcium signaling process required for saliva secretion—was decreased in the mice's 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 showed high levels of inflammatory markers in gum tissue and increased inflammation, as well as decreased mitochondrial function, in the salivary glands.
"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 systemwide impact on the health of individuals with Down syndrome," said Beverly Rothermel, a study author and professor at UT Southwestern Medical Center.
The researchers also discovered certain autoantibodies in the mice that are used to diagnose Sjögren's disease, an autoimmune condition marked by low saliva production. Through additional tests, they found hints that those with Down syndrome may be at increased risk for Sjögren's.
Looking beyond the mouth, the researchers studied the blood and gut microbiome of the mice with Down syndrome. The mice had high levels of succinate—a metabolic byproduct linked to inflammation and gum disease—in their blood, as well as succinate-producing bacteria in the gut and mouth.
"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."
A path toward treatment
According to the researchers, addressing oral health for individuals with Down syndrome could include efforts to both improve oral hygiene—for instance, more frequent dental visits or implementing practices in group homes related to diet and toothbrushing—and treat the underlying biological factors.
People who experience dry mouth due to Sjögren's or who have undergone radiation for head and neck cancer are often prescribed pilocarpine, a medication that stimulates saliva and tear production and appears on the World Health Organization's Essential Medicines List. The researchers found that giving pilocarpine to mice with Down syndrome 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.
Publication details
Dysregulated calcium signaling underlies hyposalivation and microbial dysbiosis in Down syndrome, Cell Reports (2026). DOI: 10.1016/j.celrep.2026.117619
Journal information: Cell Reports
Key medical concepts
Down SyndromeDry MouthPilocarpine
Clinical categories
DentistryClinical geneticsCommon illnesses & Prevention Provided by New York University Who's behind this story?
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