[Teeth and oral cavity at the heart of systemic health]. / Les dents et le milieu buccal au cœur de la santé globale.

Research into the interrelationships between oral and systemic diseases has been growing exponentially for over 20 years. Teeth and their supporting tissues can be affected by pathologies, particularly infectious ones, the consequences of which are felt locally in the oral cavity and at a distance in the body. Oral diseases frequently lead to the maintenance of an inflammatory state in oral bones and mucosa, which complicates the treatment of systemic inflammatory pathologies. The aim of this review is to take stock of current knowledge concerning the interrelationships that may exist between the oral environment and other organs, in both adults and children.

Title: Les dents et le milieu buccal au cœur de la santé globale. Abstract: La recherche autour des interrelations existant entre les maladies orales et les maladies systémiques connaît une croissance exponentielle depuis plus de vingt ans. Les dents et leurs tissus de soutien peuvent être atteints de maladies, notamment infectieuses, dont les conséquences se font ressentir localement, dans la cavité buccale, mais aussi à distance dans l'organisme. Ces maladies conduisent fréquemment à l'entretien d'un état inflammatoire dans la cavité orale qui complique les traitements de maladies inflammatoires systémiques. L'objectif de cette revue est de dresser un état des lieux des connaissances actuelles concernant les interrelations qui peuvent exister, chez l'adulte comme chez l'enfant.

[Oral microbiota and liver]. / Microbiote buccal et foie.

The liver has many important biological functions for the body, as it is involved in the storage and distribution of nutrients (carbohydrates to glycogen, lipids to triglycerides), the digestion of fats, the synthesis of blood proteins, and the detoxification of alcohol and drugs. The liver can be affected by various diseases such as viral or drug-induced hepatitis, fibrosis and cirrhosis, in which damaged hepatocytes are progressively replaced by scar tissue.

Title: Microbiote buccal et foie. Abstract: Le foie possède de nombreuses fonctions biologiques importantes pour l'organisme. Il peut être atteint par diverses maladies, telles que les hépatites virales ou médicamenteuses, la fibrose et la cirrhose. Lors de ces affections, les hépatocytes endommagés sont progressivement remplacés par du tissu cicatriciel. Par ailleurs, une altération du microbiote oral peut être à l'origine d'une altération des réponses immunitaires et ainsi contribuer au développement d'une inflammation qui touchera également le foie. En effet, les personnes souffrant d'hémochromatose ou de stéatose hépatique non alcoolique présentent des anomalies importantes du microbiote oral. De même, des concentrations élevées de certaines bactéries colonisant la cavité buccale, telles que Porphyromonas gingivalis, sont associées à des facteurs de risque accrus de stéatose hépatique non alcoolique.

The Role of Dysbiotic Oral Microbiota in Cardiometabolic Diseases: A Narrative Review.

Over the past decade, there have been significant advancements in the high-flow analysis of "omics," shedding light on the relationship between the microbiota and the host. However, the full recognition of this relationship and its implications in cardiometabolic diseases are still underway, despite advancements in understanding the pathophysiology of these conditions. Cardiometabolic diseases, which include a range of conditions from insulin resistance to cardiovascular disease and type 2 diabetes, continue to be the leading cause of mortality worldwide, with a persistently high morbidity rate. While the link between the intestinal microbiota and cardiometabolic risks has been extensively explored, the role of the oral microbiota, the second-largest microbiota in the human body, and specifically the dysbiosis of this microbiota in causing these complications, remains incompletely defined. This review aims to examine the association between the oral microbiota and cardiometabolic diseases, focusing on the dysbiosis of the oral microbiota, particularly in periodontal disease. Additionally, we will dive into the mechanistic aspects of this dysbiosis that contribute to the development of these complications. Finally, we will discuss potential prevention and treatment strategies, including the use of prebiotics, probiotics, and other interventions.

Obesity Is Associated with the Severity of Periodontal Inflammation Due to a Specific Signature of Subgingival Microbiota.

The aim of this study was to analyze the link between periodontal microbiota and obesity in humans. We conducted a cohort study including 45 subjects with periodontitis divided into two groups: normo-weighted subjects with a body mass index (BMI) between 20 and 25 kg/m2 (n = 34) and obese subjects with a BMI > 30 kg/m2 (n = 11). Our results showed that obesity was associated with significantly more severe gingival inflammation according to Periodontal Inflamed Surface Area (PISA index). Periodontal microbiota taxonomic analysis showed that the obese (OB) subjects with periodontitis were characterized by a specific signature of subgingival microbiota with an increase in Gram-positive bacteria in periodontal pockets, associated with a decrease in microbiota diversity compared to that of normo-weighted subjects with periodontitis. Finally, periodontal treatment response was less effective in OB subjects with persisting periodontal inflammation, reflecting a still unstable periodontal condition and a risk of recurrence. To our knowledge, this study is the first exploring both salivary and subgingival microbiota of OB subjects. Considering that OB subjects are at higher periodontal risk, this could lead to more personalized preventive or therapeutic strategies for obese patients regarding periodontitis through the specific management of oral microbiota of obese patients.

Low-Diversity Microbiota in Apical Periodontitis and High Blood Pressure Are Signatures of the Severity of Apical Lesions in Humans.

(1) Background: In developed countries, the prevalence of apical periodontitis (AP) varies from 20% to 50% for reasons that could be associated with the apical periodontitis microbiota ecology. (2) Methods: We performed a clinical study in the Odontology department of Toulouse hospital in France, to sequence the 16S rRNA gene of AP microbiota and collect clinical parameters from 94 patients. Forty-four patients were characterized with a PAI (periapical index of AP severity) score lower or equal to 3, while the others had superior scores (n = 50). (3) Results: The low diversity of granuloma microbiota is associated with the highest severity (PAI = 5) of periapical lesions (Odds Ratio 4.592, IC 95% [1.6329; 14.0728]; p = 0.001; notably, a lower relative abundance of Burkholderiaceae and a higher relative abundance of Pseudomonas and Prevotella). We also identified that high blood pressure (HBP) is associated with the increase in PAI scores. (4) Conclusions: Our data show that a low diversity of bacterial ecology of the AP is associated with severe PAI scores, suggesting a causal mechanism. Furthermore, a second risk factor was blood pressure associated with the severity of apical periodontitis.

Human liver microbiota modeling strategy at the early onset of fibrosis.

BACKGROUND: Gut microbiota is involved in the development of liver diseases such as fibrosis. We and others identified that selected sets of gut bacterial DNA and bacteria translocate to tissues, notably the liver, to establish a non-infectious tissue microbiota composed of microbial DNA and a low frequency live bacteria. However, the precise set of bacterial DNA, and thereby the corresponding taxa associated with the early stages of fibrosis need to be identified. Furthermore, to overcome the impact of different group size and patient origins we adapted innovative statistical approaches. Liver samples with low liver fibrosis scores (F0, F1, F2), to study the early stages of the disease, were collected from Romania(n = 36), Austria(n = 10), Italy(n = 19), and Spain(n = 17). The 16S rRNA gene was sequenced. We considered the frequency, sparsity, unbalanced sample size between cohorts to identify taxonomic profiles and statistical differences. RESULTS: Multivariate analyses, including adapted spectral clustering with L1-penalty fair-discriminant strategies, and predicted metagenomics were used to identify that 50% of liver taxa associated with the early stage fibrosis were Enterobacteriaceae, Pseudomonadaceae, Xanthobacteriaceae and Burkholderiaceae. The Flavobacteriaceae and Xanthobacteriaceae discriminated between F0 and F1. Predicted metagenomics analysis identified that the preQ0 biosynthesis and the potential pathways involving glucoryranose and glycogen degradation were negatively associated with liver fibrosis F1-F2 vs F0. CONCLUSIONS: Without demonstrating causality, our results suggest first a role of bacterial translocation to the liver in the progression of fibrosis, notably at the earliest stages. Second, our statistical approach can identify microbial signatures and overcome issues regarding sample size differences, the impact of environment, and sets of analyses. TRIAL REGISTRATION: TirguMECCH ROLIVER Prospective Cohort for the Identification of Liver Microbiota, registration 4065/2014. Registered 01 01 2014.

Gut microbiota dysbiosis of type 2 diabetic mice impairs the intestinal daily rhythms of GLP-1 sensitivity.

The gut-brain-beta cell glucagon-like peptide-1 (GLP-1)-dependent axis and the clock genes both control insulin secretion. Evidence shows that a keystone of this molecular interaction could be the gut microbiota. We analyzed in mice the circadian profile of GLP-1 sensitivity on insulin secretion and the impact of the autonomic neuropathy, antibiotic treated in different diabetic mouse models and in germ-free colonized mice. We show that GLP-1sensitivity is maximal during the dark feeding period, i.e., the postprandial state. Coincidently, the ileum expression of GLP-1 receptor and peripherin is increased and tightly correlated with a subset of clock gene. Since both are markers of enteric neurons, it suggests a role in the gut-brain-beta cell GLP-1-dependent axis. We evaluated the importance of gut microbiota dysbiosis and found that the abundance of ileum bacteria, particularly Ruminococcaceae and Lachnospiraceae, oscillated diurnally, with a maximum during the dark period, along with expression patterns of a subset of clock genes. This diurnal pattern of circadian gene expression and Lachnospiraceae abundance was also observed in two separate mouse models of gut microbiota dysbiosis and of autonomic neuropathy with impaired GLP-1 sensitivity (1.high-fat diet-fed type 2 diabetic, 2.antibiotic-treated/germ-free mice). Our data show that GLP-1 sensitivity relies on specific pattern of intestinal clock gene expression and specific gut bacteria. This new statement opens opportunities to treat diabetic patient with GLP-1-based therapies by using on a possible pre/probiotic co-treatment to improve the time-dependent efficiency of these therapies.

Oral Microbiota: A Major Player in the Diagnosis of Systemic Diseases.

The oral cavity is host to a complex and diverse microbiota community which plays an important role in health and disease. Major oral infections, i.e., caries and periodontal diseases, are both responsible for and induced by oral microbiota dysbiosis. This dysbiosis is known to have an impact on other chronic systemic diseases, whether triggering or aggravating them, making the oral microbiota a novel target in diagnosing, following, and treating systemic diseases. In this review, we summarize the major roles that oral microbiota can play in systemic disease development and aggravation and also how novel tools can help investigate this complex ecosystem. Finally, we describe new therapeutic approaches based on oral bacterial recolonization or host modulation therapies. Collaboration in diagnosis and treatment between oral specialists and general health specialists is of key importance in bridging oral and systemic health and disease and improving patients' wellbeing.

Obesity Drives an Oral Microbiota Signature of Female Patients with Periodontitis: A Pilot Study.

The aim of this study was to analyze the link between oral microbiota and obesity in humans. We conducted a pilot study including 19 subjects with periodontitis divided into two groups: normo-weighted subjects (NWS) with a body mass index (BMI) between 20 and 25 (n = 9) and obese subjects (OS) with a BMI > 30 (n = 10). Obesity was associated with a poor oral health status characterized by an increased number of missing teeth and a higher score of periodontal-support loss associated with dysbiotic oral microbiota (39.45 ± 3.74 vs. 26.41 ± 11.21, p = 0.03 for the Chao 1 index). Oral microbiota taxonomic analysis showed that the abundance of the Capnocytophaga genus was higher (2.47% ± 3.02 vs. 0.27% ± 0.29, p = 0.04) in OS compared to NWS. Obese females (OF) were characterized by an increase in the Streptococcus genus (34.12% ± 14.29 vs. 10.55% ± 10.42, p = 0.05) compared to obese males (OM), where the Neisseria genus was increased (5.75% ± 5.03 vs. 58.05% ± 30.64, p = 0.008). These first data suggest that sex/gender is determinant in the link between oral dysbiotic microbiota and obesity in patients with periodontitis. Our results could lead to recommendations concerning therapeutic strategies for obese patients with periodontitis following the sex/gender.

Oral microbiota-induced periodontitis: a new risk factor of metabolic diseases.

It has recently become evident that the periodontium (gingiva, desmodontal ligament, cementum and alveolar bone) and the associated microbiota play a pivotal role in regulating human health and diseases. The oral cavity is the second largest microbiota in the body with around 500 different bacterial species identified today. When disruption of oral cavity and dysbiosis occur, the proportion of strict anaerobic Gram-negative bacteria is then increased. Patients with periodontitis present 27 to 53% more risk to develop diabetes than the control population suggesting that periodontitis is an aggravating factor in the incidence of diabetes. Moreover, dysbiosis of oral microbiota is involved in both periodontal and metabolic disorders (cardiovascular diseases, dyslipidaemia …). The oral diabetic dysbiosis is characterized by a specific bacteria Porphyromonas, which is highly expressed in periodontal diseases and could exacerbate insulin resistance. In this review, we will address the nature of the oral microbiota and how it affects systemic pathologies with a bidirectional interaction. We also propose that using prebiotics like Akkermansia muciniphila may influence oral microbiota as novel therapeutic strategies. The discovery of the implication of oral microbiota for the control of metabolic diseases could be a new way for personalized medicine.

Resveratrol-mediated glycemic regulation is blunted by curcumin and is associated to modulation of gut microbiota.

The polyphenols resveratrol (RSV) and curcumin (Cur) are phytoalexines and natural antibiotics with numerous pharmacological functions and metabolic impacts. Recent evidences show a broad control of gut microbiota by polyphenols which could influence glycemic regulation. The aim of this work is to estimate the respective effect of RSV and Cur alone or in association on the control of glycemia and on gut microbiota. A 5-week chronic treatment of hyperglycemic mice with RSV and/or Cur resulted in a differential effect on glucose tolerance test and modified gut microbiome. We precisely identified groups of bacteria representing a specific signature of the glycemic effect of RSV. Inferred metagenomic analysis and metabolic pathway prediction showed that the sulfur and branched-chain amino-acid (BCAA) metabolic activities are tightly correlated with the efficacy of RSV for the control of glycaemia. The impact on BCAA metabolism was further validated by serum metabolomics analysis. Altogether, we show that polyphenols specifically impact gut microbiota and corresponding metabolic functions which could be responsible for their therapeutic role.

Infliximab Induced a Dissociated Response of Severe Periodontal Biomarkers in Rheumatoid Arthritis Patients.

OBJECTIVE: Rheumatoid arthritis and periodontal disease are associated together, but the effect of therapy provided for one disease to the second one remained under-investigated. This study investigated effect of infliximab therapy used to treat rheumatoid arthritis (RA) on various biomarkers of periodontal disease (PD) severity including serologies of Porphyromonas gingivalis and Prevotella intermedia and matrix metalloproteinase 3. METHODS: Seventy nine RA patients were enrolled at the time to start infliximab therapy and the 28 joint disease activity score (DAS28), anti-cyclic citrullinated petides 2nd generation (anti-CCP2), anti-P. gingivalis antibody, and Matrix metalloproteinase 3 (MMP-3) were monitored before and at 6 months of infliximab therapy. Joint damage and severe periodontal disease were assessed at baseline. Anti-CCP2, anti-P. gingivalis antibody, and MMP-3 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: At baseline, anti-CCP2 titers were associated with anti-P. gingivalis lipopolysaccharide (LPS)-specific antibodies titers (p < 0.05). Anti-P. gingivalis antibodies were not significantly correlated with clinical, biological, or destruction parameters of RA disease. At 6 months of infliximab therapy, MMP-3 level decreased (from 119 ± 103 ng/mL to 62.44 ± 52 ng/mL; p < 0.0001), whereas P. gingivalis antibody levels remained at the same level. DAS28 and inflammation markers C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) also decreased significantly during infliximab therapy (p < 0.05) as anti-CCP2 levels (p < 0.001). Only high MMP-3 level at baseline was associated with infliximab efficacy (p < 0.01). CONCLUSION: MMP-3 level can be a useful marker of the efficacy of infliximab in RA patients. The treatment did not affect anti-P. gingivalis antibodies.

Porphyromonas gingivalis experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat.

OBJECTIVES: Association between periodontal disease (PD) and rheumatoid arthritis (RA) has been extensively described, but direct evidence of causal involvement of PD in RA is missing. We investigated the priming role of oral Porphyromonas gingivalis (P. gingivalis) in PD and subsequent RA and we assessed biomarkers of bone resorption and arthritis development in rats. METHODS: Lewis rats were orally exposed to either P. gingivalis, Prevotella intermedia or control gel for 1 month and then followed for 8 months. The onset and development of PD was assessed by serology, gingivitis severity and micro-CT (µCT). We investigated arthritis development using circulating proinflammatory markers, anticyclic citrullinated peptide (CCP), anticitrullinated protein antibody (ACPA), ankle histology and µCT. RESULTS: PD was only observed in the P. gingivalis treated rats, as early as 1 month postexposure. Joint and systemic inflammation were detected only in the P. gingivalis group after 4 and 8 months. At 8 months, inflammatory cell infiltrate was observed in ankle joints and paralleled cortical erosions and overall cortical bone reduction. Furthermore, anti-CCP2 correlated with local and systemic bone loss. CONCLUSIONS: In our long-term study, PD induced by oral exposure to P. gingivalis triggered seropositive arthritis, with systemic inflammation and bone erosions. This is the first in vivo demonstration of arthritis induced by oral priming with P. gingivalis.

Oral health and microbiota status in professional rugby players: A case-control study.

OBJECTIVE: Elite athletes are prone to develop oral diseases, which could increase the risk for injuries. The aim of this study was to evaluate the oral health and the composition of oral microbiota of elite rugby players compared to the general population. METHODS: We set up a case-control study by screening 24 professional rugby players (PRG) and 22 control patients (CG) for dental and gingival examinations and performed a taxonomic analysis and a predicted functional analysis of oral microbiota. RESULTS: The Decay, Missing and Filled (DMF) teeth index (5.54 ± 6.18 versus 2.14 ± 3.01; p = 0.01) and the frequency of gingivitis (58,33% versus 13.63%) were significantly increased in PRG compared to CG. PRG were characterized by a dysbiotic oral microbiota (Shannon Index: 3.32 ± 0.62 in PRG versus 3.79 ± 0.68 in CG; p = 0.03) with an increase of Streptococcus (58.43 ± 16.84 versus 42.60 ± 17.45; p = 0.005), the main genus implicated in caries. Predicted metagenomics of oral microbiota in rugby players was suggestive of a cariogenic metagenome favourable to the development of caries. CONCLUSIONS: Our study shows that the oral health of PRG was poorer than the general population. PRG are characterized by a dysbiotic oral microbiota with an increase of the relative abundance of Streptococcus genus, positively correlated to the weight and negatively correlated to the diversity of oral microbiota. CLINICAL SIGNIFICANCE: Dental screening should be included in the medical follow-up of professional rugby players as a part of their health management. New strategies such as using probiotics like Lactobacillus could help to control the dysbiosis of oral microbiota.

Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.

In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.

The effects of periodontal treatment on diabetic patients: The DIAPERIO randomized controlled trial.

AIM: To assess whether periodontal treatment can lead to clinical, glycaemic control and quality of life improvements in metabolically unbalanced diabetic patients (type 1 or type 2) diagnosed with periodontitis. METHODS: In this open-labelled randomized controlled trial, diabetic subjects (n = 91) were given "immediate" or "delayed" periodontal treatment (full-mouth non-surgical scaling and root planing, systemic antibiotics, and oral health instructions). The main outcome was the effect on glycated haemoglobin (HbA1C ) and fructosamine levels. The General Oral Health Assessment Index and the SF-36 index were used to assess quality of life (QoL). RESULTS: Periodontal health significantly improved after periodontal treatment (p < 0.001). Periodontal treatment seemed to be safe but had no significant effects on glycaemic control based on HbA1C (adjusted mean difference with a 95% confidence interval (aMD) of 0.04 [-0.16;0.24]) and fructosamine levels (aMD 5.0 [-10.2;20.2]). There was no obvious evidence of improvement in general QoL after periodontal treatment. However, there was significant improvement in oral health-related QoL (aMD 7.0 [2.4;11.6], p = 0.003). CONCLUSION: Although periodontal treatment showed no clinical effect on glycaemic control in this trial, important data were provided to support periodontal care among diabetic patients. Periodontal treatment is safe and improves oral health-related QoL in patients living with diabetes. ISRCTN15334496.

Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.

Author Correction: Obese Subjects With Specific Gustatory Papillae Microbiota and Salivary Cues Display an Impairment to Sense Lipids.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Obese Subjects With Specific Gustatory Papillae Microbiota and Salivary Cues Display an Impairment to Sense Lipids.

Some obese subjects overeat lipid-rich foods. The origin of this eating behavior is unknown. We have here tested the hypothesis that these subjects could be characterized by an impaired fatty taste sensitivity linked to a change in the gustatory papillae microbial and salivary environment. The composition of microbiota and saliva surrounding the circumvallate papillae was analyzed in combination with the orosensory lipid detection threshold in normal weight (NW) and obese (O) adults. Microbial architecture was similar to what was known in feces, but with an increased frequency of Proteobacteria. No difference in the orosensory sensitivity to lipids and composition of oral microbiota and saliva was observed between NW and O subjects. By contrast, specific bacterial and salivary signatures were found in lipid non-tasters, irrespectively of BMI. A multivariate approach highlighted that the salivary flow, lysozyme activity, total antioxidant capacity and TM7 bacterial family discriminated between tasters and non-tasters. Subgroup analysis of obese tasters (OT) versus obese non-tasters (ONT) identified specific bacterial metabolic pathways (i.e. phosphotransferase and simple sugar transport systems) as being higher in ONT. Altogether with the identification of a set of significant salivary variables, our study suggests that an "obese tongue" phenotype is associated with decreased orosensory sensitivity to lipids in some obese subjects.

Gut Microbiota Interacts with Markers of Adipose Tissue Browning, Insulin Action and Plasma Acetate in Morbid Obesity.

SCOPE: To examine the potential relationship among gene expression markers of adipose tissue browning, gut microbiota, and insulin sensitivity in humans. METHODS AND RESULTS: Gut microbiota composition and gene markers of browning are analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue from morbidly obese subjects (n = 34). Plasma acetate is measured through 1 H NMR and insulin sensitivity using euglycemic hyperinsulinemic clamp. Subjects with insulin resistance show an increase in the relative abundance (RA) of the phyla Bacteroidetes and Proteobacteria while RA of Firmicutes is decreased. In all subjects, Firmicutes RA is negatively correlated with HbA1c and fasting triglycerides, whereas Proteobacteria RA was negatively correlated with insulin sensitivity. Firmicutes RA is positively associated with markers of brown adipocytes (PRDM16, UCP1, and DIO2) in SAT, but not in VAT. Multivariate regression analysis indicates that Firmicutes RA contributes significantly to SAT PRDM16, UCP1, and DIO2 mRNA variance after controlling for age, BMI, HbA1c , or insulin sensitivity. Interestingly, Firmicutes RA, specifically those bacteria belonging to the Ruminococcaceae family, is positively associated with plasma acetate levels, which are also linked to SAT PRDM16 mRNA and insulin sensitivity. CONCLUSION: Gut microbiota composition is linked to adipose tissue browning and insulin action in morbidly obese subjects, possibly through circulating acetate.