Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

After pollination outdoors, individual bilberry plants from two Northern and two Southern clones were studied for climatic effects on berry yield and quality in a controlled phytotrone experiment at 12 and 18 °C. At each temperature, the following light treatments were tested: (1) 12 h natural light, (2) 24 h natural light, and (3) 24 h natural light plus red light. The first experimental year there was no difference in yield between temperatures; however, the second experimental year the berry yields was significantly higher at 18 °C. Berry ripening was faster in the Northern than in the Southern clones at 12 °C. Northern clones also showed significantly higher contents of total anthocyanins, all measured anthocyanin derivatives, total phenolics, malic acid and sucrose. Metabolic profiling revealed higher levels of flavanols, hydroxycinnamic acids, quinic acid and carbohydrates at 12 °C.

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Apples are one of the most commonly consumed fruits and their high polyphenol content is considered one of the most important determinants of their health-promoting activities. Here we studied the nutrikinetics of apple polyphenols by UHPLC-HRMS metabolite fingerprinting, comparing bioavailability when consumed in a natural or a polyphenol-enriched cloudy apple juice. Twelve men and women participated in an acute single blind controlled crossover study in which they consumed 250 mL of cloudy apple juice (CAJ), Crispy Pink apple variety, or 250 mL of the same juice enriched with 750 mg of an apple polyphenol extract (PAJ). Plasma and whole blood were collected at time 0, 1, 2, 3 and 5 h. Urine was collected at time 0 and 0-2, 2-5, 5-8, and 8-24 h after juice consumption. Faecal samples were collected from each individual during the study for 16S rRNA gene profiling. As many as 110 metabolites were significantly elevated following intake of polyphenol enriched cloudy apple juice, with large inter-individual variations. The comparison of the average area under the curve of circulating metabolites in plasma and in urine of volunteers consuming either the CAJ or the PAJ demonstrated a stable metabotype, suggesting that an increase in polyphenol concentration in fruit does not limit their bioavailability upon ingestion. Faecal bacteria were correlated with specific microbial catabolites derived from apple polyphenols. Human metabolism of apple polyphenols is a co-metabolic process between human encoded activities and those of our resident microbiota. Here we have identified specific blood and urine metabolic biomarkers of apple polyphenol intake and identified putative associations with specific genera of faecal bacteria, associations which now need confirmation in specifically designed mechanistic studies.

Background: Improved understanding of the pathophysiology causing diabetic kidney disease (DKD) is imperative. The aim of this study was to uncover associations between serum metabolites and renal outcomes.Methods: Non-targeted serum metabolomics analyses were performed in samples from 637 persons with type 1 diabetes using two-dimensional gas chromatography coupled to time-of-flight mass-spectrometry. Longitudinal data at follow-up (median 5.5 years) on renal events were obtained from national Danish health registries. A composite renal endpoint (n = 123) consisted of estimated glomerular filtration rate (eGFR) decline from baseline (≥30%), progression to end-stage renal disease and all-cause mortality. Metabolites with significant associations (p < 0.05) in any of the cross-sectional analyses with eGFR and albuminuria were analyzed for specific and composite endpoints. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.Results: A data-driven partial correlation analysis revealed a dense fabric of co-regulated metabolites and clinical variables dominated by eGFR. Ribonic acid and myo-inositol were inversely associated with eGFR, positively associated with macroalbuminuria (p < 0.02) and longitudinally associated with higher risk of eGFR decline ≥30% (HR 2.2–2.7, CI [1.3–4.3], p < 0.001). Ribonic acid was associated with a combined renal endpoint (HR 1.8, CI [1.3–2.3], p = 0.001). The hydroxy butyrate 3,4-dihydroxybutanoic acid was cross-sectionally associated with micro- and macroalbuminuria, urinary albumin excretion rate and inversely associated with eGFR (p < 0.04) while branched chain amino acids were associated with eGFR and lower risk of the combined renal endpoint (p < 0.02).Conclusions: Alterations in serum metabolites, particularly polyols and amino acids, were associated with renal endpoints in type 1 diabetes highlighting molecular pathways associated with progression of kidney disease. External validation is needed to further assess their roles and potentials as future therapeutic targets.

Background The molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA , protein, and metabolite changes in the neonatal heart for identification of metabolism‐related mechanisms associated with cardiac regeneration. Methods and Results Mouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c‐means clustering were used to identify up‐ or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNA s and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS ( HMG ‐CoA [hydroxymethylglutaryl‐coenzyme A] synthase)–mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU‐positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle. Conclusions This study is the first systems‐level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies.

An understanding of the activities of GSS extract and resveratrol as bacterial growth inhibitors and the specific mechanisms of cell accumulation is crucial for our understanding of Camp. jejuni resistance. GSS extract inhibition of Camp. jejuni adhesion to abiotic and biotic surfaces provides a further step towards the application of new innovative strategies to control Campylobacter contamination and infection via the food chain.

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