Levels Of Circulating Metabolites Research Articles

Arginine-NO metabolites are associated with morbidity in single ventricle infants undergoing stage 2 palliation.

Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes. Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia. Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05). Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD. Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD.

DOP33 Distinct perturbances in metabolic pathways associate with disease progression in patients with Inflammatory Bowel Disease

Abstract Background Patients with inflammatory bowel diseases (IBD) exhibit distinct shifts in circulating metabolite levels that have been associated with clinical disease activity and disease phenotype. However, there are limited data on the impact of metabolomic changes on disease progression in IBD. We aimed to understand the association of circulating metabolite levels and related pathways with the risk of disease progression in patients with IBD. Methods We conducted an observational cohort study using the Mount Sinai Crohn’s and Colitis Registry (MSCCR). Patients were prospectively enrolled with baseline questionnaires and biospecimens that were then linked to longitudinal electronic health record data. A total of 1,456 serum metabolites were measured in 277 patients with UC and 375 patients with CD using untargeted metabolomics. Disease progression was defined as any new steroid or biological prescriptions, IBD-related hospitalizations, or surgery. Multivariable Cox proportional hazards regression models, adjusted for age, sex, smoking, biologic use, and surgery were used to explore metabolite associations with risk of disease progression. Metabolite set enrichment analysis (MSEA) was performed to identify underlying metabolic pathways associated with disease progression. Results During a median 2-year follow-up time (IQR 0.3-5.1 years), 375 patients (57.5%) had a disease progression event. Among CD, 151 metabolites significantly correlated with the composite outcome (FDR&amp;lt;0.1). Of these, 81 (53.6%) were linked to higher risk, mainly enriched in amino acids, purine, and pyrimidine metabolism, fibrinogen cleavage peptides, and bile acid pathways. Additionally, 70 (46.4%) metabolites associated with lower risk with enrichment in fatty acid metabolism, steroid biosynthesis, histidine, tryptophan, and antioxidant pathways. In CD, aspartate metabolism was most significantly associated with increased risk and linoleic metabolism with decreased risk. In UC, 84 metabolites were significantly associated with disease progression (FDR&amp;lt;0.1), with 29 (34.5%) associated with increased and 55 (65.5%) with decreased risk. Metabolic pathways linked to higher risk were sphingolipid, benzoate, hydrogen sulfide, polyamine, and tyrosine metabolism, while protective metabolites were enriched in branched-chain amino acid (BCAA), steroid biosynthesis, histidine, and phenylalanine pathways. In UC, sphingolipid metabolism was prominently associated with increased risk and BCAA metabolism with decreased risk. Conclusion Specific metabolites and metabolic pathways are associated with risk of disease progression in patients with IBD, highlighting potential prognostic metabolite biomarkers and pathways that may be important in modulating risk of disease progression.

An exploratory metabolomic comparison of participants with fast or absent functional progression from 2CARE, a randomized, double-blind clinical trial in Huntington’s disease

Huntington’s disease (HD) is increasingly recognized for diverse pathology outside of the nervous system. To describe the biology of HD in relation to functional progression, we previously analyzed the plasma and CSF metabolome in a cross-sectional study of participants who had various degrees of functional impairment. Here, we carried out an exploratory study in plasma from HD individuals over a 3-year time frame to assess whether differences exist between those with fast or absent clinical progression. There were more differences in circulating metabolite levels for fast progressors compared to absent progressors (111 vs 20, nominal p < 0.05). All metabolite changes in faster progressors were decreases, whereas some metabolite concentrations increased in absent progressors. Many of the metabolite levels that decreased in the fast progressors were higher at Screening compared to absent progressors but ended up lower by Year 3. Changes in faster progression suggest greater oxidative stress and inflammation (kynurenine, diacylglycerides, cysteine), disturbances in nitric oxide and urea metabolism (arginine, citrulline, ornithine, GABR), lower polyamines (putrescine and spermine), elevated glucose, and deficient AMPK signaling. Metabolomic differences between fast and absent progressors suggest the possibility of predicting functional decline in HD, and possibly delaying it with interventions to augment arginine, polyamines, and glucose regulation.

Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

Precise Metabolomics Defines Systemic Metabolic Dysregulation Distinct to Acute Myocardial Infarction Associated With Diabetes.

Acute myocardial infarction (AMI) is a leading cause of death and disability. Diabetes is an important risk factor and a common comorbidity in AMI patients. The higher mortality risk of diabetes-AMI relative to nondiabetes-AMI indicates a need for specific treatment to improve clinical outcome. However, the global metabolic dysregulation of AMI complicated with diabetes is still unclear. We aim to systematically interrogate changes in the metabolic microenvironment immediate to AMI episodes in the absence or presence of diabetes. In this work, quantitative metabolomics was used to investigate plasma metabolic differences between diabetes-AMI (n=59) and nondiabetes-AMI (n=59) patients. A diverse array of perturbed metabolic pathways involving carbohydrate metabolism, lipid metabolism, glycolysis, tricarboxylic acid cycle, and amino acid metabolism emerged. In all, our omics-oriented approach defined a metabolic signature of afflicted mitochondrial function aggravated by concurrent diabetes in AMI patients. In particular, our analyses uncovered N-lactoyl-phenylalanine and lysophosphatidylcholines as key functional metabolites that skewed the metabolic picture of diabetes-AMI relative to nondiabetes-AMI. N-lactoyl-phenylalanine was strongly associated with metabolic indicators reflective of mitochondrial overload and negatively correlated with HbA1c (glycosylated hemoglobin, type A1C) specifically in hyperglycemic AMI, suggestive of its central role in glucose utilization and mitochondrial energy production instrumental to the clinical outcome of diabetes-AMI. Reductions in lysophosphatidylcholines, which were negatively correlated with blood glucose and inflammatory markers, might further compromise glucose expenditure and aggravate inflammation leading to poorer prognosis in diabetes-AMI. As circulating metabolite levels are amenable to therapeutic intervention, such shifts in metabolic signatures provide new clues and potential therapeutic targets specific to the treatment of diabetes-AMI.

Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide.

Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often develop recurrent disease, and the disease remains incurable with median survival below 2 years. Resistance to bevacizumab is driven by hypoxia in the tumor and evofosfamide is a hypoxia-activated prodrug, which we tested in a phase 2, dual center (University of Texas Health Science Center in San Antonio and Dana Farber Cancer Institute) clinical trial after bevacizumab failure. Tumor hypoxic volume was quantified by 18F-misonidazole PET. To identify circulating metabolic biomarkers of tumor hypoxia in patients, we used a high-resolution liquid chromatography-mass spectrometry-based approach to profile blood metabolites and their specific enantiomeric forms using untargeted approaches. Moreover, to evaluate early response to treatment, we characterized changes in circulating metabolite levels during treatment with combined bevacizumab and evofosfamide in recurrent GBM after bevacizumab failure. Gamma aminobutyric acid, and glutamic acid as well as its enantiomeric form D-glutamic acid all inversely correlated with tumor hypoxia. Intermediates of the serine synthesis pathway, which is known to be modulated by hypoxia, also correlated with tumor hypoxia (phosphoserine and serine). Moreover, following treatment, lactic acid was modulated by treatment, likely in response to a hypoxia mediated modulation of oxidative vs glycolytic metabolism. In summary, although our results require further validation in larger patients’ cohorts, we have identified candidate metabolic biomarkers that could evaluate the extent of tumor hypoxia and predict the benefit of combined bevacizumab and evofosfamide treatment in GBM following bevacizumab failure.

The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium.

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.

Selected Articles from This Issue

Cancer mortality rates are high in rural areas in the United States, and practitioner uses of rural informal collaborative networks are not well understood. Carothers, Allen, and colleagues conducted network analyses in five rural service areas with agencies that address cancer risk, measuring collaborations on cancer prevention activities and health service referrals. Results were disseminated to practitioners through infographics, workshops, and online interactive applications. Practitioners used the analyses for strategic planning, to identify relationship improvement opportunities, and demonstrate network strengths to funders. Dissemination of findings to network members facilitates real-world use of results to benefit programs and policies.Aboriginal and Torres Strait Islander peoples experience lower life expectancy and poorer cancer survival rates than other Australians. Dasgupta and colleagues examine this disparity using a study cohort of more than 700,000 Australians diagnosed with an invasive solid cancer from 2005–2016. Aboriginal and Torres Strait Islanders experienced consistently lower remaining life expectancy after a cancer diagnosis than other Australians. One-third of the difference was due to cancer mortality. If the differences in cancer mortality were removed, the average life years remaining following a cancer diagnosis would increase by 17%. These important differences highlight the need for culturally appropriate, accessible and effective health services and cancer care.Prior studies of breast cancer disparities have focused primarily on differences between Black and White women, yet contemporary patterns of disparity for other groups are not well understood. Primm and colleagues used the most recent data available from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) to examine breast cancer disparities by stage at diagnosis across nine racial and ethnic groups. Analysis of breast cancer outcomes by racial and ethnic groups, the authors found persistent disparities in both the likelihood of being diagnosed at an early stage, and also in survival among women diagnosed at early stages. The results have implications for efforts to reduce entrenched racial and ethnic disparities in breast cancer early detection and survival.Metabolomics studies are usually conducted in a relatively small number of participants. Shu and colleagues performed integrative analyses to combine circulating metabolomics data with large-scale genome-wide association data to infer the associations between genetically predicted circulating metabolite levels and colorectal cancer (CRC) risk. The study identified 21 metabolites (mainly lipids) that were significantly associated with CRC risk in both European and East Asian populations. These identified metabolites should be investigated further for their potential to be developed into new tools for risk assessment of CRC in the two populations.

Metabolome Genome-Wide Association Study Identifies 74 Novel Genomic Regions Influencing Plasma Metabolites Levels.

Metabolites are small products of metabolism that provide a snapshot of the wellbeing of an organism and the mechanisms that control key physiological processes involved in health and disease. Here we report the results of a genome-wide association study of 722 circulating metabolite levels in 8809 subjects of European origin, providing both breadth and depth. These analyses identified 202 unique genomic regions whose variations are associated with the circulating levels of 478 different metabolites. Replication with a subset of 208 metabolites that were available in an independent dataset for a cohort of 1768 European subjects confirmed the robust associations, including 74 novel genomic regions not associated with any metabolites in previous works. This study enhances our knowledge of genetic mechanisms controlling human metabolism. Our findings have major potential for identifying novel targets and developing new therapeutic strategies.

Gut Microbiome-Dependent Metabolic Pathways and Risk of Lethal Prostate Cancer: Prospective Analysis of a PLCO Cancer Screening Trial Cohort.

Diet and the gut microbiome have a complex interaction that generates metabolites with an unclear effect on lethal prostate cancer risk. Identification of modifiable risk factors for lethal prostate cancer is challenging given the long natural history of this disease and difficulty of prospectively identifying lethal cancers. Mass spectrometry was performed on baseline serum samples collected from 173 lethal prostate cancer cases and 519 controls enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial. Baseline serum levels of choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, phenylacetylglutamine, hippuric acid, and p-cresol sulfate were quantified and analyzed by quartile. Conditional multivariable logistic regression analysis associated analyte levels with lethal prostate cancer incidence after adjusting for body mass index and PSA. The Cochran-Armitage test evaluated analyte level trends across quartiles. Relative to those in the first quartile, cases with the highest baseline levels of choline (Q4 OR: 2.19; 95% CI, 1.23-3.90; P-trend: 0.005) and betaine (Q4 OR: 1.86; 95% CI, 1.05-3.30; P-trend: 0.11) exhibited increased odds of developing lethal prostate cancer. Higher baseline serum levels of phenylacetylglutamine (Q4 OR: 2.55; 95% CI, 1.40-4.64; P-trend: 0.003), a gut microbiome metabolite of phenylalanine with adrenergic activity, were also associated with lethal prostate cancer. Baseline serum levels of one-carbon methyl donors and adrenergic compounds resulting from human and gut microbiota-mediated metabolism are associated with increased lethal prostate cancer risk. Dietary composition, circulating metabolite levels, and downstream signaling pathways may represent modifiable risk factors associated with incident lethal prostate cancer. Beta-adrenergic blockade represents an additional target for oncologic risk reduction.

Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder.

Ghrelin may influence several alcohol-related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD). We used serum samples from a randomized, crossover, double-blind, placebo-controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3µg/kg) followed by continuous infusion (16.9ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self-administration (IV-ASA) session and the second experiment included an IV alcohol clamp (IV-AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session. In both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV-ASA q-value=0.0003 and IV-AC q<0.0001), corticosterone (IV-ASA q=0.0202 and IV-AC q<0.0001), and glycochenodeoxycholic acid (IV-ASA q=0.0375 and IV-AC q=0.0013). In the IV-ASA experiment, ghrelin infusion increased levels of cortisone (q=0.0352) and fatty acids 18:1 (q=0.0406) and 18:3 (q=0.0320). Moreover, in the IV-AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q<0.0001) and phenylalanine (q=0.0458). IV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine-conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol.

Exploring the Multimodal Role of Yucca schidigera Extract in Protection against Chronic Ammonia Exposure Targeting: Growth, Metabolic, Stress and Inflammatory Responses in Nile Tilapia (Oreochromis niloticus L.).

Simple SummaryAmmonia is a problematic environmental toxicant for aquatic species. The current study aimed to declare the modulatory effect(s) of YSE against chronic ammonia intoxication in Nile tilapia through its effects on growth performance, haemato-biochemical and antioxidant-related parameters, and histopathological changes, as well as the molecular gene expression of some genes related to appetite and growth, glucose and lipid metabolism and some inflammatory cytokines. Our results indicated that Yucca schidigera extract alleviated the adverse impacts induced by ammonia intoxication. YSE could be used as a functional water supplement in aquaculture.Ammonia is a critical hazardous nitrogen metabolic product in aquaculture. Despite trials for its control, ammonia intoxication remains one of the most critical issues to overcome. In this study, we explored the modulatory effect and potential mechanism by which Yucca schidigera extract (YSE) can ameliorate ammonia intoxication-induced adverse effects on tilapia health and metabolism. A total number of 120 Nile tilapia were evenly assigned into four groups with three replicates each. The first group served as normal control group; the second group was exposed to ammonia alone from the beginning of the experiment and for four weeks. The third group was supplied with YSE in water at a dose of 8 mg/L and exposed to ammonia. The fourth group was supplied with YSE only in water at a dose of 8 mg/L. YSE supplementation succeeded in improving water quality by reducing pH and ammonia levels. Moreover, YSE supplementation markedly alleviated chronic ammonia-induced adverse impacts on fish growth by increasing the final body weight (FBW), specific growth rate (SGR), feed intake and protein efficiency ratio (PER) while reducing the feed conversion ratio (FCR) via improvements in food intake, elevation of hepatic insulin-like growth factor (ILGF-1) and suppression of myostatin (MSTN) expression levels with the restoration of lipid reserves and the activation of lipogenic potential in adipose tissue as demonstrated by changes in the circulating metabolite levels. In addition, the levels of hepato-renal injury biomarkers were restored, hepatic lipid peroxidation was inhibited and the levels of hepatic antioxidant biomarkers were enhanced. Therefore, the current study suggests that YSE supplementation exerted an ameliorative role against chronic ammonia-induced oxidative stress and toxic effects due to its free radical-scavenging potential, potent antioxidant activities and anti-inflammatory effects.

POS0421 COMBINED ANALYSIS OF METABOLIC AND TRANSCRIPTOMIC KIDNEY PROFILES OF NZW/B-F1 MURINE LUPUS UNCOVERS BIOLOGICAL MECHANISMS PRECEDING THE ONSET OF NEPHRITIS

Background:Metabolic pathways are important regulators of immune differentiation and activation in kidneys. Kidneys directly impact systemic metabolism, circulating metabolite levels, and express intrinsic metabolic activity. The integration of renal metabolomic and transcriptomic profiles may unravel unique gene-metabolite pairs of biological significance in lupus nephritis (LN).Objectives:To decipher gene-metabolite signatures at both pre-nephritic and nephritic stages of lupus.Methods:Kidneys were isolated and snap-frozen after perfusion from female NZB/NZW-F1 lupus mice at the pre-nephritic (3-month-old) and nephritic (6-month-old exhibiting ≥100 ng/dL of urine protein) stage of lupus (n=6/group). Age-matched female C57BL/6 mice were used as healthy controls. Sample extracts were used for RNA sequencing and 1H-NMR spectroscopy metabolic profiling. DESeq2 was used to identify differentially expressed genes. Univariate analysis was used to reveal metabolic differences characteristic for nephritis.Results:Comparative transcriptomic analyses uncovered multiple transcripts related to metabolic pathways: In pre-nephritic kidneys, lipid metabolism, cellular respiration, TCA cycle, amino acid metabolism processes were overrepresented in the upregulated genes while in nephritic kidneys, amino acid metabolism processes were overrepresented among the downregulated genes (Figure 1). 1H-NMR analysis revealed a total of 49 metabolites. Comparison of the metabolic levels of nephritic and pre-nephritic animals revealed that ADP, ATP, NAD+, Taurine and Myo-inositol decreased, while Thr increased significantly. The comparison to corresponding control animals, demonstrated that only myo-inositol increased significantly. Integration of kidney metabolomics and transcriptomics indicated the involvement of processes related to glutathione metabolism, leukocyte trans-endothelial migration and antigen presentation during the established renal disease stage.Conclusion:The combined transcriptomics and metabolomics analysis revealed metabolic derangements in lupus-affected kidneys both during subclinical and overt LN. Deregulated tissue-levels of taurine and myo-inositol at the subclinical stage of the disease suggest aberrant renal biochemistry preceding the development of overt LN that may directly impact systemic metabolism and circulating metabolite levels.Figure 1.Pathways linked to cell metabolism were overrepresented among 3-month upregulated and 6-month lupus mice (F1) downregulated DEGS (differentially expressed genes) compared to controls (C57BL/6).Acknowledgements:This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390).Disclosure of Interests:None declared

Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m2) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.

Effects of myocardial ischemia/reperfusion injury on plasma metabolomic profile during aging.

BackgroundHeart disease is a frequent cause of hospitalization and mortality for elderly patients. A common feature of both heart disease and aging itself is the involvement of metabolic organ alterations ultimately leading to changes in circulating metabolite levels. However, the specific contribution of aging and ischemic injury to the metabolic dysregulation occurring in older adults with ischemic heart disease is still unknown.AimTo evaluate the effects of aging and ischemia/reperfusion (I/R) injury on plasma metabolomic profiling in mice.MethodsYoung and aged mice were subjected to a minimally invasive model of I/R injury or sham operation. Complete evaluation of cardiac function and untargeted plasma metabolomics analysis were performed.ResultsWe confirmed that aged mice from the sham group had impaired cardiac function and augmented left ventricular (LV) dimensions compared to young sham‐operated mice. Further, we found that ischemic injury did not drastically reduce LV systolic/diastolic function and dyssynchrony in aged compared to young mice. Using an untargeted metabolomics approach focused on aqueous metabolites, we found that ischemic injury does not affect the plasma metabolomic profile either in young or old mice. Our data also demonstrate that age significantly affects circulating metabolite levels (predominantly amino acids, phospholipids and organic acids) and perturbs several pathways involved in amino acid, glucid and nucleic acid metabolism as well as pyridoxal‐5′‐phosphate salvage pathway in both sham and ischemic mice.ConclusionsOur approach increases our understanding of age‐associated plasma metabolomic signatures in mice with and without heart disease excluding confounding factors related to metabolic comorbidities.

Nutrient metabolism and cancer in the invivo context: a metabolic game of give and take.

Nutrients are indispensable resources that provide the macromolecular building blocks and energy requirements for sustaining cell growth and survival. Cancer cells require several key nutrients to fulfill their changing metabolic needs as they progress through stages of development. Moreover, both cell-intrinsic and microenvironment-influenced factors determine nutrient dependencies throughout cancer progression-for which a comprehensive characterization remains incomplete. In addition to the widely studied role of genetic alterations driving cancer metabolism, nutrient use in cancer tissue may be affected by several factors including the following: (i) diet, the primary source of bodily nutrients which influences circulating metabolite levels; (ii) tissue of origin, which can influence the tumor's reliance on specific nutrients to support cell metabolism and growth; (iii) local microenvironment, which dictates the accessibility of nutrients to tumor cells; (iv) tumor heterogeneity, which promotes metabolic plasticity and adaptation to nutrient demands; and (v) functional demand, which intensifies metabolic reprogramming to fuel the phenotypic changes required for invasion, growth, or survival. Here, we discuss the influence of these factors on nutrient metabolism and dependence during various steps of tumor development and progression.

Global Plasma Metabolomics to Identify Potential Biomarkers of Blood Pressure Progression.

The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/-0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort. Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.

The influence of rare variants in circulating metabolic biomarkers.

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.

Untargeted serum metabolomics of hepatocellular carcinoma in a prospective cohort of European populations

Introduction Hepatocellular carcinoma (HCC) is characterised by increasing incidence, late diagnosis and high mortality rates. Changes in liver metabolism during HCC development may alter circulating metabolite levels, which could be identified years before HCC diagnosis. Also, a detailed understanding of metabolic dysfunction in HCC may lead to the identification of better prevention strategies. In this context, we aimed to characterise pre-diagnostic circulating biomarkers of HCC risk using an LC-MS untargeted metabolomics approach. Methods A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of > 520,000 participants from 10 European countries. Extensive metabolic profiling was conducted using liquid chromatography-mass spectrometry (LC-MS) and compared between serum samples of 129 HCC cases and their 1:1 matched controls. Multivariable univariate conditional logistic regression models adjusted for anthropometric factors, physical activity, alcohol intake, smoking status and education were used to estimate HCC risk associated with each biomarker and calculated as odds ratios (OR) per 1 standard deviation of log-transformed value. Results Out of 9206 detected metabolic features, 220 significantly discriminated HCC cases from controls after Benjamini-Hochberg correction for multiple testing. Among 37 key compounds that were annotated, 14 were identified with high confidence using authentic chemical standards. Among those, retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethylhydroxychroman and creatine were inversely associated with HCC risk (ORs ranging from 0.27 to 0.56). Nine metabolites exhibited positive associations (OR = 6.78 to 2.04): 7-methylguanine, glycocholic acid, glycocheno-deoxycholic acid, L,L-cyclo(leucyl-prolyl), sphingosine, p-hydroxyphenyllactic acid, isatin, N1-acetylspermidine and tyrosine. The remaining 23 annotated metabolites were mainly represented by phospoholipids (mostly inverse associations) and two bilirubin metabolites (positive associations). Conclusions Our findings indicate that dietary factors, altered cholesterol and phospholipid metabolism, DNA damage, and gut bacterial metabolism appear to be involved in HCC development. If validated, these profile changes may be explored as markers of early HCC diagnosis.

Metabolite profiling of obese individuals before and after a one year weight loss program.

We and others have previously characterized changes in circulating metabolite levels following diet-induced weight loss. Our aim was to investigate whether baseline metabolite levels and weight-loss-induced changes in these are predictive of or associated with changes in body mass index (BMI) and metabolic risk traits. Serum metabolites were analyzed with gas and liquid chromatography/mass spectrometry in 91 obese individuals at baseline and after participating in a 1 year non-surgical weight loss program.ResultsA total of 137 metabolites were identified and semi-quantified at baseline (BMI 42.7±5.8, mean±s.d.) and at follow-up (BMI 36.3±6.6). Weight-loss-induced modification was observed for levels of 57 metabolites in individuals with ⩾10% weight loss. Lower baseline levels of xylitol was predictive of a greater decrease in BMI (β=0.06, P<0.01) and ⩾10% weight loss (odds ratio (OR)=0.2, confidence interval (CI)=0.07-0.7, P=0.01). Decreases in levels of isoleucine, leucine, valine and tyrosine were associated with decrease in BMI (β>0.1, P<0.05) and ⩾10% weight loss (isoleucine: OR=0.08, CI=0.01-0.3, leucine: OR=0.1, CI=0.01-0.6, valine: OR=0.1, CI=0.02-0.5, tyrosine: OR=0.1, CI=0.03-0.6, P<0.02). Diet-induced weight loss leads to mainly reduced levels of metabolites that are elevated in obese insulin resistant individuals. We identified multiple new associations with metabolic risk factors and validated several previous findings related to weight loss-mediated metabolite changes. Levels of specific metabolites, such as xylitol, may be predictive of the response to non-surgical weight loss already at baseline.