Targeting the succinate receptor effectively inhibits periodontitis.

Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone loss. Here, we report an abnormal elevation of succinate in the subgingival plaque of subjects with severe PD. Succinate activates succinate receptor-1 (SUCNR1) and stimulates inflammation. We detected SUCNR1 expression in the human and mouse periodontium and hypothesize that succinate activates SUCNR1 to accelerate periodontitis through the inflammatory response. Administration of exogenous succinate enhanced periodontal disease, whereas SUCNR1 knockout mice were protected from inflammation, oral dysbiosis, and subsequent periodontal bone loss in two different models of periodontitis. Therapeutic studies demonstrated that a SUCNR1 antagonist inhibited inflammatory events and osteoclastogenesis in vitro and reduced periodontal bone loss in vivo. Our study reveals succinate's effect on periodontitis pathogenesis and provides a topical treatment for this disease. [Display omitted] • Elevation of succinate accelerates periodontitis progression • Succinate promotes dysbiosis, inflammation, and bone loss through SUCNR1 • An antagonist is developed to suppress activation of SUCNR1 • Topical application of the SUCNR1 antagonist impedes manifestation of periodontitis Periodontitis is the most prevalent adult oral disease. Guo et al. show elevation of succinate in periodontitis, which aggravates the disease through the succinate receptor (SUCNR1). They developed a gel formulation of a small compound specifically blocking SUCNR1 to prevent and treat periodontitis by inhibiting dysbiosis, inflammation, and bone loss. [ABSTRACT FROM AUTHOR]