For the first time, researchers have uncovered how Gram-positive bacteria can result in alveolar bone resorption, severe inflammation, and tooth loss, paving the way for the development of better medications to treat gum disease.
If you think that your mouth is clean, think again. As one of the largest microbiomes of the human body, only second to the gastrointestinal tract, our mouths harbour over six billion bacteria, including 700 different species, as well as other types of microorganisms like fungi, mycoplasma, protozoa, and even viruses. Amongst these various microorganisms, some helpful types of bacteria can help to break down food and contribute to healthy teeth and gums, among other responsibilities. But there are also harmful ones that can lead to various diseases and oral infections.
In the specific case of gum disease, it is well-established that the bacteria associated with periodontitis, a serious gum infection that damages the soft tissue and bone supporting the teeth, are predominantly Gram-negative anaerobic bacteria, like Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia. However, in a recent study by researchers at Tokyo University of Agriculture and Technology, they have discovered for the first time that Gram-positive bacteria are also capable of causing periodontitis.
“This finding is a new concept: both Gram-positive and -negative bacteria are involved in the progression of periodontal bone loss,” explained lead author Masaki Inada, Associate Professor in the Department of Biotechnology and Life Science at the Tokyo University of Agriculture and Technology. “In a healthy condition, the tooth root is embedded into a socket in the alveolar bone in periodontal tissue. Infection of mixed multiple Gram-negative bacteria resulted in alveolar bone resorption and tooth loss induced by severe inflammation in periodontal tissues. It is well-known that the major pathogens of periodontitis are dominantly Gram-negative bacteria. It was unclear whether Gram-positive bacteria are associated with or contribute to the progression of periodontal bone loss.”
Previously, the researchers have tried to analyse the development of periodontitis by injecting lipopolysaccharide from Gram-negative bacteria into mice that were engineered without the gene that produces prostaglandin E2, a molecule that gathers at sites of damaged tissues. Their experiment showed that the absence of prostaglandin E2 caused the failure of the injected lipopolysaccharide to induce bone loss, thus indicating the critical role of prostaglandin E2 in the progress of periodontitis.
“[Lipopolysaccharide] is considered to be a dominant pathogen causing inflammatory bone resorption in periodontitis,” Inada said. “On the other hand, Gram-positive bacteria have been known to contribute to the inflammation of the periodontal gums in the initial phases of periodontitis; however, there was little evidence to show that these pathogens contribute to the induction of inflammatory bone resorption in the late phase of periodontitis.”
Because of this gap, the team is keen to investigate the difference between how Gram-positive and Gram-negative contribute to periodontitis. They also hoped to identify the point at which cell death, caused by the infection, outpaces the body’s effort to create new bone cells since this is an important question to “clarify the cross-talk of Gram-positive and -negative bacteria for the pathogenesis and progression of periodontal bone loss,” as explained by Inada.
In the current study, they examined the effects of lipoteichoic acid, a major cell-wall factor of Gram-positive bacteria, on the progression of inflammatory alveolar bone loss using models of periodontitis. Using ex vivo organ cultures of mouse alveolar bone, the team analysed osteoclast differentiation and bone-resorbing activity. Their findings revealed that lipoteichoic acid induced alveolar resorption, triggered the production of prostaglandin E2 in osteoblasts, and acted on osteoclasts to prolong cell survival. They were also able to confirm that lipoteichoic acid induced alveolar bone loss in an in vivo model of periodontitis.
When the team compared the mechanisms by which Gram-positive and Gram-negative bacteria contribute to periodontitis, they emphasised several key observations. When Gram-negative lipopolysaccharides were injected into mice that lacked prostaglandin E2, the balance stayed in favour of bone formation. However, when the researchers introduced Gram-positive lipoteichoic acid, the balanced tipped to bone resorption. They also saw that the Gram-positive bacteria proliferated at a higher rate than Gram-negative bacteria and preferred to occupy the depths of teeth pockets.
Given the severe effects of periodontitis, the researchers explored possible medications that could suppress infections caused by Gram-positive bacteria. They discovered that indomethacin, a medication often used to relieve pain, tenderness, and swelling caused by various forms of arthritis, could inhibit the production of prostaglandin E2. Moreover, the drug could also effectively suppress alveolar bone resorption induced by lipoteichoic acid. By uncovering new knowledge regarding the roles of lipoteichoic acid, its receptors, signalling, and inflammatory cascades, it is hoped that more of such drugs can be developed to provide targeted treatment for periodontal bone loss.
Source: Tominari et al. (2021). Gram-positive bacteria cell wall-derived lipoteichoic acid induces inflammatory alveolar bone loss through prostaglandin E production in osteoblasts. Scientific Reports, 11, 13353.