Branched chain α-ketoacids aerobically activate HIF1α signaling in vascular cells.

Hypoxia-inducible factor 1α (HIF1α) is a master regulator of numerous biological processes under low oxygen tensions. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in primary cells remain elusive. Here, we show that HIF1α signaling is activated in several human primary vascular cells under ambient oxygen tensions, and in vascular smooth muscle cells (VSMCs) of normal human lung tissue, which contributed to a relative resistance to further enhancement of glycolytic activity in hypoxia. Mechanistically, aerobic HIFα activation is mediated by paracrine secretion of three branched chain α-ketoacids (BCKAs), which suppress prolyl hydroxylase domain-containing protein 2 (PHD2) activity via direct inhibition and via lactate dehydrogenase A (LDHA)-mediated generation of L-2-hydroxyglutarate (L2HG). Metabolic dysfunction induced by BCKAs was observed in the lungs of rats with pulmonary arterial hypertension (PAH) and in pulmonary artery smooth muscle cells (PASMCs) from idiopathic PAH patients. BCKA supplementation stimulated glycolytic activity and promoted a phenotypic switch to the synthetic phenotype in PASMCs of normal and PAH subjects. In summary, we identify BCKAs as novel signaling metabolites that activate HIF1α signaling in normoxia and that the BCKA-HIF1α pathway modulates VSMC function and may be relevant to pulmonary vascular pathobiology.

Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension.

Importance: Blood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension. Objective: To identify protein markers associated with EBP and test their association with incident hypertension. Design, Setting, and Participants: This study assayed 4977 plasma proteins in 681 healthy participants (from 763 assessed) of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE; data collection from January 1993 to December 1997 and plasma proteomics from January 2019 to January 2020) Family Study at rest who underwent 2 cardiopulmonary exercise tests. Individuals were free of CVD at the time of recruitment. Individuals with resting SBP ≥160 mm Hg or DBP ≥100 mm Hg or taking antihypertensive drug therapy were excluded from the study. The association between resting plasma protein levels to both resting BP and EBP was evaluated. Proteins associated with EBP were analyzed for their association with incident hypertension in the Framingham Heart Study (FHS; n = 1177) and validated in the Jackson Heart Study (JHS; n = 772) and Multi-Ethnic Study of Atherosclerosis (MESA; n = 1367). Proteins associated with incident hypertension were tested for putative causal links in approximately 700 000 individuals using cis-protein quantitative loci mendelian randomization (cis-MR). Data were analyzed from January 2023 to January 2024. Exposures: Plasma proteins. Main Outcomes and Measures: EBP was defined as the BP response during a fixed workload (50 W) on a cycle ergometer. Hypertension was defined as BP ≥140/90 mm Hg or taking antihypertensive medication. Results: Among the 681 participants in the HERITAGE Family Study, the mean (SD) age was 34 (13) years; 366 participants (54%) were female; 238 (35%) were self-reported Black and 443 (65%) were self-reported White. Proteomic profiling of EBP revealed 34 proteins that would not have otherwise been identified through profiling of resting BP alone. Transforming growth factor ß receptor 3 (TGFBR3) and prostaglandin D2 synthase (PTGDS) had the strongest association with exercise systolic BP (SBP) and diastolic BP (DBP), respectively (TGFBR3: exercise SBP, ß estimate, -3.39; 95% CI, -4.79 to -2.00; P = 2.33 × 10-6; PTGDS: exercise DBP ß estimate, -2.50; 95% CI, -3.29 to -1.70; P = 1.18 × 10-9). In fully adjusted models, TGFBR3 was inversely associated with incident hypertension in FHS, JHS, and MESA (hazard ratio [HR]: FHS, 0.86; 95% CI, 0.75-0.97; P = .01; JHS, 0.87; 95% CI, 0.77-0.97; P = .02; MESA, 0.84; 95% CI, 0.71-0.98; P = .03; pooled cohort, 0.86; 95% CI, 0.79-0.92; P = 6 × 10-5). Using cis-MR, genetically predicted levels of TGFBR3 were associated with SBP, hypertension, and CVD events (SBP: ß, -0.38; 95% CI, -0.64 to -0.11; P = .006; hypertension: odds ratio [OR], 0.99; 95% CI, 0.98-0.99; P < .001; heart failure with hypertension: OR, 0.86; 95% CI, 0.77-0.97; P = .01; CVD: OR, 0.84; 95% CI, 0.77-0.92; P = 8 × 10-5; cerebrovascular events: OR, 0.77; 95% CI, 0.70-0.85; P = 5 × 10-7). Conclusions and Relevance: Plasma proteomic profiling of EBP identified a novel protein, TGFBR3, which may protect against elevated BP and long-term CVD outcomes.

Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.

AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

24-h urinary sodium and potassium excretions, plasma metabolomic profiles, and cardiometabolic biomarkers in the United States adults: a cross-sectional study.

BACKGROUND: High-sodium and low-potassium intakes are associated with a higher risk of hypertension and cardiovascular disease, but there are limited data on the circulating metabolomics profiles of 24-h urinary sodium and potassium excretions in free-living individuals. OBJECTIVES: We aimed to characterize the metabolomics signatures of a high-sodium and low-potassium diet in a cross-sectional study. METHODS: In 1028 healthy older adults from the Women's and Men's Lifestyle Validation Studies, we investigated the association of habitual sodium and potassium intakes measured by 2 to 4 24-h urine samples with plasma metabolites (quantified using liquid chromatography-tandem mass spectrometry) and metabolomic pathways. Our primary exposures were energy-adjusted 24-h urinary sodium excretion, potassium excretion, and sodium-to-potassium ratio, calculated based on energy expenditure derived from the doubly labeled water method. We then assessed the partial correlations of their metabolomics scores, derived from elastic net regressions, with cardiometabolic biomarkers. RESULTS: Higher sodium excretion was associated with 38 metabolites including higher piperine, phosphatidylethanolamine, and C5:1 carnitine. In pathway analysis, higher sodium excretion was associated with enhanced biotin and propanoate metabolism and enhanced degradation of lysine and branched-chain amino acids (BCAAs). Metabolites associated with higher potassium and lower sodium-to-potassium ratio included quinic acid and proline-betaine. After adjusting for confounding factors, the metabolomics score for sodium-to-potassium ratio positively correlated with fasting insulin (Spearman's rank correlation coefficient ρ = 0.27), C-peptide (ρ = 0.30), and triglyceride (ρ = 0.46), and negatively with adiponectin (ρ = -0.40), and high-density lipoprotein cholesterol (ρ = -0.42). CONCLUSIONS: We discovered metabolites and metabolomics pathways associated with a high-sodium diet, including metabolites related to biotin, propanoate, lysine, and BCAA pathways. The metabolomics signature for a higher sodium low-potassium diet is associated with multiple components of elevated cardiometabolic risk.

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.

Cancer cells convert nutrients into energy differently compared to healthy cells. This difference in metabolism allows them to grow and divide more quickly and sometimes to migrate to different areas of the body. The environment around cancer cells ­ known as the tumor microenvironment ­ contains a variety of different cells and blood vessels, which are bathed in interstitial fluid. This microenvironment provides nutrients for the cancer cells to metabolize, and therefore influences how well a tumor grows and how it might respond to treatment. Recent advances with techniques such as mass spectrometry, which can measure the chemical composition of a substance, have allowed scientists to measure nutrient levels in the tumor microenvironments of mice. However, it has been more difficult to conduct such studies in humans, as well as to compare the tumor microenvironment to the healthy tissue the tumors arose from. Abbott, Ali, Reinfeld et al. aimed to fill this gap in knowledge by using mass spectrometry to measure the nutrient levels in the tumor microenvironment of 55 patients undergoing surgery to remove kidney tumors. Comparing the type and levels of nutrients in the tumor interstitial fluid, the neighboring healthy kidney and the blood showed that nutrients in the tumor and healthy kidney were more similar to each other than those in the blood. For example, both the tumor and healthy kidney interstitial fluids contained less glucose than the blood. However, the difference between nutrient composition in the tumor and healthy kidney interstitial fluids was insignificant, suggesting that the healthy kidney and its tumor share a similar environment. Taken together, the findings indicate that kidney cancer cells must adapt to the nutrients available in the kidney, rather than changing what nutrients are available in the tissue. Future studies will be required to investigate whether this finding also applies to other types of cancer. A better understanding of how cancer cells adapt to their environments may aid the development of drugs that aim to disrupt the metabolism of tumors.

Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and lacks disease-modifying therapies. We developed a Drosophila model for identifying novel glial-based therapeutic targets for PD. Human alpha-synuclein is expressed in neurons and individual genes are independently knocked down in glia. We performed a forward genetic screen, knocking down the entire Drosophila kinome in glia in alpha-synuclein expressing flies. Among the top hits were five genes (Ak1, Ak6, Adk1, Adk2, and awd) involved in adenosine metabolism. Knockdown of each gene improved locomotor dysfunction, rescued neurodegeneration, and increased brain adenosine levels. We determined that the mechanism of neuroprotection involves adenosine itself, as opposed to a downstream metabolite. We dove deeper into the mechanism for one gene, Ak1, finding rescue of dopaminergic neuron loss, alpha-synuclein aggregation, and bioenergetic dysfunction after glial Ak1 knockdown. We performed metabolomics in Drosophila and in human PD patients, allowing us to comprehensively characterize changes in purine metabolism and identify potential biomarkers of dysfunctional adenosine metabolism in people. These experiments support glial adenosine as a novel therapeutic target in PD.

Metabolic liability for weight gain in early adulthood.

While weight gain is associated with a host of chronic illnesses, efforts in obesity have relied on single "snapshots" of body mass index (BMI) to guide genetic and molecular discovery. Here, we study >2,000 young adults with metabolomics and proteomics to identify a metabolic liability to weight gain in early adulthood. Using longitudinal regression and penalized regression, we identify a metabolic signature for weight liability, associated with a 2.6% (2.0%-3.2%, p = 7.5 × 10-19) gain in BMI over ≈20 years per SD higher score, after comprehensive adjustment. Identified molecules specified mechanisms of weight gain, including hunger and appetite regulation, energy expenditure, gut microbial metabolism, and host interaction with external exposure. Integration of longitudinal and concurrent measures in regression with Mendelian randomization highlights the complexity of metabolic regulation of weight gain, suggesting caution in interpretation of epidemiologic or genetic effect estimates traditionally used in metabolic research.

Differences in metabolomic profiles between Black and White women in the U.S.: Analyses from two prospective cohorts.

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences ≥ |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation.

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved. In addition, these studies represent unique "N of 1" human crossover metabolic-physiologic experiments during which specific molecular pathways central to nutrient metabolism may be discerned. Here, we quantified 263 circulating metabolites during a ≈40-day inpatient admission in which up to 94 participants underwent seven monitored 24-h nutritional interventions of differing macronutrient composition in a whole-room indirect calorimeter to capture precision metabolic responses. Broadly, we observed heterogenous responses in metabolites across dietary chambers, with the exception of carnitines which tracked with 24-h respiratory quotient. We identified excursions in shared metabolic species (e.g., carnitines, glycerophospholipids, amino acids) that mapped onto gold-standard calorimetric measures of substrate oxidation preference and lipid availability. These findings support a coordinated metabolic-physiologic response to nutrition, highlighting the relevance of these controlled settings to uncover biological pathways of energy utilization during precision nutrition studies.

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection.

BACKGROUND: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. METHODS: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins. RESULTS: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. CONCLUSION: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.

Mechanism of Action and Translational Potential of (S)-Meclizine in Preemptive Prophylaxis Against Stroke.

BACKGROUND: Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney. Here, we examine the mechanism of action of meclizine and report the efficacy and improved safety of the (S) enantiomer. METHODS: We determined the anoxic depolarization latency, tissue and neurological outcomes, and glucose uptake using micro-positron emission tomography after transient middle cerebral artery occlusion in mice pretreated (-17 and -3 hours) with either vehicle or meclizine. To exclude a direct effect on tissue excitability, we also examined spreading depression susceptibility. Furthermore, we accomplished the chiral synthesis of (R)- and (S)-meclizine and compared their effects on oxygen consumption and histamine H1 receptor binding along with their brain concentrations. RESULTS: Micro-positron emission tomography showed meclizine increases glucose uptake in the ischemic penumbra, providing the first in vivo evidence that the neuroprotective effect of meclizine indeed stems from its ability to toggle metabolism toward glycolysis. Consistent with reduced reliance on oxidative phosphorylation to sustain the metabolism, meclizine delayed anoxic depolarization onset after middle cerebral artery occlusion. Moreover, the (S) enantiomer showed reduced H1 receptor binding, a dose-limiting side effect for the racemate, but retained its effect on mitochondrial respiration. (S)-meclizine was at least as efficacious as the racemate in delaying anoxic depolarization onset and decreasing infarct volumes after middle cerebral artery occlusion. CONCLUSIONS: Our data identify (S)-meclizine as a promising new drug candidate with high translational potential as a chemical preconditioning agent for preemptive prophylaxis in patients with high imminent stroke or myocardial infarction risk.

Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria.

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

Gut microbiome composition and metabolic activity in women with diverticulitis.

The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.

Plasma metabolites and physical function in patients undergoing hemodialysis.

Impaired physical function contributes to falls, fractures, and mortality among patients undergoing dialysis. Using a metabolomic approach, we identified metabolite alterations and effect size-based composite scores for constructs of impaired gait speed and grip strength. 108 participants incident to dialysis had targeted plasma metabolomics via liquid chromatography-mass spectrometry and physical function assessed (i.e., 4 m walk, handgrip strength). Physical function measures were categorized as above/ below median, with grip utilizing sex-based medians. To develop composite scores, metabolites were identified via Wilcoxon uncorrected p < 0.05 and effect size > 0.40. Receiver operating characteristic analyses tested whether scores differentiated between above/below function groups. Participants were 54% male, 77% Black and 53 ± 14 y with dialysis vintage of 101 ± 50 days. Median (IQR) grip strength was 35.5 (11.1) kg (males) and 20 (8.4) kg (females); median gait speed was 0.82 (0.34) m/s. Of 246 measured metabolites, composite scores were composed of 22 and 12 metabolites for grip strength and gait speed, respectively. Area under the curve for metabolite composite was 0.88 (gait) and 0.911 (grip). Composite scores of physical function performed better than clinical parameters alone in patients on dialysis. These results provide potential pathways for interventions and needed validation in an independent cohort.

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma.

BACKGROUND: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. METHODS: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. FINDINGS: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10-5), SLC8A1 (P-value = 3.9 × 10-5); and TENM4 (P-value = 4.9 × 10-5). INTERPRETATION: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. FUNDING: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Integrated annotation prioritizes metabolites with bioactivity in inflammatory bowel disease.

Microbial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP/HMP2) metabolomes, using a newly developed methodology for bioactive compound prioritization from microbial communities. This suggested >1000 metabolic features as potentially bioactive in IBD and associated ~43% of prevalent, unannotated features with at least one well-characterized metabolite, thereby providing initial information for further characterization of a significant portion of the fecal metabolome. Prioritized features included known IBD-linked chemical families such as bile acids and short-chain fatty acids, and less-explored bilirubin, polyamine, and vitamin derivatives, and other microbial products. One of these, nicotinamide riboside, reduced colitis scores in DSS-treated mice. The method, MACARRoN, is generalizable with the potential to improve microbial community characterization and provide therapeutic candidates.

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: a randomized clinical trial.

BACKGROUND: The health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood. OBJECTIVES: Our goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors. METHODS: A total of 400 participants (200 from each study group), aged 55-75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry was used to profile endogenous fecal metabolites, and 16S amplicon sequencing was employed to profile the fecal microbiota. RESULTS: Compared with the control group, the intervention group exhibited greater weight loss and improvement in various cardiovascular disease risk factors. We identified intervention effects on 4 stool metabolites and subnetworks primarily composed of bile acids, ceramides, and sphingosines, fatty acids, carnitines, nucleotides, and metabolites of purine and the Krebs cycle. Some of these were associated with changes in several cardiovascular disease risk factors. In addition, we observed a reduction in the abundance of the genera Eubacterium hallii group and Dorea, and an increase in alpha diversity in the intervention group after 1 y of follow-up. Changes in the intervention-related microbiota profiles were also associated with alterations in different fecal metabolite subnetworks and some cardiovascular disease risk factors. CONCLUSIONS: An intervention based on an energy-reduced MedDiet and physical activity promotion, compared with an ad libitum MedDiet, was associated with improvements in cardiometabolic risk factors, potentially through modulation of the fecal microbiota and metabolome. This trial was registered at https://www.isrctn.com/ as ISRCTN89898870 (https://doi.org/10.1186/ISRCTN89898870).

Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial.

BACKGROUND: Distinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. OBJECTIVES: We investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. METHODS: This study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 mo after the weight-loss diet intervention. The ASCVD risk estimates were calculated using the validated equations. RESULTS: At baseline, higher concentrations of specific BA subtypes were related to higher concentrations of atherogenic very low-density lipoprotein lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions in triglycerides and total cholesterol [every 1 standard deviation (SD) decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to ß (standard error) -3.3 (1.3), -3.4 (1.3), or -3.8 (1.3) mg/dL, respectively; PFDR < 0.05 for all]. Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 mo; there was ß -4.0 (1.1) mg/dL per 1-SD decrease of glycoursodeoxycholate (PFDR =0.003) for changes in low-density lipoprotein cholesterol. We found significant interactions (P-interaction < 0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet, but not after consuming a low-fat diet. CONCLUSIONS: Decreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk. This trial was registered at clinicaltrials.gov as NCT00072995.