The new topical gel that blocks the receptor for a molecule called succinate treats periodontitis — also known as gum disease or periodontal disease — by suppressing inflammation and changing the makeup of bacteria in the mouth, according to new research.
Guo et al. reveal succinate’s effect on periodontitis pathogenesis and provides a topical treatment for this disease. Image credit: Guo et al., doi: 10.1016/j.celrep.2022.111389.
“No current treatment for gum disease simultaneously reduces inflammation, limits disruption to the oral microbiome, and prevents bone loss,” said Dr. Yuqi Guo, a researcher in the Department of Molecular Pathobiology at the New York University College of Dentistry.
“There is an urgent public health need for more targeted and effective treatments for this common disease.”
Past research has linked increased succinate to periodontitis, with higher succinate levels associated with higher levels of inflammation.
In 2017, Dr. Guo and her colleagues discovered that elevated levels of succinate activate the succinate receptor and stimulate bone loss. Their findings made the succinate receptor an appealing target for countering inflammation and bone loss — and potentially stopping periodontitis in its tracks.
The researchers started by examining dental plaque samples from humans and blood samples from mice.
Using metabolomic analyses, they found higher succinate levels in people and mice with periodontitis compared to those with healthy gums, confirming what previous studies have found.
They also saw that the succinate receptor was expressed in human and mouse gums.
To test the connection between the succinate receptor and the components of periodontitis, they genetically altered mice to ‘knockout’ (inactivate) the succinate receptor.
In knockout mice with periodontitis, the scientists 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: mice with periodontitis had a greater imbalance of bacteria than did ‘knockout’ mice.
This held true when the researchers administered extra succinate to both types of mice, which worsened periodontitis in normal mice; however, knockout mice were protected against inflammation, increases in unhealthy bacteria, and bone loss.
“Mice without active succinate receptors were more resilient to disease,” said Dr. Fangxi Xu, a researcher in the Department of Molecular Pathobiology at the New York University College of Dentistry.
“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.”
To see if blocking the succinate receptor could ameliorate periodontitis, the authors developed a gel formulation of a small compound that targets the succinate receptor and prevents it from being activated.
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 periodontitis, which reduced local and systemic inflammation and bone loss in a matter of days.
In one test, the team applied the gel to the gums of mice with periodontitis every other day for four weeks, which cut their bone loss in half compared to mice who did not receive the gel.
Mice treated with the gel also had significant changes to the community of bacteria in their mouths.
Notably, bacteria in the family Bacteroidetes — which include pathogens that are known to be dominant in periodontitis — were depleted in those treated with the gel.
“We conducted additional tests to see if the compound itself acted as an antibiotic, and found that it does not directly affect the growth of bacteria,” said Professor Deepak Saxena, a researcher in the Department of Molecular Pathobiology at the New York University College of Dentistry and the Department of Surgery at the New York University Grossman School of Medicine.
“This suggests that the gel changes the community of bacteria through regulating inflammation.”
The team’s findings are published in the journal Cell Reports.
Yuqi Guo et al. 2022. Targeting the succinate receptor effectively inhibits periodontitis. Cell Reports 40 (12): 111389; doi: 10.1016/j.celrep.2022.111389
Source : Breaking Science News