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Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein‐coupled receptor, SUCNR1. Modulating succinate‐induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis‐induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host‐microbial community structure, with enrichment in succinate producers and consumers and mucin‐degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels. [ABSTRACT FROM AUTHOR]

The effect of electronic cigarette (e‐cigarette) smoking, especially its long‐term impact on oral health, is poorly understood. Here, we conducted a longitudinal clinical study with two study visits, 6 months apart, to investigate the effect of e‐cigarette use on the bacterial community structure in the saliva of 101 periodontitis patients. Our data demonstrated that e‐cigarette use altered the oral microbiome in periodontitis patients, enriching members of the Filifactor, Treponema, and Fusobacterium taxa. For patients at the same periodontal disease stage, cigarette smokers and e‐cigarette smokers shared more similarities in their oral bacterial composition. E‐cigarette smoking may have a similar potential as cigarette smoking at altering the bacterial composition of saliva over time, leading to an increase in the relative abundance of periodontal disease‐associated pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum. The correlation analysis showed that certain genera, such as Dialister, Selenomonas, and Leptotrichia in the e‐cigarette smoking group, were positively correlated with the levels of proinflammatory cytokines, including IFN‐γ, IL‐1β, and TNF‐α. E‐cigarette use was also associated with elevated levels of proinflammatory cytokines such as IFN‐γ and TNF‐α, which contribute to oral microbiome dysbiosis and advanced disease state. [ABSTRACT FROM AUTHOR]

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]