And topical gel that blocks the receptor for a metabolic byproduct called succinate treats disease of the gums suppressing inflammation and changing the composition of bacteria in the mouth, according to a new study led by researchers at the NYU School of Dentistry and published in “Cell Reports.”
The research, carried out in mice with human cells and plaque samples, lays the groundwork for a treatment non-invasive of gum disease that people could apply at home to prevent or treat.
Gum disease, also known as periodontal disease, is one of the most common inflammatory diseases, affecting almost half of adults aged 30 and over.
It is characterized by three components: inflammation, a imbalance of bacteriaias healthy and unhealthy in the mouth, and the bone destruction and the structures that support the teeth.
“No current treatment for gum disease simultaneously reduces inflammation, limits disruption of the oral microbiome, and prevents bone loss. There is a urgent public health need of more specific and effective treatments for this common disease”, explains Yuqi Guo, co-first author of the study.
Previous research has linked increased levels of succinate – a molecule produced during metabolism – to gum disease, and higher levels of succinate are associated with higher levels of inflammation. Guo and colleagues at NYU Dentistry also discovered in 2017 that elevated levels of succinate activate the succinate receptor and stimulate bone loss. These findings made the succinate receptor an attractive target for counteracting inflammation and bone loss, and potentially stopping gum disease in its tracks.
The researchers began by examining dental plaque samples from humans and blood samples from mice. Using metabolomics analysis, they found that succinate levels were higher in people and mice with gum disease than in those with healthy gums, confirming earlier findings.
They also saw that the succinate receptor was expressed in the gums of humans and mice. To test the relationship between the succinate receptor and components of gum disease, they genetically altered mice to inactivate, or “delete,” the succinate receptor.
In the “knockout” mice with gum disease, the researchers measured lower levels of inflammation in both the gum tissue and blood, as well as less bone loss. They also found different bacteria in their mouths: The mice with gum disease had a greater imbalance of bacteria than the “knockout” mice.
This held true when the researchers gave additional succinate to both types of mice, which worsened the gum disease in the normal mice; however, the “knockout” mice were protected against inflammation, increased unhealthy bacteria, and bone loss.
“Mice without active succinate receptors were more resistant to disease,” says Fangxi Xu, co-first author of the study. “Although we already knew there was some connection between succinate and gum disease, we now have stronger evidence that elevated succinate and the succinate receptor are the main drivers of the disease.”
The gel reduced local and systemic inflammation and bone loss within days
To see if blocking the succinate receptor could improve 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 with 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 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 reduced your bone loss in half compared to mice that did not receive the gel.
The gel-treated mice also experienced significant changes in the community of bacteria in their mouths. Specifically, bacteria from the Bacteroidetes family – which includes pathogens known to be dominant in gum disease – were reduced in those treated with the gel.