Ronaldo Lira-Junior

Periodontal and inflammatory bowel diseases: Is there evidence of complex pathogenic interactions?

Periodontal disease and inflammatory bowel disease (IBD) are both chronic inflammatory diseases. Their pathogenesis is mediated by a complex interplay between a dysbiotic microbiota and the host immune-inflammatory response, and both are influenced by genetic and environmental factors. This review aimed to provide an overview of the evidence dealing with a possible pathogenic interaction between periodontal disease and IBD. There seems to be an increased prevalence of periodontal disease in patients with IBD when compared to healthy controls, probably due to changes in the oral microbiota and a higher inflammatory response. Moreover, the induction of periodontitis seems to result in gut dysbiosis and altered gut epithelial cell barrier function, which might contribute to the pathogenesis of IBD. Considering the complexity of both periodontal disease and IBD, it is very challenging to understand the possible pathways involved in their coexistence. In conclusion, this review points to a complex pathogenic interaction between periodontal disease and IBD, in which one disease might alter the composition of the microbiota and increase the inflammatory response related to the other. However, we still need more data derived from human studies to confirm results from murine models. Thus, mechanistic studies are definitely warranted to clarify this possible bidirectional association.

Severe Chronic Periodontitis Is Associated With Endothelial and Microvascular Dysfunctions: A Pilot Study

BACKGROUNDnPeriodontitis is an inflammatory chronic disease that has been implicated as a risk factor for cardiovascular disease (CVD). Endothelium has a central role in CVD pathogenesis, and chronic inflammation can make it dysfunctional, contributing to CVD emergence. Thus, the aim of this study is to investigate the existence of an association between severe chronic periodontitis (CP) and nailfold microvascular, gingival microvascular, and endothelial functions.nnnMETHODSnTwenty-three patients were included, 13 with severe periodontitis (median age, 46 years; interquartile range, 9.5 years) and 10 healthy control patients (median age, 35.5 years; interquartile range, 12.5 years). Clinical and laboratorial variables were gathered, and patients were examined by the following: 1) nailfold videocapillaroscopy to assess functional capillary density (FCD), capillary diameters, red blood cell velocity at rest (RBCV) and after 1-minute arterial occlusion (RBCVmax), and time taken to reach RBCVmax (TRBCVmax); 2) side-stream dark-field imaging to determine gingival capillary density (GCD); and 3) venous occlusion plethysmography to assess endothelium-dependent (% Hyper) and endothelium-independent vasodilatation (% Nitro).nnnRESULTSnPatients with CP have smaller values for FCD, RBCV, RBCVmax, and % Hyper and higher values for TRBCVmax and GCD compared with controls (P <0.05). There were significant correlations between periodontal parameters with FCD, RBCV, RBCVmax, TRBCVmax, GCD, and % Hyper. There was also a negative correlation between FCD and GCD (r = -0.7; P <0.01). Associations between periodontitis and FCD, RBCVmax, TRBCVmax, GCD, and % Hyper remained significant after adjustments for age and systolic blood pressure.nnnCONCLUSIONnSevere CP was directly associated with endothelial and microvascular dysfunctions.

Oral-gut connection: one step closer to an integrated view of the gastrointestinal tract?

Although an enrichment of orally derived bacteria is reported in the gut microbiota of patients with several diseases, it is mostly unknown whether oral bacteria can colonize and induce intestinal inflammation. In a recent paper in Science, Atarashi et al.1 from Kenya Honda’s laboratory show that a subset of orally derived bacteria colonizes and persists in the gut, leading to activation of the intestinal immune system and subsequent chronic inflammation in a susceptible host. The impact of oral health status as a potential contributor to inflammatory diseases at distal sites of the body deserves consideration.

Colony stimulating factor-1 in saliva in relation to age, smoking, and oral and systemic diseases

Colony stimulating factor (CSF)-1 is a growth factor that stimulates the survival, proliferation and differentiation of mononuclear phagocytes, which has been implicated in several inflammatory diseases. This study evaluated the possible influence of age, sex, smoking, periodontitis, caries, and several systemic conditions on salivary levels of CSF-1. Four-hundred and forty-one individuals were enrolled in this study. All participants answered a health questionnaire and underwent a comprehensive oral examination. Stimulated saliva was collected and CSF-1 levels were analysed by enzyme-linked immunosorbent assay. Salivary levels of CSF-1 were significantly increased in participants over 64 years old and in non-smoking individuals, whereas no difference was observed between men and women. Individuals having periodontitis and manifest caries had significantly higher levels of CSF-1. Participants with muscle and joint disease exhibited increased CSF-1 levels as compared to those without. Age, smoking, percentage of pockets ≥4u2009mm, number of manifest caries lesions, and presence of tumor were associated with CSF-1 levels. Salivary levels of CSF-1 are associated with age, smoking, periodontitis, manifest caries, and the presence of muscle and joint diseases and tumors. CSF-1 might be a promising biomarker candidate in saliva of both local and systemic conditions that needs further investigation.

Salivary and Serum Markers Related to Innate Immunity in Generalized Aggressive Periodontitis

BACKGROUNDnHost inflammatory and immune responses play an important role in aggressive periodontitis (AgP). Thus, this study aims to evaluate levels of the innate immunity-related markers calprotectin, colony-stimulating factor (CSF)-1, macrophage migration inhibitory factor (MIF), monokine induced by interferon-γ (MIG), and matrix metalloproteinase (MMP)-8 in serum and saliva from patients with generalized AgP and those with gingivitis or a healthy periodontium.nnnMETHODSnThis study enrolled 40 individuals (17 males and 23 females; mean age 33.30 ± 9.31 years), 15 with generalized AgP, 15 with gingivitis, and 10 who were periodontally healthy. Full-mouth periodontal examinations were performed, and serum and saliva were collected. Levels of calprotectin, CSF-1, MIF, MIG, and MMP-8 were measured using enzyme-linked immunosorbent assays.nnnRESULTSnIn serum, mean levels of calprotectin were 2.06-fold higher in patients with AgP than in healthy patients (P = 0.01). Serum levels of MMP-8 were significantly elevated in patients with AgP compared with both healthy patients and those with gingivitis, by 2.60-fold and 2.77-fold, respectively (P = 0.03 and P = 0.009, respectively). In saliva, levels of MMP-8 were 5.66-fold higher in patients with AgP than in healthy patients (P = 0.02). CSF-1, MIF, and MIG levels in both serum and saliva did not differ significantly among the groups.nnnCONCLUSIONSnSerum levels of calprotectin and MMP-8 are elevated in patients with AgP. MMP-8 levels are also increased in saliva from patients with AgP. These results support involvement of innate immune response in the pathogenesis of AgP.

Salivary microbial profiles in relation to age, periodontal, and systemic diseases

Background Analysis of saliva is emerging as a promising tool to diagnose and monitor diseases which makes determination of the salivary microbial profile in different scenarios essential. Objective To evaluate the effects of age, periodontal disease, sex, smoking, and medical conditions on the salivary microbial profile. Design A randomly selected sample of 441 individuals was enrolled (51% women; mean age 48.5±16.8). Participants answered a health questionnaire and underwent an oral examination. Stimulated saliva was collected and the counts of 41 bacteria were determined by checkerboard DNA-DNA hybridization. Results Elderly participants (> 64 years old) presented a significant increase in 24 out of 41 bacterial species compared to adults (≤ 64 years old). Eubacterium nodatum, Porphyromonas gingivalis, and Tannerella forsythia were significantly higher in participants with generalized bone loss compared to without. Males and non-smokers had higher bacteria counts in saliva. Individuals having mental disorders or muscle and joint diseases showed significantly altered microbial profiles whereas small or no differences were found for subjects with high blood pressure, heart disease, previous heart surgery, bowel disease, tumors, or diabetes. Conclusion Age, periodontal status, sex, smoking, and certain medical conditions namely, mental disorders and muscle and joint diseases, might affect the microbial profile in saliva.

MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation

&NA; Matrix metalloproteinase (MMP)‐12, S100A8/A9, and S100A12 are involved in innate immune responses. We addressed whether different aspects of oral health and non‐disease‐related covariates influence their levels in saliva. 436 participants were clinically examined, completed a health questionnaire, and provided stimulated saliva. Salivary levels of MMP‐12, S100A8/A9, and S100A12 were determined by enzyme‐linked immunosorbent assays. Lower MMP‐12 levels were observed in individuals 40–64 years old (yo) compared to < 40 yo, and higher S100A8/A9 levels were found in individuals > 64 yo compared to 40–64 yo. Smokers exhibited lower MMP‐12 and S100A12 levels compared to non‐smokers. All three proteins were elevated in individuals with bleeding on probing (BOP) > 20% compared to those with BOP ≤ 20%, and the S100A8/A9 levels were higher in individuals having ≥ 10% gingival pocket depths (PPD) ≥ 4 mm compared to the ones with shallow pockets < 4 mm. The extent of alveolar bone loss or presence of manifest caries did not alter any of the markers. MMP‐12, S100A8/A9, and S100A12 levels were higher in participants with high periodontal inflammatory burden. All three proteins correlated positively to BOP, PPD, and to several inflammatory mediators. The explanatory variables for MMP‐12 in saliva were age, smoking, presence of any tumor, and percentage of PPD ≥ 4 mm. The determinant of salivary S100A8/A9 was percentage of BOP, while S100A12 levels were associated with percentage of BOP and presence of any tumor. Taken together, MMP‐12 and the S100/calgranulin levels in saliva reflect different aspects of periodontal inflammation. Smoking and age should be taken into account in further investigation of these proteins as biomarker candidates of periodontal disease.

Periodontal and inflammatory bowel diseases: Is there evidence for complex pathogenic interactions?

The two major risk factors of gastric cancer (GC) are Helicobacter pylori (HP) infection and atrophic gastritis (AG). It is currently possible to diagnose HP-infection and AG reliably by using serological testing with a panel of biomarkers (GastroPanel®, Biohit Oyj, Finland): pepsinogen I (PGI), pepsinogen II (PGII), gastrin-17 (G-17) and HP-antibodies. Severe AG leads in acid-free stomach colonized by HP and other bacteria, producing acetaldehyde (Group I human carcinogen; IARC). Together with other conditions leading to a) acid-free stomach (e.g. chronic users of PPI medication, autoimmune AG) or b) those exposing the subjects to increased concentrations of acetaldehyde (e.g. cigarette smokers, alcohol intake, ALDH2 enzyme mutations), these subjects are at high-risk for gastric and esophageal cancer. This document has a dual purpose: First, to give an introduction to the GastroPanel® as the first non-invasive diagnostic tool for i) dyspeptic symptoms, and for ii) screening of asymptomatic subjects for the risks of GC. Second, to describe a novel formulation (Acetium® Capsule, Biohit Oyj) based on slow-release L-cysteine, designed to protect the stomach mucosa in these high-risk subjects by its capacity to eliminate carcinogenic acetaldehyde. GastroPanel® is based on stomach physiology both in health and disease. Accordingly, pepsinogen levels and their ratio is decreased in corpus atrophy (AGC), accompanied by elevated G-17b (basal). G-17b level also sensitively responds to gastric acid output, being low with high acid output and high when the stomach is acid-free (due to PPI-treatment or AGC). In antrum atrophy (AGA), G-17b is low and, importantly, does not respond to a protein stimulation (G-17s), because the G-cells are disappeared. The results of GastroPanel® test are interpreted by a specially designed software (GastroSoft®) identifying 8 diagnostic marker profiles (Figure 1). Of those, four (profiles 1,2,3 and 8) represent purely functional disorders (of acid output), while three others specify structural abnormalities (profiles 5,6, and 7 for AGC, AGA, and AGpan, respectively). The remaining (profile 4) is typical to HP-infection, with three possible outcomes: a) active HP-infection, b) successful eradication, and c) failed eradication. During the past 10 years, GastroPanel® has been validated in an increasing number of studies both in clinical and screening settings, and its excellent clinical performance was validated in two recent meta-analysis. In addition to its high specificity for both AGA and AGC, GastroPanel® test has excellent longitudinal predictive values (NPV and PPV) for incident GC as shown in two recent cohort studies. Acetium® Capsule is a novel formulation of slow-release L-cysteine, being a unique medical device designed to elimination of carcinogenic acetaldehyde in the stomach. A regular use of Acetium® Capsule is indicated for all those who have acid-free stomach, irrespective of its cause. This formulation effectively protects the stomach against the exposure to acetaldehyde. The most common high-risk groups include the following: 1) AG associated with HP infection; 2) AG caused by autoimmune mechanisms; 3) cigarette smokers; 4) alcohol consumers; 5) chronic users of PPI medication, and 6) those (500 million) people in Asia who have a mutation 173 Serum Biomarker Panel (GastroPanel®) and Slow-Release L-cysteine (Acetium® Capsule): Rationale for the Primary Prevention of Gastric Cancer Citation: Kari Syrjänen. “Serum Biomarker Panel (GastroPanel®) and Slow-Release L-cysteine (Acetium® Capsule): Rationale for the Primary Prevention of Gastric Cancer”. EC Gastroenterology and Digestive System 3.6 (2017): 172-192. of the aldehyde dehydrogenase (ALDH2) enzyme, failing to metabolize acetaldehyde to acetic acid, and exposed to higher local concentrations of acetaldehyde. The efficacy of Acetium® Capsule in acetaldehyde elimination has been documented in controlled clinical experiments. In all studies, L-cysteine concentration in the gastric juice remained elevated for up to 3 hours, suggesting that an insignificant amount of L-cysteine is absorbed from the stomach or transported into the small intestine. It was demonstrated that slow-release L-cysteine effectively (by 60 80%) eliminates carcinogenic acetaldehyde in patients with acid-free stomach caused by either AG or PPI treatment. This was the case in individuals with either active or deficient ALDH2 enzyme. This capacity of slow-release L-cysteine to eliminate acetaldehyde persisted for up to three hours after ingestion of two Acetium® Capsules. L-cysteine was combined with acetaldehyde locally in the stomach, forming a stable and non-carcinogenic 2-methylthiazolidine carboxylic acid (MTCA). MTCA concentrations in the gastric juice remained significantly elevated for up to three hours after the administration of alcohol and Acetium® Capsules. With a rational use of these two medical devices, one can diagnose the gastric high-risk conditions and subsequently protect the stomach against acetaldehyde exposure.

Systemic Chemokine Levels with “Gut-Specific” Vedolizumab in Patients with Inflammatory Bowel Disease—A Pilot Study

Vedolizumab, a gut-specific biological treatment for inflammatory bowel disease (IBD), is an antibody that binds to the α4β7 integrin and blocks T-cell migration into intestinal mucosa. We aimed to investigate chemokine levels in serum of IBD-patients treated with vedolizumab. In this pilot study, we included 11 IBD patients (8 Crohn’s disease, 3 ulcerative colitis) previously non-respondent to anti-tumor necrosis factor (TNF)-agents. Patients received vedolizumab at week 0, 2 and 6 and were evaluated for clinical efficacy at week 10. Clinical characteristics and routine laboratory parameters were obtained and patients were classified as responders or non-responders. Expression of 21 chemokines in serum was measured using Proximity Extension Assay and related to clinical outcome. At week 10, 6 out of 11 patients had clinically responded. Overall expression of CCL13 increased after treatment. In non-responders, expression of CCL13 and CXCL8 increased after treatment, and CCL20 and CXCL1 expressions were higher compared to responders. In responders, CCL28 decreased after treatment. C-reactive protein (CRP) correlated negatively with 6 chemokines before therapy, but not after therapy. Systemic CCL13 expression increases in IBD-patients after vedolizumab therapy and several chemokine levels differ between responders and non-responders. An increased CCL13-level when starting vedolizumab treatment, might indicate potential prognostic value of measuring chemokine levels when starting therapy with vedolizumab. This study provides new information on modulation of systemic chemokine levels after vedolizumab treatment.

Self-Reported Periodontitis and Complications in Type 1 Diabetes Patients: A Brazilian Nationwide Survey

This study aimed to evaluate the possible association between periodontitis and systemic complications in a Brazilian type 1 diabetes population. A multicentre, sectional study was carried out in 28 public clinics located in 20 Brazilian cities. Data from 3,591 patients were obtained (56.0% females, 57.2% Caucasians), with an average age of 21.2 ± 11.7 years and whose mean duration of type 1 diabetes was 9.6 ± 8.1 years. Periodontitis was evaluated through self-report. Odds ratios (OR) and 95% confidence intervals were calculated to evaluate the association between periodontitis and systemic diabetes complications (chronic micro and macrovascular complications and hospitalizations by hyperglycemia and diabetic ketoacidosis). The prevalence of periodontitis was 4.7% (n=170). Periodontitis patients had mean age of 27.4 ± 12.9. This group was older (p<0.001), exhibited longer diabetes duration (p<0.0001) and had elevated total cholesterol (p<0.05), triglycerides (p<0.001) and lower HDL (p<0.05) values than patients without periodontitis. Systolic and diastolic blood pressures were significantly increased in periodontitis patients (p<0.01). Periodontitis patients had increased odds of microvascular complications (2.43 [1.74-3.40]) and of hospitalizations related to hyperglycemia (2.76 [1.72-4.42]) and ketoacidosis (2.72 [1.53-4.80]). In conclusion, periodontitis was associated to systemic complications in Brazilian type 1 diabetes patients.