Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance.

Diet and obesity contribute to insulin resistance and type 2 diabetes, in part via the gut microbiome. To explore the role of gut-derived metabolites in this process, we assessed portal/peripheral blood metabolites in mice with different risks of obesity/diabetes, challenged with a high-fat diet (HFD) + antibiotics. In diabetes/obesity-prone C57BL/6J mice, 111 metabolites were portally enriched and 74 were peripherally enriched, many of which differed in metabolic-syndrome-resistant 129S1/129S6 mice.

Prospective study of circulating metabolomic profiles and breast cancer incidence among predominantly premenopausal women.

Background: Associations between premenopausal plasma metabolites and breast cancer incidence are largely unknown.

Methods: We conducted a prospective, matched case-control study in which we measured pre-diagnostic metabolomic profiles among predominantly premenopausal women in the Nurses' Health Study II (n = 2010). Lipids, carbohydrates, and organic acid-related metabolites (n = 218) were profiled via liquid chromatography-tandem mass spectrometry.

Steroid hormone biosynthesis and dietary related metabolites associated with excessive daytime sleepiness.

Background: Excessive daytime sleepiness (EDS) is a complex sleep problem that affects approximately 33% of the United States population. Although EDS usually occurs in conjunction with insufficient sleep and other sleep and circadian disorders, recent studies have shown unique genetic markers and metabolic pathways underlying EDS. Here, we aimed to further elucidate the biological profile of EDS using large-scale single- and pathway-level metabolomics analyses.

Association of the HDL lipidome with HDL traits before and after exercise training: HERITAGE family study.

Introduction: HDL particle functionality is influenced by its structure, including lipid composition. However, the effects of exercise training on the HDL lipidome and its relationship with HDL-related traits are largely unknown.

Objective: To investigate the HDL lipidome of 154 adults before and after 20 weeks of endurance exercise training in the HERITAGE Family Study.

Compartment-Specific Metabolic Alterations to Insulin Reflect Adiposity-Driven Variation and Predict Type 2 Diabetes.

Context: The metabolic mechanisms underlying insulin resistance (IR) are not fully understood. Metabolomic profiling can reveal compartment-specific variations and identify individuals at risk for type 2 diabetes (T2D).

Objective: To characterize insulin-induced metabolomic changes during a hyperinsulinemic-euglycemic clamp and evaluate a derived risk score's predictive value for T2D.

The Dietary Biomarkers Development Consortium: An Initiative for Discovery and Validation of Dietary Biomarkers for Precision Nutrition.

Unlabelled: Diet is a complex exposure that affects health across the lifespan. Objective biomarkers that can reliably reflect intake of nutrients, foods, and dietary patterns with sufficient accuracy are an important tool for assessing associations of diet with health outcomes. Advances in metabolomics, coupled with feeding trials and high-dimensional bioinformatics analyses, pave the way for discovering compounds that can serve as sensitive and specific biomarkers of dietary exposures.

Plasma and ovarian metabolomic responses to chronic stress in female mice.

Introduction: Chronic stress has been linked with higher risk of ovarian cancer and one posited pathway is through altered metabolism of amino acids, lipids, and other small molecule metabolites. However, the types of alterations that occur may not be uniform across tissue types.

Objectives: We aim to examine and compare the impacts of chronic stress on metabolomic changes in circulation and ovarian tissue.

Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy.

Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization. Here we show that metabolic shifts in the neovascular niche define angiogenic fate.

Neural Spectral Prediction for Structure Elucidation with Tandem Mass Spectrometry.

Structural elucidation using untargeted tandem mass spectrometry (MS/MS) has played a critical role in advancing scientific discovery [1, 2]. However, differentiating molecular fragmentation patterns between isobaric structures remains a prominent challenge in metabolomics [3-10], drug discovery [11-13], and reaction screening [14-17], presenting a significant barrier to the cost-effective and rapid identification of unknown molecular structures. Here, we present a geometric deep learning model, ICEBERG, that simulates collision-induced dissociation in mass spectrometry to generate chemically plausible fragments and their relative intensities with awareness of collision energies and polarities.

Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway.

Sphingolipids derived from Bacteroides species are associated with changes in host inflammation and metabolic syndrome; however, the signaling mechanisms within host cells are unknown. We utilize outer membrane vesicles (OMVs) from wild-type and sphingolipid-deficient Bacteroides strains to understand how these lipids modulate host inflammation. Characterization of the lipidome of B.

Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality.

Background: Dysregulation of cerebrospinal fluid (CSF) tryptophan metabolism contributes to the high mortality of tuberculous meningitis (TBM). We aimed to identify novel metabolic pathways associated with TBM mortality through untargeted metabolome-wide analysis.

Methods: We measured 619 metabolites using untargeted liquid chromatography-mass spectrometry in pre-treatment CSF from adults with TBM from Indonesia (n = 388, 34 HIV positive) and Vietnam (n = 679, 250 HIV positive).

Eclipse: a Python package for alignment of two or more nontargeted LC-MS metabolomics datasets.

Summary: Nontargeted LC-MS (liquid chromatography-tandem mass spectrometry) metabolomics datasets contain a wealth of information but present many challenges during analysis and processing. Often, two or more independently processed datasets must be aligned to form a complete dataset, but existing software does not fully meet our needs. For this, we have created an open-source Python package called Eclipse.

Associations of APOE variants with sphingomyelin and cholesterol metabolites across the life-course in diverse populations.

Introduction: Two alleles (ε2 and ε4) in the APOE gene are known to be strongly associated with lipid metabolism disorders, such as dyslipidemia, which are important risk factors for the development of cardiovascular diseases. While prior research has largely centered on adult populations, establishing APOE-lipid associations in infants, children, and adolescents-especially those from historically understudied groups-could inform earlier interventions and treatments.

Objectives: This study aimed to evaluate the dependence of the metabolome on the APOE variants using five diverse cohorts that span infancy through adulthood, comprising a total of over 190,000 individuals.

Metabolomic profiling of a cholesterol lowering plant-based diet from two randomized controlled feeding trials.

Background: Objective biomarkers of diet, such as metabolomics, may improve dietary assessment and provide additional insight into how diet influences disease risk. The portfolio diet, a cholesterol-lowering plant-based diet, is recommended for lowering low-density lipoprotein cholesterol (LDL-C). This diet is low in saturated fat and includes nuts, plant protein (legumes), viscous fiber, and phytosterols.

On the analysis of metabolite quantitative trait loci: Impact of different data transformations and study designs.

Metabolomic genome-wide association studies (mGWASs), or metabolomic quantitative trait locus (metQTL) analyses, are gaining growing attention. However, robust methods and analysis guidelines, vital to address the complexity of metabolomic data, remain to be established. Here, we use whole-genome sequencing and metabolomic data from two independent studies to compare different approaches.

Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles.

Key Points: We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which variants may be linked to kidney disease. We report distinct methylation profiling between risk allele carriers and noncarriers, many near gene family. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers.

Metabolomic Pathways of Inflammation and Mitochondrial Dysfunction Are Related to Worsening Healthy Aging Index and Mortality.

Background: Metabolic-inflammatory states are central to multiorgan mechanisms of aging, but precise functional biomarkers of physiological aging remain less clear.

Methods: In the Health, Aging, and Body Composition study, we defined metabolomic profiles of the Healthy Aging Index (HAI), a composite of cardiovascular, lung, cognitive, metabolic, and renal function (0-10, with higher scores indicating poorer health) in a split set design from 2015 older participants (mean age 73.6 years; 50% women; 35% Black).

A multi-metabolite signature robustly predicts long-term mortality in the PREDIMED trial and several US cohorts.

Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseline plasma metabolites repeatedly assessed at baseline and after 1 year, 38 plasma metabolites were identified as predictors of all-cause mortality. Gamma-amino-butyric acid (GABA), homoarginine, serine, creatine, 1-methylnicotinamide and a set of sphingomyelins, plasmalogens, phosphatidylethanolamines and cholesterol esters were inversely associated with all-cause mortality, whereas plasma dimethylguanidino valeric acid (DMGV), choline, short and long-chain acylcarnitines, 4-acetamidobutanoate, pseudouridine, 7-methylguanine, N6-acetyllysine, phenylacetylglutamine and creatinine were associated with higher mortality.

Cross-Ancestry Comparison of Aptamer and Antibody Proteomics Measures.

Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants (pQTL) and phenotypes. Here, we examined 2,157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1,930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2,157 proteins followed a bimodal distribution (median r=0.

ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states.

Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive.

Persistent PTSD symptoms are associated with plasma metabolic alterations relevant to long-term health: A metabolome-wide investigation in women.

Background: Post-traumatic stress disorder (PTSD) is characterized by severe distress and associated with cardiometabolic diseases. Studies in military and clinical populations suggest that dysregulated metabolomic processes may be a key mechanism. Prior work identified and validated a metabolite-based distress score (MDS) linked with depression and anxiety and subsequent cardiometabolic diseases.

Soluble Immune Checkpoint Protein and Lipid Network Associations with All-Cause Mortality Risk: Trans-Omics for Precision Medicine (TOPMed) Program.

Adverse cardiovascular events are emerging with the use of immune checkpoint therapies in oncology. Using datasets in the Trans-Omics for Precision Medicine program (Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study [JHS], and Framingham Heart Study), we examined the association of immune checkpoint plasma proteins with each other, their associated protein network with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and the association of HDL-C- and LDL-C-associated protein networks with all-cause mortality risk. Plasma levels of LAG3 and HAVCR2 showed statistically significant associations with mortality risk.