Saliva and Plasma Reflect Metabolism Altered by Diabetes and Periodontitis

Abstract

Periodontitis is an inflammatory disorder caused by disintegration of the balance between the periodontal microbiome and host response. While growing evidence suggests links between periodontitis and various metabolic disorders including type 2 diabetes (T2D), non-alcoholic liver disease, and cardiovascular disease (CVD), which often coexist in individuals with abdominal obesity, factors linking periodontal inflammation to common metabolic alterations remain to be fully elucidated. More detailed characterization of metabolomic profiles associated with multiple oral and cardiometabolic traits may provide better understanding of the complexity of oral-systemic crosstalk and its underlying mechanism. We performed comprehensive profiling of plasma and salivary metabolomes using untargeted gas chromatography/mass spectrometry to investigate multivariate covariation with clinical markers of oral and systemic health in 31 T2D patients with metabolic comorbidities and 30 control subjects. Orthogonal partial least squares (OPLS) results enabled more accurate characterization of associations among 11 oral and 25 systemic clinical outcomes, and 143 salivary and 78 plasma metabolites. In particular, metabolites that reflect cardiometabolic changes were identified in both plasma and saliva, with plasma and salivary ratios of (mannose + allose):1,5-anhydroglucitol achieving areas under the curve of 0.99 and 0.92, respectively, for T2D diagnosis. Additionally, OPLS analysis of periodontal inflamed surface area (PISA) as the numerical response variable revealed shared and unique responses of metabolomic and clinical markers to PISA between healthy and T2D groups. When combined with linear regression models, we found a significant correlation between PISA and multiple metabolites in both groups, including threonate, cadaverine and hydrocinnamate in saliva, as well as lactate and pentadecanoic acid in plasma, of which plasma lactate showed a predominant trend in the healthy group. Unique metabolites associated with PISA in the T2D group included plasma phosphate and salivary malate, while those in the healthy group included plasma gluconate and salivary adenosine. Remarkably, higher PISA was correlated with altered hepatic lipid metabolism in both groups, including higher levels of triglycerides, aspartate aminotransferase and alanine aminotransferase, leading to increased risk of cardiometabolic disease based on a score summarizing levels of CVD-related biomarkers. These findings revealed the potential utility of saliva for evaluating the risk of metabolic disorders without need for a blood test, and provide evidence that disrupted liver lipid metabolism may underlie the link between periodontitis and cardiometabolic disease.

Metabolomics profiling reveals berberine-inhibited inflammatory response in human gingival fibroblasts by regulating the LPS-induced apoptosis signaling pathway

“…It is well known that PS-mediated apoptotic body recognition is an important phagocytic response ( Rodrigues et al, 2021 ). Macrophages are reprogrammed to secrete proinflammatory mediators, for instance, IL-10 and transforming growth factor-B ( Sakanaka et al, 2021 ). PS-containing liposomes have been used as a strategy to ultimately extinguish inflammation ( Yan et al, 2015 ).…”

Alterations and Correlations of Gut Microbiota and Fecal Metabolome Characteristics in Experimental Periodontitis Rats

“… Li et al (2020) suggest that gut microbial alterations caused by periodontitis can lead to systemic inflammation and metabolic dysfunction, which will accelerate the progression of T2DM. Sakanaka et al (2021) explored the potential link between periodontitis and cardiometabolic diseases by studying metabolites. Previous studies have pointed out that the use of metabolomics to study the relationship between periodontitis and obesity gets significantly more outputs than the pure oral microbiome ( Chen et al, 2021 ).…”

Salivary metabolic signatures of carotid atherosclerosis in patients with type 2 diabetes hospitalized for treatment

“…In addition, state-of-the-art metabolomics data related to the risk of type 2 diabetes and its complications, analyzed from a wide variety of biological samples (plasma, serum, and urine), have been published ( Sharma et al, 2013 ; Morze et al, 2022 ). Previously, we investigated the association of paired plasma and salivary metabolomic datasets from patients with T2D, and demonstrated the potential utility of salivary metabolites for evaluating systemic metabolic dysfunction ( Sakanaka et al, 2021 ). However, there remains a lack of metabolomic studies that sought to address the complexity of T2D-CVD crosstalk, such as how atherosclerotic burden can alter metabolic profiles in plasma and saliva in T2D patients.…”