A new study led by researchers at the New York University School of Dentistry and published in the journal NYU, reports that a topical gel that blocks the receptors for a metabolic by-product called succinate treats gum disease by inhibiting inflammation and altering the composition of bacteria in the mouth. cell reports.
The research, conducted in mice and using human cells and plaque samples, lays the foundation for a non-invasive treatment of gum disease that people can apply to their gums at home to prevent or treat gum disease.
Gum disease (also known as periodontitis or periodontal disease) is the most common inflammatory disease, affecting nearly half of adults age 30 or older. It is characterized by three components: inflammation, an imbalance of healthy and unhealthy bacteria in the mouth, and the destruction of the bones and structures that support the teeth. Uncontrolled gum disease can lead to sore, bleeding gums, difficulty chewing, and tooth loss.
“There is no current treatment for gum disease that simultaneously reduces inflammation, limits disruption of the oral microbiome, and prevents bone loss. There is an urgent public health need for more targeted and effective treatments for this common disease,” said Yuki Guo, an associate research scientist. in the Department of Dental Molecular Biology at New York University and co-first author of the study.
Previous research has linked increased succinate – a molecule produced during metabolism – and gum disease, with higher sugar levels linked to higher levels of inflammation. Guo and her colleagues at New York University Dentistry also discovered in 2017 that high levels of succinate activate succinate receptors and stimulate bone loss. These findings make succinate receptors an attractive target for counteracting inflammation and bone loss — and possibly stopping gum disease in its tracks.
Strengthening the association between succinate and periodontal disease
The researchers began by examining plaque samples from humans and blood samples from mice. Using metabolic analyses, they found higher levels of succinate in people and mice with periodontal disease than in those with healthy gums, confirming previous studies.
They also saw that succinate receptors are expressed in human and mouse gums. To test the link between succinate receptors and components of periodontal disease, they genetically altered mice to disable, or “disable,” the succinate receptor.
In mice with periodontal disease, the researchers measured lower levels of inflammation in both gum tissue and blood, as well as less bone loss. They also found different bacteria in their mouths: mice with periodontal disease had a greater imbalance of bacteria than mice with periodontal disease.
This was true when the researchers administered more succinate to both types of mice, which exacerbated gum disease in normal mice. However, the “knockout” mice were protected from infections, an increase in unhealthy bacteria, and bone loss.
“Mice without active succinate receptors were more disease resistant,” said Fangxi Xu, an assistant researcher in the Department of Dental Molecular Pathology at New York University and co-first author of the study. “While we already knew there was some link between succinate and periodontal disease, we now have stronger evidence that hyperglycemia and succinate receptors are the main drivers of the disease.”
To see if blocking the succinate receptor can alleviate gum disease, researchers developed a gel formulation of a small compound that targets the succinate receptor and prevents its activation. In laboratory studies of human gum cells, the compound reduced inflammation and processes that lead to bone loss.
The compound was then applied as a topical gel to the gums of mice with periodontal disease, which reduced local and systemic inflammation and bone loss within days. In one test, researchers applied the gel to the gums of mice with periodontal disease every two days for four weeks, which cut bone loss in half compared to mice who didn’t get the gel.
The mice treated with the gel also had significant changes in the bacterial community in their mouths. It is worth noting that the bacteria present in germs The family–which includes pathogens known to be prevalent in periodontal disease–was depleted in those treated with the gel.
“We did additional tests to see if the same compound acts as an antibiotic, and we found that it doesn’t directly affect bacterial growth. This suggests that the gel changes the bacteria community by regulating inflammation,” said Deepak Saxena, a university professor. Molecular Dental Biology at New York University and co-author of the study.
Researchers continue to study the gel in animal models to find the appropriate dose and timing of application, as well as to determine any toxicity. Their long-term goal is to develop an oral gel and strip that can be used at home by people with or at risk of gum disease, as well as a stronger slow-release formula that dentists can apply to pockets that form in the gums during periodontal disease.
“Current treatments for severe gum disease can be invasive and painful. In the case of antibiotics, which may help temporarily, kill both good and bad bacteria, disrupting the oral microbiome. This new compound that blocks succinate receptors has clear therapeutic value,” said Shen Li, Professor New York University Dental Biologist and lead author of the study, Treating periodontal disease with more targeted and appropriate procedures.
Additional study authors include Scott Thomas, Yanli Zhang, Pedicha Paul, Songpil Chai, Patti Lee, Caleb Almeter and Angela Kamer of New York University Dentistry. Satish Sakilam and Paramjit Arora from New York University’s Department of Chemistry; and Dana Graves of the University of Pennsylvania School of Dentistry.
The research was supported by the National Institutes of Health (DE027074, DE028212, AG068857, and R01DE017732); The development of the oral gel and tape is funded by the National Dental and Craniofacial Research Institute (R41DE028212). Lee and Saxena are co-founders of Periomics Care, an early-stage biotechnology company within New York University dentistry.