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Specific sweat metabolite profile in ocular Behcet's disease.
Cui, X, Zhang, L, Su, G, Kijlstra, A, Yang, P
International immunopharmacology. 2021;:107812
Abstract
BACKGROUND Behcet's disease (BD) is an autoimmune disorder with the serious possibility of blindness, calling for further research on its pathogenesis. Our aim was to study the metabolite composition of sweat in BD and to identify possible biomarkers. METHODS Metabolomics analysis was performed on sweat samples from 20 BD patients and 18 normal controls by liquid chromatography tandem mass spectrometry. RESULTS A significantly different metabolic profile of sweat was observed when BD patients were compared with healthy controls. The result of the orthogonal partial least squared-discrimination analysis (OPLS-DA) showed that these two comparison groups could be separated with a relatively satisfactory fitting degree (R2Y = 0.995 and Q2 = 0.817 in positive ion mode; R2Y = 0.991 and Q2 = 0.721 in negative ion mode). Based on OPLS-DA, a panel of metabolites was selected as candidate biomarkers, including l-citrulline, l-pyroglutamic acid, urocanic acid, 2-oxoadipic acid, cholesterol 3-sulfate, and pentadecanoic acid. CONCLUSION This is the first report on the metabolite profile of sweat in BD. Our results demonstrated a significantly different metabolite composition of sweat in BD compared to that of healthy controls.
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Metabolic imaging of human cumulus cells reveals associations among metabolic profiles of cumulus cells, patient clinical factors, and oocyte maturity.
Venturas, M, Yang, X, Kumar, K, Wells, D, Racowsky, C, Needleman, DJ
Fertility and sterility. 2021;(6):1651-1662
Abstract
OBJECTIVE To determine whether fluorescence lifetime imaging microscopy (FLIM) detects differences in metabolic state among cumulus cell samples and whether their metabolic state is associated with patient age, body mass index (BMI), and antimüllerian hormone (AMH) level and maturity of the oocyte. DESIGN Prospective observational study. SETTING Academic laboratory. PATIENT(S): Cumulus cell (CC) clusters from cumulus-oocyte complexes were collected from patients undergoing assisted reproductive technology treatment after oocyte retrieval and vitrified. INTERVENTION(S): Cumulus cell metabolism was assessed using FLIM to measure autofluorescence of nicotinamide adenine (phosphate) dinucleotide and flavine adenine dinucleotide, endogenous coenzymes essential for cellular respiration and glycolysis. Patient age, BMI, and AMH level and the maturity of the corresponding oocytes were recorded. MAIN OUTCOME MEASURE(S): Quantitative information from FLIM was obtained regarding metabolite concentrations from fluorescence intensity and metabolite enzyme engagement from fluorescence lifetimes. Associations were investigated between each FLIM parameter and oocyte maturity and patient age, BMI, and AMH. Variance between CC clusters within and between patients was determined. RESULT(S): Of 619 CC clusters from 193 patients, 90 were associated with immature oocytes and 505 with metaphase II oocytes. FLIM enabled quantitative measurements of the metabolic state of CC clusters. These parameters were significantly correlated with patient age and AMH independently, but not with BMI. Cumulus cell nicotinamide adenine (phosphate) dinucleotide FLIM parameters and redox ratio were significantly associated with maturity of the enclosed oocyte. CONCLUSION(S): FLIM detects variations in the metabolic state of CCs, showing a greater variance among clusters from each patient than between patients. Fluorescence lifetime imaging microscopy can detect CC metabolic associations with patient age and AMH and variations between mature and immature oocytes, suggesting the potential utility of this technique to help identify superior oocytes.
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Multi-omics data integration in anorexia nervosa patients before and after weight regain: A microbiome-metabolomics investigation.
Monteleone, AM, Troisi, J, Fasano, A, Dalle Grave, R, Marciello, F, Serena, G, Calugi, S, Scala, G, Corrivetti, G, Cascino, G, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(3):1137-1146
Abstract
BACKGROUND & AIMS We have recently reported specific fecal metabolomic changes in acute and short-term weight restored patients with anorexia nervosa (AN). In this study we explored the association between those metabolomic changes and patients' gut microbiome composition. METHODS The gut microbiome of AN women was sequenced in both the underweight phase (n = 21) and after short-term weight restoration (n = 16) and compared to that of 20 healthy women. According to a multi-omics approach, microbiome data were correlated with 49 relevant fecal metabolites previously characterized in our participants by an untargeted metabolomic procedure. RESULTS Compared to healthy women, AN patients showed a decreased intra-individual bacterial richness, an increased Bacteroidetes-to-Firmicutes abundance ratio and significant changes in the relative abundances of several bacteria at phylum, class, order, family and genus levels. These changes were observed in both the underweight and weight-restored condition. Moreover, the relationships among the 49 previously selected fecal metabolites and bacteria genera showed structures of different complexity among the 3 groups. In particular, a quarter of those relationships showed a divergent direction in the acutely ill patients with respect to the weight-restored ones or normal controls. Finally, in acutely ill patients 70% of those correlations showed a negative sign suggesting a prevalent metabolites consummation by gut microbiome. CONCLUSIONS These data confirm a profound perturbation in the gut microbiome composition of AN patients. Moreover, for the first time, they provide the evidence that in AN gut bacteria are connected with several fecal metabolites in a different way from normal controls and with divergent directions in the acute phase with respect to the weight-restored phase.
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Metabolomic signature of the seminal plasma in men with severe oligoasthenospermia.
Boguenet, M, Bocca, C, Bouet, PE, Serri, O, Chupin, S, Tessier, L, Blanchet, O, El Hachem, H, Chao de la Barca, JM, Reynier, P, et al
Andrology. 2020;(6):1859-1866
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Abstract
BACKGROUND Male factor is incriminated in approximately 50% of cases of infertility. The metabolomic approach has recently been used in the assessment of sperm quality and male fertility. MATERIALS AND METHODS We analyzed the metabolomic signatures of the seminal plasma in 20 men with severe oligoasthenospermia (prewash total motile sperm count < 5.106 ) (SOA) and compared it to 20 men with normal semen parameters, with a standardized approach of targeted and quantitative metabolomics using high-performance liquid chromatography, coupled with tandem mass spectrometry, and the Biocrates Absolute IDQ p180 kit. RESULTS Among the 188 metabolites analyzed, 110 were accurately measured in the seminal plasma. A robust model discriminating the two populations (Q2(cum) = 55.2%) was obtained by OPLS-DA (orthogonal partial least-squares discriminant analysis), based on the drop in concentrations of 37 metabolites with a VIP (variable important for projection) greater than 1. Overall, in men with SOA, there was a significant decrease in: 17 phosphatidylcholines and four sphingomyelins; acylcarnitines, with free L-carnitine being the most discriminating metabolite; polyunsaturated fatty acids; six amino acids (glutamate, aspartate, methionine, tryptophan, proline, and alanine); and four biogenic amines (spermine, spermidine, serotonin, and alpha-aminoadipate). DISCUSSION Our signature includes several metabolic changes with different impacts on the sperm quality: a change in phospholipid composition and the saturation of their fatty acids that is potentially linked to the deterioration of sperm membranes; a carnitine deficiency that can negatively impact the energy production via fatty acid oxidation and oxidative phosphorylation; and a decreased level of amino acids and biogenic amines that can lead to dysregulated metabolic and signaling pathways. CONCLUSION We provide a global overview of the metabolic defects contributing to the structural and functional alteration of spermatozoa in severe oligoasthenospermia. These findings offer new insights into the pathophysiology of male factor infertility that could help to develop future specific treatments.
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Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.
Mahajan, UV, Varma, VR, Griswold, ME, Blackshear, CT, An, Y, Oommen, AM, Varma, S, Troncoso, JC, Pletnikova, O, O'Brien, R, et al
PLoS medicine. 2020;(1):e1003012
Abstract
BACKGROUND There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. METHODS AND FINDINGS We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. CONCLUSIONS In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.
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Microbiota Supplementation with Bifidobacterium and Lactobacillus Modifies the Preterm Infant Gut Microbiota and Metabolome: An Observational Study.
Alcon-Giner, C, Dalby, MJ, Caim, S, Ketskemety, J, Shaw, A, Sim, K, Lawson, MAE, Kiu, R, Leclaire, C, Chalklen, L, et al
Cell reports. Medicine. 2020;(5):100077
Abstract
Supplementation with members of the early-life microbiota as "probiotics" is increasingly used in attempts to beneficially manipulate the preterm infant gut microbiota. We performed a large observational longitudinal study comprising two preterm groups: 101 infants orally supplemented with Bifidobacterium and Lactobacillus (Bif/Lacto) and 133 infants non-supplemented (control) matched by age, sex, and delivery method. 16S rRNA gene profiling on fecal samples (n = 592) showed a predominance of Bifidobacterium and a lower abundance of pathobionts in the Bif/Lacto group. Metabolomic analysis showed higher fecal acetate and lactate and a lower fecal pH in the Bif/Lacto group compared to the control group. Fecal acetate positively correlated with relative abundance of Bifidobacterium, consistent with the ability of the supplemented Bifidobacterium strain to metabolize human milk oligosaccharides into acetate. This study demonstrates that microbiota supplementation is associated with a Bifidobacterium-dominated preterm microbiota and gastrointestinal environment more closely resembling that of full-term infants.
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The Influence of the Duration of Breastfeeding on the Infant's Metabolic Epigenome.
Pauwels, S, Symons, L, Vanautgaerden, EL, Ghosh, M, Duca, RC, Bekaert, B, Freson, K, Huybrechts, I, Langie, SAS, Koppen, G, et al
Nutrients. 2019;(6)
Abstract
Nutrition in the postnatal period is associated with metabolic programming. One of the presumed underlying mechanisms involves epigenetic modifications (e.g., DNA methylation). Breastfeeding has an unknown impact on DNA methylation at a young age. Within the Maternal Nutrition and Offspring's Epigenome (MANOE) study, we assessed the effect of breastfeeding duration on infant growth and buccal methylation in obesity-related genes (n = 101). A significant difference was found between infant growth and buccal RXRA and LEP methylation at 12 months of breastfeeding. For RXRA CpG2 methylation, a positive association was found with duration of breastfeeding (slope = 0.217; 95% confidence interval (CI) 1.03, 0.330; p < 0.001). For RXRA CpG3 and CpG, mean methylation levels were significantly lower when children were breastfed for 4-6 months compared to non-breastfed children (only CpG3), and those breastfed for 7-9 months, 10-12 months, or 1-3 months. On the other hand, higher LEP CpG3 methylation was observed when mothers breastfed 7-9 months (6.1%) as compared to breastfeeding for 1-3 months (4.3%; p = 0.007) and 10-12 months (4.6%; p = 0.04). In addition, we observed that infant weight was significantly lower when children were breastfed for 10-12 months. Breastfeeding duration was associated with epigenetic variations in RXRA and LEP at 12 months and with infant biometry/growth. Our results support the hypothesis that breastfeeding could induce epigenetic changes in infants.
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Metabolome-wide association study of anti-epileptic drug treatment during pregnancy.
Walker, DI, Perry-Walker, K, Finnell, RH, Pennell, KD, Tran, V, May, RC, McElrath, TF, Meador, KJ, Pennell, PB, Jones, DP
Toxicology and applied pharmacology. 2019;:122-130
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Abstract
Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one‑carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.
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Impact of Intragastric Balloon Treatment on Adipokines, Cytokines, and Metabolic Profile in Obese Individuals.
Guedes, MR, Fittipaldi-Fernandez, RJ, Diestel, CF, Klein, MRST
Obesity surgery. 2019;(8):2600-2608
Abstract
BACKGROUND Obesity is accompanied by adipose tissue remodeling characterized by increased production of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, leptin and resistin and reduced secretion of adiponectin, which favors inflammation, metabolic disorders, and cardiovascular diseases. Although intragastric balloon (IGB) can be considered safe and effective for weight loss, its effect on serum levels of these biomarkers has been evaluated only in a few studies, while no previous study evaluated its effect on circulating levels of resistin, TNF-α, and IL-6. The aim of this study was to evaluate the changes in serum levels of metabolic and inflammatory biomarkers in obese patients submitted to IGB treatment. METHODS A prospective observational study involving 42 patients with obesity using IGB for 6 months. The patients were evaluated, on the day of insertion and withdrawal or adjustment of IGB, for the following: anthropometric measures and serum levels of adiponectin, leptin, resistin, TNF-α, IL-6, high-sensitivity C-reactive protein (hs-CRP), glucose, insulin, uric acid, triglycerides, and total cholesterol and fractions. RESULTS The body mass index decreased from 35.15 ± 0.41 to 29.50 ± 0.54 kg/m2. There was a reduction (p < 0.05) in leptin, hs-CRP, glucose, insulin, HOMA-IR, and triglycerides, while the adiponectin/leptin ratio increased (p < 0.05). Moreover, weight loss presented (1) a positive association with the decrease in leptin, hs-CRP, glucose, insulin, HOMA-IR, uric acid, and total cholesterol and (2) a negative association with the reduction in adiponectin/leptin ratio. CONCLUSIONS The present study suggests that 6 months of IGB treatment in obese individuals reduce serum leptin and hs-CRP and improves insulin resistance and lipid profile which may decrease cardiovascular risk.
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Untargeted metabolomics identifies a plasma sphingolipid-related signature associated with lifestyle intervention in prepubertal children with obesity.
Leal-Witt, MJ, Ramon-Krauel, M, Samino, S, Llobet, M, Cuadras, D, Jimenez-Chillaron, JC, Yanes, O, Lerin, C
International journal of obesity (2005). 2018;(1):72-78
Abstract
OBJECTIVE Childhood obesity is a strong risk factor for adult obesity and metabolic diseases, including type 2 diabetes and cardiovascular disease. Early lifestyle intervention in children with obesity reduces future disease risk. The objective of this study is to identify metabolic signatures associated with lifestyle intervention in prepubertal children with obesity. METHODS Thirty-five prepubertal children (7-10 years) with obesity (body mass index (BMI)>2 standard deviations) were enrolled in the study and participated in a 6-month-long lifestyle intervention program. Physiological and biochemical data and blood samples were collected both at baseline and after the intervention. A liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach was applied to obtain a comprehensive profiling of plasma samples, identifying 2581 distinct metabolite. Principal component analysis (PCA) was performed to consolidate all features into 8 principal components. Associations between metabolites and physiological and biochemical variables were investigated. RESULTS The intervention program significantly decreased mean (95% CI) BMI standard deviation score from 3.56 (3.29-3.84) to 3.11 (2.88-3.34) (P<0.001). PCA identified one component (PC1) significantly altered by the intervention (Bonferroni adjusted P=0.008). A sphingolipid metabolism-related signature was identified as the major contributor to PC1. Sphingolipid metabolites were decreased by the intervention, and included multiple sphingomyelin, ceramide, glycosylsphingosine and sulfatide species. Changes in several sphingolipid metabolites were associated with intervention-induced improvements in HbA1c levels. CONCLUSIONS Decreased circulating sphingolipid-related metabolites were associated with lifestyle intervention in prepubertal children with obesity, and correlated to improvements in HbA1c.