Saliva and Plasma Reflect Metabolism Altered by Diabetes and Periodontitis

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.Sakanaka A., Kuboniwa M., Katakami N., et al. Saliva and Plasma Reflect Metabolism Altered by Diabetes and Periodontitis. Frontiers in Molecular Biosciences, 8, , 742002. https://doi.org/https://doi.org/10.3389/fmolb.2021.742002

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

Atherosclerosis is a life-threatening disease associated with morbidity and mortality in patients with type 2 diabetes (T2D). This study aimed to characterize a salivary signature of atherosclerosis based on evaluation of carotid intima-media thickness (IMT) to develop a non-invasive predictive tool for diagnosis and disease follow-up. Metabolites in saliva and plasma samples collected at admission and after treatment from 25 T2D patients hospitalized for 2 weeks to undergo medical treatment for diabetes were comprehensively profiled using metabolomic profiling with gas chromatography-mass spectrometry. Orthogonal partial least squares analysis, used to explore the relationships of IMT with clinical markers and plasma and salivary metabolites, showed that the top predictors for IMT included salivary allantoin and 1,5-anhydroglucitol (1,5-AG) at both the baseline examination at admission and after treatment. Furthermore, though treatment induced alterations in salivary levels of allantoin and 1,5-AG, it did not modify the association between IMT and these metabolites (pinteraction > 0.05), and models with these metabolites combined yielded satisfactory diagnostic accuracy for the high IMT group even after treatment (area under curve = 0.819). Collectively, this salivary metabolite combination may be useful for non-invasive identification of T2D patients with a higher atherosclerotic burden in clinical settings.Sakanaka A, Katakami N, Furuno M, Nishizawa H, Omori K, Taya N, Ishikawa A, Mayumi S, Inoue M, Tanaka Isomura E, Amano A, Shimomura I, Fukusaki E and Kuboniwa M (2022) Salivary metabolic signatures of carotid atherosclerosis in patients with type 2 diabetes hospitalized for treatment. Front. Mol. Biosci. 9:1074285. doi: 10.3389/fmolb.2022.107428

Functional dissection of polymicrobial synergy between Porphyromonas gingivalis and Streptococcus gordonii

Whole proteome proteomics data for P. gingivalis in the presence or absence of 4 aminobenzoate/para-amino benzoic acid (pABA)Many human infections are polymicrobial in origin, and synergistic interactions among community inhabitants control colonization and pathogenic potential (Murray et al., 2014). However, few interspecies interactions have been functionally dissected at the molecular level or characterized on a systems level. Periodontitis, which is the sixth most prevalent infectious disease worldwide (Kassebaum et al., 2014), is associated with a dysbiotic microbial community, and the keystone pathogen Porphyromonas gingivalis forms synergistic communities with the accessory pathogen Streptococcus gordonii (Lamont and Hajishengallis, 2015). P. gingivalis and S. gordonii communicate through co-adhesion and metabolite perception, and close association between P. gingivalis and S. gordonii results in significant changes in the expressed proteomes of both organisms (Kuboniwa et al., 2012, Hendrickson et al., 2012). Here we show that streptococcal 4 aminobenzoate/para-amino benzoic acid (pABA) is required for maximal accumulation of P. gingivalis in communities with S. gordonii. Exogenous pABA upregulates production of fimbrial interspecies adhesins and of a tyrosine phosphorylation-dependent signaling system in P. gingivalis. Consequently, fimbrial-dependent attachment and invasion of epithelial cells by P. gingivalis is also increased by pABA. Moreover, trans-omics studies performed by proteomics and metabolomics showed that pABA induces metabolic shifts within P. gingivalis, predominantly folate derivative biosynthesis. In a murine oral infection model, pABA increased colonization and survival of P. gingivalis, but did not increase virulence. The results establish streptococcal pABA as a major component of the interspecies S. gordonii-P. gingivalis interaction which regulates distinct aspects of polymicrobial synergy