Succinate: Unveiling its role in periodontal disease and therapeutic implications

One of my least fond memories of dental hygiene school was the Kreb’s cycle, also known as the TCA cycle (tricarboxylic acid cycle) or citric acid cycle. Those memories have thankfully dimmed in over 30-plus years; however, a little sparkle was shining to create this article. Also while in hygiene school, an association between an increase in succinate in gingival crevicular fluid and periodontitis was emerging, which I don't believe was covered.¹

Succinate and inflammation

Succinate is a short-chain fatty acid (SCFA) that, in general, is produced during the TCA cycle (Krebs cycle) through the oxidation of succinyl-CoA. For this discussion, succinyl-CoA is of no matter, but succinate is a key intermediate metabolite in the Krebs cycle, and as a circulating metabolite, the relationship between abnormal changes in the physiological concentration of succinate and inflammatory diseases caused by the overreaction of certain immune cells has become the focus of recent research.

Succinate accumulates in macrophages during inflammation, serving as a signal to activate pro-inflammatory gene expression.² The underlying mechanisms of periodontal disease involve complex interactions between the host immune response, microbial flora, and metabolic factors. Succinate has emerged as a molecule of interest due to its involvement in both cellular metabolism and immune regulation that creates potential therapeutic strategies for managing and preventing periodontal disease.³

Succinate and its relationship to oral health

The role of succinate in periodontal disease is complex, but in simple terms, succinate is a chemical compound that plays a crucial role in the process by which cells generate energy. It is part of a series of chemical reactions that occur in the mitochondria of cells. Succinate is a key player in helping convert nutrients from food into a form of energy that cells can use.

Additionally, recent research has identified succinate as having signaling functions that influence various physiological processes in the body.⁴ Overall, succinate is a vital molecule involved in both energy production and cellular communication. Succinate first accumulates in mitochondria. Accumulation occurs when there is an imbalance between energy demand and oxygen supply. Succinate is eventually released into the extracellular environment where it activates the SUCNR1 receptor on the target cells, stimulating inflammation.

Saliva samples were analyzed by nuclear magnetic resonance (NMR) metabolomics. The profiles of patients with generalized chronic periodontitis had higher concentrations of succinate, compared with controls.⁵ Succinate promotes dysbiosis, inflammation, and bone loss through the SUCNR1 receptors.³ There is a positive correlation between succinate and periodontal disease-associated bacteria such as Bacteroidetes, Porphyromonas gingivalis (Pg), Treponema denticola (Td), and Fusobacterium nucleatum (Fn).³ Even a red-complex pathogen like Td benefits from succinate, unfortunately from production as a metabolic by-product of Pg.⁶

Bacterial production of succinate can increase virulence gene expression, proposing that an elevation may initiate a shift toward pathogenic existence of microbiota. Succinate and butyrate correlate with clinical measures of inflammation and disease severity.^7-9 With respect to bone health, stimulation of osteoclast formation by succinate was found in the research by Guo et al.¹⁰ Pathogens not considered periodontal—e.g., Rothia, Streptococcus, Neisseria, Haemophilus, Actinomyces, and Lautropia—proved an inverse relationship.³

Succinate and systemic disease

Accumulation of succinate and activation of SUCNR1 is associated with a multitude of diseases such as rheumatoid arthritis, diabetic retinopathy, hypertension, and obesity.^11-15 Research suggests that succinate may have implications in the development and progression of diabetes, and some studies have investigated its role in insulin resistance and glucose homeostasis. However, the relationship between succinate and diabetes is multifaceted; the exact mechanisms are not fully understood.¹⁶ If succinate increases inflammation and the immune response, it would make sense because both play a role in the development of diabetes.

The intestinal succinate level and SUCNR1 expression in patients with inflammatory bowel disease (IBD) are higher than those in healthy individuals.^17,18 Dysregulation of this signaling pathway could potentially contribute to the pathogenesis of IBD. Li et al. reported that succinate GPR91 (SUCNR1) signaling is involved in the regulation of the immune responses in the gut.¹⁹

Succinate and periodontal disease

Inflammation: Succinate has been recognized as a signaling molecule that can modulate immune responses. In the context of periodontal disease, the interaction between succinate and its receptors, such as GPR91 (SUCNR1), may contribute to the activation and regulation of immune cells in the gingival tissues. Excessive or dysregulated immune responses can lead to chronic inflammation, which is a characteristic of periodontal diseases.

Tissue damage: If chronic inflammation in the periodontal tissues is not properly regulated, it can contribute to tissue destruction. Succinate’s involvement in immune activation may play a role in the breakdown of connective tissues and bone supporting the teeth, which is a hallmark of the advanced stages of periodontal disease.

Metabolic dysregulation: Changes in metabolic processes within the periodontal tissues can impact the progression of periodontal disease. Alterations in the TCA cycle, where succinate is a key player, may influence the metabolic environment in a way that exacerbates inflammation and compromises tissue health.

Studies suggest that metabolic changes within the periodontal tissues may contribute to the progression of periodontal disease. The TCA cycle, where succinate plays a central role, is intricately connected to cellular metabolism. Dysregulation of this cycle, including altered succinate levels, has been implicated in inflammatory responses and tissue damage associated with periodontal disease.

Immune modulation: Imbalances in immune responses can contribute to chronic inflammation and tissue destruction characteristic of periodontal disease. Understanding the role of succinate in periodontal disease opens new avenues for potential therapeutic interventions. Targeting metabolic and immune pathways influenced by succinate may offer innovative strategies for managing and preventing the progression of periodontal disease.

Anti-inflammatory approaches: Given the link between succinate and immune regulation, therapeutic interventions that target inflammation may prove beneficial in managing periodontal disease. Drugs or interventions that modulate the succinate-GPR91 axis could potentially mitigate the inflammatory response within the gingival tissues.

New York University is currently studying succinate and working on a topical gel to be used as an antagonist of SUCNR1. The beauty is that it is a noninvasive tool to help reduce inflammation, prevent bone loss, and limit disruption to the microbiome.

Editor's note: This article appeared in the March 2024 print edition of RDH magazine. Dental hygienists in North America are eligible for a complimentary print subscription. Sign up here.

References

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Anne O. Rice, BS, RDH, CDP, FAAOSH, founded Oral Systemic Seminars after almost 30 years of clinical practice and is passionate about educating the community on modifiable risk factors for dementia and their relationship to dentistry. Anne is a certified dementia practitioner, a longevity specialist, a fellow with AAOSH, and has consulted for Weill Cornell Alzheimer’s Prevention Clinic, FAU, and Atria Institute. Reach out to Anne at anneorice.com.