Non-targeted LC-MS/MS metabolomic profiling of human plasma uncovers a novel Mediterranean diet biomarker panel.

INTRODUCTION: Consumption of a Mediterranean diet (MD) has established health benefits, and the identification of novel biomarkers could enable objective monitoring of dietary pattern adherence. OBJECTIVES: The present investigation performed untargeted metabolomics on blood plasma from a controlled study of MD adherence, to identify novel blood-based metabolite biomarkers associated with the MD pattern, and to build a logistic regression model that could be used to characterise MD adherence. METHODS: A hundred and thirty-five plasma samples from n = 58 patients collected at different time points were available. Using a 14-point scale MD Score (MDS) subjects were divided into 'high' or 'low' MDS adherence groups and liquid chromatography-mass spectrometry (LC-MS/MS) was applied for analysis. RESULTS: The strongest association with MDS was pectenotoxin 2 seco acid (r = 0.53; ROC = 0.78), a non-toxic marine xenobiotic metabolite. Several lipids were useful biomarkers including eicosapentaenoic acid, the structurally related lysophospholipid (20:5(5Z,8Z,11Z,14Z,17Z)/0:0), a phosphatidylcholine (P-18:1(9Z)/16:0) and also xi-8-hydroxyhexadecanedioic acid. Two metabolites negatively correlated with MDS, these were the monoacylglycerides (0:0/16:1(9Z)/0:0) and (0:0/20:3(5Z,8Z,11Z)/0:0). By stepwise elimination we selected a panel of 3 highly discriminatory metabolites and developed a linear regression model which identified 'high MDS' individuals with high sensitivity and specificity [AUC (95% CI) 0.83 (0.76-0.97)]. CONCLUSION: Our study highlights the utility of metabolomics as an approach for developing novel panels of dietary biomarkers. Quantitative profiling of these metabolites is required to validate their utility for evaluating dietary adherence.

Integrative Analysis Unveils the Correlation of Aminoacyl-tRNA Biosynthesis Metabolites with the Methylation of the SEPSECS Gene in Huntington's Disease Brain Tissue.

The impact of environmental factors on epigenetic changes is well established, and cellular function is determined not only by the genome but also by interacting partners such as metabolites. Given the significant impact of metabolism on disease progression, exploring the interaction between the metabolome and epigenome may offer new insights into Huntington's disease (HD) diagnosis and treatment. Using fourteen post-mortem HD cases and fourteen control subjects, we performed metabolomic profiling of human postmortem brain tissue (striatum and frontal lobe), and we performed DNA methylome profiling using the same frontal lobe tissue. Along with finding several perturbed metabolites and differentially methylated loci, Aminoacyl-tRNA biosynthesis (adj p-value = 0.0098) was the most significantly perturbed metabolic pathway with which two CpGs of the SEPSECS gene were correlated. This study improves our understanding of molecular biomarker connections and, importantly, increases our knowledge of metabolic alterations driving HD progression.

Application of 1H-NMR Metabolomics for the Discovery of Blood Plasma Biomarkers of a Mediterranean Diet.

The Mediterranean diet (MD) is a dietary pattern well-known for its benefits in disease prevention. Monitoring adherence to the MD could be improved by discovery of novel dietary biomarkers. The MEDiterranean Diet in Northern Ireland (MEDDINI) intervention study monitored the adherence of participants to the MD for up to 12 months. This investigation aimed to profile plasma metabolites, correlating each against the MD score of participants (n = 58). Based on an established 14-point scale MD score, subjects were classified into two groups ("low" and "high"). 1H-Nuclear Magnetic Resonance (1H-NMR) metabolomic analysis found that citric acid was the most significant metabolite (p = 5.99 × 10-4*; q = 0.03), differing between 'low' and 'high'. Furthermore, five additional metabolites significantly differed (p < 0.05; q < 0.35) between the two groups. Discriminatory metabolites included: citric acid, pyruvic acid, betaine, mannose, acetic acid and myo-inositol. Additionally, the top five most influential metabolites in multivariate models were also citric acid, pyruvic acid, betaine, mannose and myo-inositol. Metabolites significantly correlated with the consumption of certain food types. For example, citric acid positively correlated fruit, fruit juice and vegetable constituents of the diet, and negatively correlated with sweet foods alone or when combined with carbonated drinks. Citric acid was the best performing biomarker and this was enhanced by paired ratio with pyruvic acid. The present study demonstrates the utility of metabolomic profiling for effectively assessing adherence to MD and the discovery of novel dietary biomarkers.

Targeted biochemical profiling of brain from Huntington's disease patients reveals novel metabolic pathways of interest.

Huntington's disease (HD) is a devastating, progressive neurodegenerative disease with a distinct phenotype characterized by chorea and dystonia, incoordination, cognitive decline and behavioral difficulties. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene. Herein DI/LC-MS/MS was used to accurately identify and quantify 185 metabolites in post mortem frontal lobe and striatum from HD patients and healthy control cases. The findings link changes in energy metabolism and phospholipid metabolism to HD pathology and also demonstrate significant reductions in neurotransmitters. Further investigation into the oxidation of fatty acids and phospholipid metabolism in pre-clinical models of HD are clearly warranted for the identification of potential therapies. Additionally, panels of 5 metabolite biomarkers were identified in both the frontal lobe (AUC = 0.962 (95% CI: 0.85-1.00) and striatum (AUC = 0.988 (95% CI: 0.899-1.00). This could have clinical utility in more accessible biomatrices such as blood serum for the early detection of those entering the prodromal phase of the disease, when treatment is believed to be most effective. Further evaluation of these biomarker panels in human cohorts is justified to determine their clinical efficacy.