The Skin and Nose Microbiome and Its Association with Filaggrin Gene Mutations in Pediatric Atopic Dermatitis

BACKGROUND: Interactions between the skin barrier, immune system, and microbiome underlie the development of atopic dermatitis (AD). OBJECTIVE: To investigate the skin and nasal microbiome in relation to filaggrin gene (FLG) mutations. METHODS: A cross-sectional study including 77 children with difficult-to-treat AD. The entire encoding region of FLG was screened for mutations using single molecule molecular inversion probes and next-generation sequencing. Bacterial swabs from the anterior nares, lesional and nonlesional skin were analyzed using 16S rRNA sequencing. For skin samples, additional qPCR was performed for Staphylococcus aureus and Staphylococcus epidermidis. RESULTS: The prevalence of patients with a mutation in FLG was 40%, including 10 different mutations. Analyzing bacterial swabs from all three niches showed a significant effect for both niche and FLG mutation status on the overall microbiome composition. Using a subset analysis to test the effect of FLG mutation status per niche separately did not show a significant association to the microbiome. Shannon diversity and S. aureus abundance were significantly affected by the niche, but not by the presence of an FLG mutation. CONCLUSIONS: Our results suggest only a minor role for FLG mutation status on the overall microbiome, which is rather caused by differences in the present genera than by microbe richness and evenness

Altered bile acid kinetics contribute to postprandial hypoglycaemia after Roux-en-Y gastric bypass surgery

Background/objectives: Bile acids (BA) act as detergents in intestinal fat absorption and as modulators of metabolic processes via activation of receptors such as FXR and TGR5. Elevated plasma BA as well as increased intestinal BA signalling to promote GLP-1 release have been implicated in beneficial health effects of Roux-en-Y gastric bypass surgery (RYGB). Whether BA also contribute to the postprandial hypoglycaemia that is frequently observed post-RYGB is unknown. Methods: Plasma BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), GLP-1, insulin and glucose levels were determined during 3.5 h mixed-meal tolerance tests (MMTT) in subjects after RYGB, either with (RYGB, n = 11) or without a functioning gallbladder due to cholecystectomy (RYGB-CC, n = 11). Basal values were compared to those of age, BMI and sex-matched obese controls without RYGB (n = 22). Results: Fasting BA as well as FGF19 levels were elevated in RYGB and RYGB-CC subjects compared to non-bariatric controls, without significant differences between RYGB and RYGB-CC. Postprandial hypoglycaemia was observed in 8/11 RYGB-CC and only in 3/11 RYGB. Subjects who developed hypoglycaemia showed higher postprandial BA levels coinciding with augmented GLP-1 and insulin responses during the MMTT. The nadir of plasma glucose concentrations after meals showed a negative relationship with postprandial BA peaks. Plasma C4 was lower during MMTT in subjects experiencing hypoglycaemia, indicating lower hepatic BA synthesis. Computer simulations revealed that altered intestinal transit underlies the occurrence of exaggerated postprandial BA responses in hypoglycaemic subjects. Conclusion: Altered BA kinetics upon ingestion of a meal, as frequently observed in RYGB-CC subjects, appear to contribute to postprandial hypoglycaemia by stimulating intestinal GLP-1 release

The influence of treatment in alpine and moderate maritime climate on the composition of the skin microbiome in patients with difficult to treat atopic dermatitis

Background: The skin microbiome, characterized by an overgrowth of Staphylococcus aureus, plays an important role in the pathogenesis of atopic dermatitis (AD). Multidisciplinary treatment in alpine climate is known for its positive effect on disease severity in children with AD and can result in a different immune response compared with moderate maritime climate. However, the effect on the composition of the skin microbiome in AD is unknown. Objective: To determine the effect of treatment in alpine climate and moderate maritime climate on the microbiome for lesional and non-lesional skin in children with difficult to treat AD. Results: Alpine climate treatment led to a significant change in the microbiota on lesional skin, whereas no significant change was found after moderate maritime climate. On both lesional and non-lesional skin, we observed a significant increase in Shannon diversity and a significant decrease in both Staphylococcus abundance and S aureus load after alpine climate treatment. The decrease in S aureus was significantly larger on lesional skin following alpine climate treatment compared with moderate maritime climate treatment. Staphylococcus epidermidis load was stable over time. Conclusions and clinical relevance: Alpine climate treatment leads to significant changes in the composition of the skin microbiome in children with AD, mainly caused by a reduction in the Staphylococcus genus. This study shows new perspectives in the potential mode of action for therapies in AD

Effect of statins on mitochondrial function and contractile force in human skeletal and cardiac muscle

Objectives and Background: The success of statin therapy in reducing cardiovascular morbidity and mortality is contrasted by the skeletal muscle complaints, which often leads to nonadherence. Previous studies have shown that inhibition of mitochondrial function plays a key role in statin intolerance. Recently, it was found that statins may also influence energy metabolism in cardiomyocytes. This study assessed the effects of statin use on cardiac muscle ex vivo from patients using atorvastatin, rosuvastatin, simvastatin or pravastatin and controls. Methods: Cardiac tissue and skeletal muscle tissue were harvested during open heart surgery after patients provided written informed consent. Patients included were undergoing cardiac surgery and either taking statins (atorvastatin, rosuvastatin, simvastatin or pravastatin) or without statin therapy (controls). Contractile behaviour of cardiac auricles was tested in an ex vivo set-up and cellular respiration of both cardiac and skeletal muscle tissue samples was measured using an Oxygraph-2k. Finally, statin acid and lactone concentrations were quantified in cardiac and skeletal homogenates by LC-MS/MS. Results: Fatty acid oxidation and mitochondrial complex I and II activity were reduced in cardiac muscle, while contractile function remained unaffected. Inhibition of mitochondrial complex III by statins, as previously described, was confirmed in skeletal muscle when compared to control samples, but not observed in cardiac tissue. Statin concentrations determined in skeletal muscle tissue and cardiac muscle tissue were comparable. Conclusions: Statins reduce skeletal and cardiac muscle cell respiration without significantly affecting cardiac contractility

An altered microbiota pattern precedes Type 2 diabetes mellitus development: From the CORDIOPREV study

Introduction. A distinctive gut microbiome have been linked to type 2 diabetes mellitus (T2DM). We aimed to evaluate whether gut microbiota composition, in addition to clinical biomarkers, could improve the prediction of new incident cases of diabetes in patients with coronary heart disease. Methods All the patients from the CORDIOPREV (Clinical Trials.gov.Identifier: NCT00924937) study without T2DM at baseline were included (n = 462). Overall, 107 patients developed it after a median of 60 months. The gut microbiota composition was determined by 16S rRNA gene sequencing and predictive models were created using hold-out method. Results. A gut microbiota profile associated with T2DM development was determined through a microbiome-based predictive model. The addition of microbiome data to clinical parameters (variables included in FINDRISC risk score and the diabetes risk score of the American Diabetes Association, HDL, triglycerides and HbA1c) improved the prediction increasing the area under the curve from 0.632 to 0.946. Furthermore, a microbiome-based risk score including the ten most discriminant genera, was associated with the probability of develop T2DM. Conclusión. These results suggest that a microbiota profile is associated to the T2DM development. An integrate predictive model of microbiome and clinical data that can improve the prediction of T2DM is also proposed, if is validated in independent populations to prevent this disease

A novel approach to investigate tissue-specific trinucleotide repeat instability

Abstract Background In Huntington's disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors. Results Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG repeat instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability. Conclusion Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Digital Biomarkers for Personalized Nutrition: Predicting Meal Moments and Interstitial Glucose with Non-Invasive, Wearable Technologies

Digital health technologies may support the management and prevention of disease through personalized lifestyle interventions. Wearables and smartphones are increasingly used to continuously monitor health and disease in everyday life, targeting health maintenance. Here, we aim to demonstrate the potential of wearables and smartphones to (1) detect eating moments and (2) predict and explain individual glucose levels in healthy individuals, ultimately supporting health self-management. Twenty-four individuals collected continuous data from interstitial glucose monitoring, food logging, activity, and sleep tracking over 14 days. We demonstrated the use of continuous glucose monitoring and activity tracking in detecting eating moments with a prediction model showing an accuracy of 92.3% (87.2–96%) and 76.8% (74.3–81.2%) in the training and test datasets, respectively. Additionally, we showed the prediction of glucose peaks from food logging, activity tracking, and sleep monitoring with an overall mean absolute error of 0.32 (+/−0.04) mmol/L for the training data and 0.62 (+/−0.15) mmol/L for the test data. With Shapley additive explanations, the personal lifestyle elements important for predicting individual glucose peaks were identified, providing a basis for personalized lifestyle advice. Pending further validation of these digital biomarkers, they show promise in supporting the prevention and management of type 2 diabetes through personalized lifestyle recommendations

Exploring the potential of personalized dietary advice for health improvement in motivated individuals with premetabolic syndrome : Pretest-posttest study

Background: Dietary quality plays an essential role in the prevention and management of metabolic syndrome (MetS). Objective: The aim of this pilot study is to organize personalized dietary advice in a real-life setting and to explore the effects on dietary intake, metabolic health, and perceived health. Methods: We followed a one-group pretest-posttest design and included 37 individuals at risk of MetS, who indicated motivation to change dietary behavior. For a period of 16 weeks, participants received personalized advice (t=0 and t=8) and feedback (t=0, t=4, t=8, t=12 and t=16) on dietary quality and metabolic health (ie, waist circumference, BMI, blood pressure, lipid profile, fasting glucose levels, and C-peptide). Personalized advice was generated in a two-stage process. In stage 1, an automated algorithm generated advice per food group, integrating data on individual dietary quality (Dutch Healthy Diet Index; total score 8-80) and metabolic health parameters. Stage 2 included a telephone consultation with a trained dietitian to define a personal dietary behavior change strategy and to discuss individual preferences. Dietary quality and metabolic health markers were assessed at t=0, t=8, and t=16. Self-perceived health was evaluated on 7-point Likert scales at t=0 and t=16. Results: At the end of the study period, dietary quality was significantly improved compared with the baseline (Dutch Healthy Diet Index +4.3; P<.001). In addition, lipid profile (triglycerides, P=.02; total cholesterol, P=.01; high-density lipoprotein, P<.001; and low-density lipoprotein, P<.001), BMI (P<.001), waist circumference (P=.01), and C-peptide (P=.01) were all significantly improved, whereas plasma glucose increased by 0.23 nmol/L (P=.04). In line with these results, self-perceived health scores were higher at t=16 weeks than at baseline (+0.67; P=.005). Conclusions: This exploratory study showed that personalized dietary advice resulted in positive effects on dietary behavior, metabolic health, and self-perceived health in motivated pre-MetS adults. The study was performed in a do-it-yourself setting, highlighting the potential of at-home health improvement through dietary changes.</p