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Gel Treats Gum Disease by Fighting Inflammation

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Targeted topical therapies promise treatment at home

A topical gel that blocks the receptor for a metabolic byproduct called succinate treats gum disease by suppressing inflammation and altering the makeup of bacteria in the mouth, according to a new study led by researchers at the NYU College of Dentistry and published in Cell Reports became.

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The research, conducted on mice and using human cells and plaque samples, lays the groundwork for a non-invasive gum disease treatment that people could apply to their gums at home to prevent or treat gum disease.

Gum disease (also known as periodontitis or periodontitis) is one of the most common inflammatory diseases, affecting nearly half of adults aged 30 and over. It is characterized by three components: inflammation, an imbalance between unhealthy and healthy bacteria in the mouth, and destruction of the bones and structures that support teeth. Uncontrolled gum disease can lead to painful and bleeding gums, difficulty chewing and tooth loss.

“No current treatment for gum disease 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 Yuqi Guo, an associate research scientist in the Department of Molecular Pathobiology at NYU Dentistry and co-first author of the study.

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Previous research has linked elevated succinate — a molecule produced during metabolism — to gum disease, with higher succinate levels being associated with higher degrees of inflammation. Guo and her colleagues at the NYU College of Dentistry also discovered in 2017 that elevated levels of succinate activate the succinate receptor and stimulate bone loss. These results made the succinate receptor an attractive target to counteract inflammation and bone loss — and potentially stop gum disease.

Strengthening the link between succinate and gum disease

Researchers began by examining plaque samples from humans and plasma samples from mice. Using metabolomics analysis, they found higher levels of succinate in humans and mice with gum disease compared to those with healthy gums, confirming the results of previous studies.

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They also saw that the succinate receptor was expressed in human and mouse gums. To test the link between the succinate receptor and components of gum disease, they genetically engineered mice to inactivate, or “turn off,” the succinate receptor.

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In “knockout” mice with gum disease, the researchers measured lower levels of inflammation in both gum tissue and blood, and less bone loss. They also found different bacteria in their mouths: mice with gum disease had a greater imbalance of bacteria than “knockout” mice.

This was true when researchers gave both types of mice supplemental succinate, which worsened gum disease in normal mice; However, “knockout” mice were protected from inflammation, an increase in unhealthy bacteria and bone loss.

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“Mice without active succinate receptors were more resistant to disease,” said Fangxi Xu, a research assistant in the Department of Molecular Pathobiology at NYU Dentistry and co-first author of the study. “While we already knew there was an association between succinate and gum disease, we now have stronger evidence that elevated succinate and succinate receptors are the primary drivers of the disease.”

A novel treatment

To see if blocking the succinate receptor could alleviate gum disease, the researchers developed a gel formulation of a small compound that targets the succinate receptor and prevents it from being activated. In laboratory studies on human gum cells, the compound reduced inflammation and processes that lead to bone loss.

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The compound was then applied as a topical gel to the gums of mice with gum disease, reducing local and systemic inflammation and bone loss within days. In one test, the researchers applied the gel to the gums of mice with gum disease every other day for four weeks, which cut bone loss in half compared to mice that didn’t receive the gel.

Mice treated with the gel also showed significant changes in the bacterial community in their mouth. In particular, bacteria from the Bacteroidetes family — which include pathogens known to be dominant in gum disease — were depleted in patients treated with the gel.

“We ran additional tests to see if the compound itself acts as an antibiotic and found that it didn’t directly affect the growth of bacteria. This suggests that the gel alters the bacterial community by regulating inflammation,” said Deepak Saxena, a professor at NYU Dentistry and a co-author of the study.

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Researchers are continuing to study the gel in animal models to determine the appropriate dosage and timing of application and to determine any toxicities. Their long-term goal is to develop a gel and oral strip that people with gum disease or at risk of gum disease can use at home, as well as a more potent, slow-release formulation that dentists can apply to pockets that form in the gums gum disease.

“Current treatments for severe gum disease can be invasive and painful. In the case of antibiotics, which can help temporarily, they kill both good and bad bacteria and disrupt the oral microbiome. This new compound, which blocks the succinate receptor, has clear therapeutic value in treating gum disease with more targeted and convenient procedures,” said Xin Li, professor at NYU Dentistry and lead author of the study.

Additional study authors include Scott Thomas, Yanli Zhang, Bidisha Paul, Sungpil Chae, Patty Li, Caleb Almeter, and Angela Kamer of NYU College of Dentistry; Satish Sakilam and Paramjit Arora from NYU’s Department of Chemistry; and Dana Graves of the University of Pennsylvania School of Dental Medicine.

The research was supported by the National Institutes of Health (DE027074, DE028212, AG068857 and R01DE017732); Development of the gel and oral strip is funded by the National Institute of Dental and Craniofacial Research (R41DE028212). Li and Saxena are the co-founders of Periomics Care, an early-stage biotechnology company within NYU Dentistry.

About the NYU College of Dentistry

Founded in 1865, New York University College of Dentistry (NYU Dentistry) is the third oldest and largest dental school in the United States, training nearly 10 percent of the nation’s dentists. NYU Dentistry has significant global reach with a very diverse student body. Visit dental.nyu.edu for more information.

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