Dietary Polyphenols and Periodontitis—A Mini-Review of Literature

Periodontitis, which is a chronic infection and disease of the periodontium, is a significant global health burden and is linked to other chronic health conditions such as diabetes and cardiovascular diseases. Dietary polyphenols present in a wide variety of plant-based foods, herbs, and botanicals have been shown to exert antimicrobial, anti-inflammatory, and reduced osteoclast and alveolar bone loss activities in animal models of periodontitis. Polyphenol-containing beverages and foods especially green tea and its active catechin epigallocatechin-3-gallate, cranberries, pomegranates, and fruit and vegetable extracts have reported bacteriostatic/bactericidal activity against microbial species such as P. gingivalis and shown total bacterial burden in clinical studies. These polyphenols also exhibit anti-inflammatory and antioxidant effects, which have the potential to impact various biological mechanisms for reducing the initiation and progression of periodontitis. The main objective of this mini-review is to focus on the mechanisms of action of dietary polyphenols in improving the pathophysiology underlying chronic inflammatory diseases like periodontitis based on pre-clinical and clinical models

Oral Microbiome and Gingival Gene Expression of Inflammatory Biomolecules with Aging and Periodontitis

Although data describe the presence and increase of inflammatory mediators in the local environment in periodontitis vs. health in humans, details regarding how these responses evolve in the transition from health to disease, changes during disease progression, and features of a resolved lesion remain unknown. This study used a nonhuman primate model of ligature-induced periodontitis in young, adolescent, adult, and aged animals to document features of inflammatory response affected by age. Rhesus monkeys had ligatures tied and provided gingival tissue biopsy specimens at baseline, 0.5, 1, and 3 months of disease and at 5 months of the study, which was 2 months post-ligature removal for clinically resolved tissues. The transcriptome was assessed using microarrays for chemokine (n = 41), cytokine (n = 45), chemokine receptor (n = 21), cytokine receptor (n = 37), and lipid mediator (n = 31) genes. Limited differences were noted in healthy tissues for chemokine expression with age; however, chemokine receptor genes were decreased in young but elevated in aged samples. IL1A, IL36A, and IL36G cytokines were decreased in the younger groups, with IL36A elevated in aged animals. IL10RA/IL10RB cytokine receptors were altered with age. Striking variation in the lipid mediator genes in health was observed with nearly 60% of these genes altered with age. A specific repertoire of chemokine and chemokine receptor genes was affected by the disease process, predominated by changes during disease initiation. Cytokine/cytokine receptor genes were also elevated with disease initiation, albeit IL36B, IL36G, and IL36RN were all significantly decreased throughout disease and resolution. Significant changes were observed in similar lipid mediator genes with disease and resolution across the age groups. Examination of the microbiome links to the inflammatory genes demonstrated that specific microbes, including Fusobacterium, P. gingivalis, F. alocis, Pasteurellaceae, and Prevotella are most frequently significantly correlated. These correlations were generally positive in older animals and negative in younger specimens. Gene expression and microbiome patterns from baseline were distinctly different from disease and resolution. These results demonstrate patterns of inflammatory gene expression throughout the phases of the induction of a periodontal disease lesion. The patterns show a very different relationship to specific members of the oral microbiome in younger compared with older animals

Gingival Transcriptome of Innate Antimicrobial Factors and the Oral Microbiome with Aging and Periodontitis

The epithelial barrier at mucosal sites comprises an important mechanical protective feature of innate immunity, and is intimately involved in communicating signals of infection/tissue damage to inflammatory and immune cells in these local environments. A wide array of antimicrobial factors (AMF) exist at mucosal sites and in secretions that contribute to this innate immunity. A non-human primate model of ligature-induced periodontitis was used to explore characteristics of the antimicrobial factor transcriptome (n = 114 genes) of gingival biopsies in health, initiation and progression of periodontal lesions, and in samples with clinical resolution. Age effects and relationship of AMF to the dominant members of the oral microbiome were also evaluated. AMF could be stratified into 4 groups with high (n = 22), intermediate (n = 29), low (n = 18) and very low (n = 45) expression in healthy adult tissues. A subset of AMF were altered in healthy young, adolescent and aged samples compared with adults (e.g., APP, CCL28, DEFB113, DEFB126, FLG2, PRH1) and were affected across multiple age groups. With disease, a greater number of the AMF genes were affected in the adult and aged samples with skewing toward decreased expression, for example WDC12, PGLYRP3, FLG2, DEFB128, and DEF4A/B, with multiple age groups. Few of the AMF genes showed a \u3e2-fold increase with disease in any age group. Selected AMF exhibited significant positive correlations across the array of AMF that varied in health and disease. In contrast, a rather limited number of the AMF significantly correlated with members of the microbiome; most prominent in healthy samples. These correlated microbes were different in younger and older samples and differed in health, disease and resolution samples. The findings supported effects of age on the expression of AMF genes in healthy gingival tissues showing a relationship to members of the oral microbiome. Furthermore, a dynamic expression of AMF genes was related to the disease process and showed similarities across the age groups, except for low/very low expressed genes that were unaffected in young samples. Targeted assessment of AMF members from this large array may provide insight into differences in disease risk and biomolecules that provide some discernment of early transition to disease

Oral Microbial Biofilm Stimulation of Epithelial Cell Responses

Oral bacterial biofilms trigger chronic inflammatory responses in the host that can result in the tissue destructive events of periodontitis. However, the characteristics of the capacity of specific host cell types to respond to these biofilms remain ill-defined. This report describes the use of a novel model of bacterial biofilms to stimulate oral epithelial cells and profile select cytokines and chemokines that contribute to the local inflammatory environment in the periodontium. Monoinfection biofilms were developed with Streptococcus sanguinis, Streptococcus oralis, Streptococcus gordonii, Actinomyces naeslundii, Fusobacterium nucleatum, and Porphyromonas gingivalis on rigid gas-permeable contact lenses. Biofilms, as well as planktonic cultures of these same bacterial species, were incubated under anaerobic conditions with a human oral epithelial cell line, OKF4, for up to 24 h. Gro-1α, IL1α, IL-6, IL-8, TGFα, Fractalkine, MIP-1α, and IP-10 were shown to be produced in response to a range of the planktonic or biofilm forms of these species. P. gingivalis biofilms significantly inhibited the production of all of these cytokines and chemokines, except MIP-1α. Generally, the biofilms of all species inhibited Gro-1α, TGFα, and Fractalkine production, while F. nucleatum biofilms stimulated significant increases in IL-1α, IL-6, IL-8, and IP-10. A. naeslundii biofilms induced elevated levels of IL-6, IL-8 and IP-10. The oral streptococcal species in biofilms or planktonic forms were poor stimulants for any of these mediators from the epithelial cells. The results of these studies demonstrate that oral bacteria in biofilms elicit a substantially different profile of responses compared to planktonic bacteria of the same species. Moreover, certain oral species are highly stimulatory when in biofilms and interact with host cell receptors to trigger pathways of responses that appear quite divergent from individual bacteria

Integrated Biomarker Profiling of Smokers with Periodontitis

Background In the context of precision medicine, understanding patient‐specific variation is an important step in developing targeted and patient‐tailored treatment regimens for periodontitis. While several studies have successfully demonstrated the usefulness of molecular expression profiling in conjunction with single classifier systems in discerning distinct disease groups, the majority of these studies do not provide sufficient insights into potential variations within the disease groups. Aim The goal of this study was to discern biological response profiles of periodontitis and non‐periodontitis smoking subjects using an informed panel of biomarkers across multiple scales (salivary, oral microbiome, pathogens and other markers). Material & Methods The investigation uses a novel ensemble classification approach (SVA‐SVM) to differentiate disease groups and patient‐specific biological variation of systemic inflammatory mediators and IgG antibody to oral commensal and pathogenic bacteria within the groups. Results Sensitivity of SVA‐SVM is shown to be considerably higher than several traditional independent classifier systems. Patient‐specific networks generated from SVA‐SVM are also shown to reveal crosstalk between biomarkers in discerning the disease groups. High‐confidence classifiers in these network abstractions comprised of host responses to microbial infection elucidated their critical role in discerning the disease groups. Conclusions Host adaptive immune responses to the oral colonization/infection contribute significantly to creating the profiles specific for periodontitis patients with potential to assist in defining patient‐specific risk profiles and tailored interventions

Gingival transcriptomic patterns of macrophage polarization during initiation, progression, and resolution of periodontitis.

Phenotypic and functional heterogeneity of macrophages is clearly a critical component of their effective functions in innate and adaptive immunity. This investigation hypothesized that altered profiles of gene expression in gingival tissues in health, disease, and resolution would reflect changes in macrophage phenotypes occurring in these tissues. The study used a nonhuman primate model to evaluate gene expression profiles as footprints of macrophage variation using a longitudinal experimental model of ligature-induced periodontitis in animals from 3 to 23 years of age to identify aging effects on the gingival environment. Significant differences were observed in distribution of expressed gene levels for M0, M1, and M2 macrophages in healthy tissues with the younger animals showing the least expression. M0 gene expression increased with disease in all but the aged group, while M1 was increased in adult and young animals, and M2 in all age groups, as early as disease initiation (within 0.5 months). Numerous histocompatibility genes were increased with disease, except in the aged samples. An array of cytokines/chemokines representing both M1 and M2 cells were increased with disease showing substantial increases with disease initiation (e.g. IL1A, CXCL8, CCL19, CCL2, CCL18), although the aged tissues showed a more limited magnitude of change across these macrophage genes. The analytics of macrophage genes at sites of gingival health, disease, and resolution demonstrated distinct profiles of host response interactions that may help model the disease mechanisms occurring with the formation of a periodontal lesion

Dietary Strawberries Improve Biomarkers of Antioxidant Status and Endothelial Function in Adults With Cardiometabolic Risks in a Randomized Controlled Crossover Trial

Strawberries, a popularly consumed berry fruit, are rich in bioactive compounds with antioxidant effects. In this study, we examined the effects of two dietary achievable doses of strawberries on the antioxidant status and biomarkers of endothelial function in adults with features of metabolic syndrome and a confirmed low baseline of fruit and vegetable intake. In a 14-week randomized controlled crossover study, participants were assigned to one of three groups for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or 2.5 servings (high dose: 32 g strawberry powder/day). Blood samples and health data were collected at baseline and at the end of each four-week phase of intervention. Thirty-three participants completed all three phases of the trial. Significant increases were observed in serum antioxidant capacity and superoxide dismutase activity as well as decreases in lipid peroxidation after both low and high dose strawberry phases when compared with the control phase. Significant decreases were also observed in soluble vascular cell adhesion molecule-1 and tumor necrosis factor-α with the high dose strawberry phase. These data confirm that consuming strawberries for four weeks significantly improves antioxidant status, endothelial function, and inflammation in adults with cardiometabolic risks

Cross-Talk Between Clinical and Host-Response Parameters of Periodontitis in Smokers

Background and Objective Periodontal diseases are a major public health concern leading to tooth loss and have also been shown to be associated with several chronic systemic diseases. Smoking is a major risk factor for the development of numerous systemic diseases, as well as periodontitis. While it is clear that smokers have a significantly enhanced risk for developing periodontitis leading to tooth loss, the population varies regarding susceptibility to disease associated with smoking. This investigation focused on identifying differences in four broad sets of variables, consisting of: (i) host‐response molecules; (ii) periodontal clinical parameters; (iii) antibody responses to periodontal pathogens and oral commensal bacteria; and (iv) other variables of interest, in a population of smokers with (n = 171) and without (n = 117) periodontitis. Material and Methods Bayesian network structured learning (BNSL) techniques were used to investigate potential associations and cross‐talk between the four broad sets of variables. Results BNSL revealed two broad communities with markedly different topology between the populations of smokers, with and without periodontitis. Confidence of the edges in the resulting network also showed marked variations within and between the periodontitis and nonperiodontitis groups. Conclusion The results presented validated known associations and discovered new ones with minimal precedence that may warrant further investigation and novel hypothesis generation. Cross‐talk between the clinical variables and antibody profiles of bacteria were especially pronounced in the case of periodontitis and were mediated by the antibody response profile to Porphyromonas gingivalis

Associations of Diet with Cardiometabolic and Inflammatory Profiles in Pregnant Women at Risk for Metabolic Complications

Dietary intakes play an important role in the development of metabolic complications during pregnancy. While reported observational studies reveal an inverse association of healthy diets with weight gain, gestational diabetes, and hypertensive complications during pregnancy, there is a paucity of studies conducted among women of specific ethnicities vulnerable to higher risks of pregnancy complications. This is a secondary cross sectional analysis using baseline data from a previously reported clinical trial. We aim to identify associations of maternal habitual dietary intakes with cardiometabolic risks and inflammatory profiles in primarily African American (AA) and Hispanic women in the first half of pregnancy. Fifty-two women met the study criteria and anthropometric, clinical, and dietary data were obtained at baseline. Linear regression analysis was used to determine associations after covariate adjustments. Among the maternal dietary nutrient intakes, total fats were positively associated with maternal body weight, BMI, and serum CRP (β ± SE: 0.25 ± 0.13, 0.28 ± 0.18, and 0.29 ± 0.14, respectively, all p \u3c 0.05), and saturated fats were positively associated with glycated hemoglobin (0.32 ± 0.12). Dietary fiber intake showed a consistent inverse association with body weight (−0.26 ± 0.13), BMI (−0.19 ± 0.15), glycated hemoglobin (−0.22 ± 0.16), as well as serum CRP (−0.19 ± 0.14). Among the maternal food group intakes, dairy intake was inversely associated with systolic blood pressure (−0.18 ± 0.15) and serum IL-6 (−0.22 ± 0.17), and vegetable intake showed an inverse association with serum CRP (−0.17 ± 0.12) all in adjusted analyses (all p \u3c 0.05). Thus, maternal diet modifications, especially decreasing fats and increasing fiber and dairy may help address obesity and inflammation leading to pregnancy complications in AA and Hispanic women

Transcriptomic Phases of Periodontitis Lesions Using the Nonhuman Primate Model

We used a nonhuman primate model of ligature-induced periodontitis to identify patterns of gingival transcriptomic after changes demarcating phases of periodontitis lesions (initiation, progression, resolution). A total of 18 adult Macaca mulatta (12–22 years) had ligatures placed (premolar, 1st molar teeth) in all 4 quadrants. Gingival tissue samples were obtained (baseline, 2 weeks, 1 and 3 months during periodontitis and at 5 months resolution). Gene expression was analyzed by microarray [Rhesus Gene 1.0 ST Array (Affymetrix)]. Compared to baseline, a large array of genes were significantly altered at initiation (n = 6049), early progression (n = 4893), and late progression (n = 5078) of disease, with the preponderance being up-regulated. Additionally, 1918 genes were altered in expression with disease resolution, skewed towards down-regulation. Assessment of the genes demonstrated specific profiles of epithelial, bone/connective tissue, apoptosis/autophagy, metabolism, regulatory, immune, and inflammatory responses that were related to health, stages of disease, and tissues with resolved lesions. Unique transcriptomic profiles occured during the kinetics of the periodontitis lesion exacerbation and remission. We delineated phase specific gene expression profiles of the disease lesion. Detection of these gene products in gingival crevicular fluid samples from human disease may contribute to a better understanding of the biological dynamics of the disease to improve patient management