This novel compound, which inhibits the succinate receptor, has clear therapeutic benefit for the treatment of periodontal disease using more targeted and efficient methods.
According to a new study conducted by scientists at NYU College of Dentistry and published today in Cell Reports, a topical gel that blocks the receptor for a metabolic waste called succinate treats gum disease by lowering inflammation and modifying the composition of bacteria in the mouth.
The study, which was carried out in mice and used human cells and plaque samples, provides the framework for a non-invasive gum disease treatment that patients might apply to their gums at home to stop or treat gum disease.
Nearly half of people aged 30 and older have gum disease, commonly known as periodontitis or periodontal disease, which is one of the most common inflammatory disorders. It is characterised by three factors: inflammation, an imbalance of unhealthy and healthy bacteria in the mouth, and deterioration of the bones and structures supporting the teeth. Uncontrolled gum disease can result in tooth loss, painful and bleeding gums, and difficulties chewing.
There is currently no medication for gum disease that can stop bone loss, lessen damage to the oral microbiome, and simultaneously reduce inflammation.
“There is an urgent public health need for more targeted and effective treatments for this common disease,” says first co-author Yuqi Guo.
Previous studies have shown a correlation between elevated levels of the metabolic byproduct succinate and the inflammatory condition known as gum disease. In addition, in 2017, Guo and her colleagues at NYU Dentistry found that increased levels of succinate activate the succinate receptor and induce bone loss. These results suggest that the succinate receptor is a promising target for preventing bone loss and inflammation, as well as a potential treatment for gum disease.
Sucinate and gum disease relation
The researchers first looked at samples of dental plaque from people and blood from mice. Metabolomic research confirmed prior findings that people and mice with gum disease have increased succinate levels compared to those with healthy gums.
Additionally, they observed that both mouse and human gums expressed the succinate receptor. They genetically modified mice to “knock out” or inactivate the succinate receptor in order to investigate the relationship between the succinate receptor and the components of gum disease.
Researchers observed reduced bone loss and lower levels of inflammation in the blood and gum tissue of “knockout” mice with gum disease. Additionally, they discovered various bacteria in their mouths: “knockout” mice had a higher imbalance of bacteria than mice with gum disease.
This was true even when the researchers gave both types of mice extra succinate, which made gum disease worse in normal mice but protected “knockout” mice from inflammation, growth of bad bacteria, and bone loss.
“Mice without active succinate receptors were more resilient to disease,” adds co-first author Fangxi Xu. “While we already knew that there was some connection between succinate and gum disease, we now have stronger evidence that elevated succinate and the succinate receptor are major drivers of the disease.”
A new approach
To determine whether inhibiting the succinate receptor could improve gum disease, the researchers designed a gel formulation of a tiny chemical that inhibits the activation of the succinate receptor. In lab tests with human gum cells, the compound reduced inflammation and slowed down the processes that cause bone loss.
The substance was then given topically as a gel to the gums of mice with periodontal disease, resulting in a rapid reduction in local and systemic inflammation and bone loss. In one experiment, the gums of mice with gum disease were treated with the gel every other day for four weeks; this reduced the animals’s bone loss by 50% compared to the mice who did not get the gel.
The microbial ecology in the mouths of mice treated with the gel was also significantly altered. Notably, those who received the gel had lower levels of bacteria from of the family Bacteroidetes, which includes pathogens that are known to be common in gum disease.
“We conducted additional tests to see if the compound itself acted as an antibiotic,” adds co-senior author Deepak Saxena, “and found that it does not directly affect the growth of bacteria. This suggests that the gel changes the community of bacteria through regulating inflammation.”
Researchers are still testing the gel on animal models to figure out the right amount to use and when, as well as to see if it is harmful. Their long-term objective is to produce a gel and oral strip that patients with or at risk for gum disease can use at home, as well as a stronger, slow-release formulation that dentists can apply to pockets that form in gum disease.
“Current treatments for severe gum disease can be invasive and painful,” according to lead author Xin Li.
“In the case of antibiotics, which may help temporarily,” add the lead author, “they kill both good and bad bacteria, disrupting the oral microbiome.”
“This new compound that blocks the succinate receptor,” the author concludes, “has clear therapeutic value for treating gum disease using more targeted and convenient processes.”
Source: 10.1016/j.celrep.2022.111389
Image Credit: Getty
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