25 results found
Sayers B, Wijeyesekera A, Gibson G, 2021, Exploring the potential of prebiotic and polyphenol-based dietary interventions for the alleviation of cognitive and gastrointestinal perturbations associated with military specific stressors, Journal of Functional Foods, Vol: 87, Pages: 104753-104753, ISSN: 1756-4646
Lawson MAE, O'Neill IJ, Kujawska M, et al., 2020, Breast milk-derived human milk oligosaccharides promote Bifidobacterium interactions within a single ecosystem, ISME JOURNAL, Vol: 14, Pages: 635-648, ISSN: 1751-7362
Wijeyesekera A, Wagner J, De Goffau M, et al., 2019, Multi-compartment profiling of bacterial and host metabolites identifies intestinal dysbiosis and its functional consequences in the critically ill child, Critical Care Medicine, Vol: 47, Pages: e727-e734, ISSN: 0090-3493
OBJECTIVES: Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children. DESIGN: Prospective multicenter cohort study. SETTING: Three U.K.-based PICUs. PATIENTS: Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55). INTERVENTIONS: Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls. MEASUREMENTS AND MAIN RESULTS: Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = -0.2; p = 0.037). CONCLUSIONS: Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. P
Parkinson JRC, Wijeyesekera A, Hyde MJ, et al., 2017, Early preterm nutrition and the urinary metabolome in young adult life; follow-up of a randomised controlled trial, BMJ Paediatrics Open, Vol: 1, ISSN: 2399-9772
Objective We aimed to test the hypothesis that early diet programmes the metabolic profile of young adults born preterm.Design We analysed banked urine samples obtained at a 20-year follow-up visit from adults that had participated as neonates in controlled trials involving randomisation within 48 hours of birth to feeds of preterm formula (PTF), banked breast milk (BBM) or term formula (TF) for 1 month postnatally.Main outcome measures We performed proton nuclear magnetic resonance spectroscopy, analysing spectra by dietary group and sex. Orthogonal projections to latent structure discriminant analyses was used to model class differences and identify metabolites contributing to the differences between groups. Additionally, spectra were correlated with birth weight, gestational age and weight z score at 2 weeks of age.Results Of the original number of 926 trial participants, urine samples were available from 197 (21%) healthy young adults (42% men) born preterm (mean 30.7±2.8 weeks) and randomised to BBM (n=55; 28 men), TF (n=48; 14 men) and PTF (n=93; 40 men). We found no significant differences in urinary spectra between dietary groups including when stratified by sex. Correlation analysis revealed a weak association between metabolic profile and gestational age that was lost on controlling for ethanol excretion.Conclusions We found no evidence that dietary exposures in the neonatal period influence the metabolic phenotype in young adult life.
Chekmeneva E, Correia GDS, Chan Q, et al., 2017, Optimization and Application of Direct Infusion Nanoelectrospray HRMS Method for Large-Scale Urinary Metabolic Phenotyping in Molecular Epidemiology, JOURNAL OF PROTEOME RESEARCH, Vol: 16, Pages: 1646-1658, ISSN: 1535-3893
Large-scale metabolic profiling requires the development of novel economical high-throughput analytical methods to facilitate characterization of systemic metabolic variation in population phenotypes. We report a fit-for-purpose direct infusion nanoelectrospray high-resolution mass spectrometry (DI-nESI-HRMS) method with time-of-flight detection for rapid targeted parallel analysis of over 40 urinary metabolites. The newly developed 2 min infusion method requires <10 μL of urine sample and generates high-resolution MS profiles in both positive and negative polarities, enabling further data mining and relative quantification of hundreds of metabolites. Here we present optimization of the DI-nESI-HRMS method in a detailed step-by-step guide and provide a workflow with rigorous quality assessment for large-scale studies. We demonstrate for the first time the application of the method for urinary metabolic profiling in human epidemiological investigations. Implementation of the presented DI-nESI-HRMS method enabled cost-efficient analysis of >10 000 24 h urine samples from the INTERMAP study in 12 weeks and >2200 spot urine samples from the ARIC study in <3 weeks with the required sensitivity and accuracy. We illustrate the application of the technique by characterizing the differences in metabolic phenotypes of the USA and Japanese population from the INTERMAP study.
Baker L, Lanz B, Andreola F, et al., 2016, New technologies - new insights into the pathogenesis of hepatic encephalopathy, METABOLIC BRAIN DISEASE, Vol: 31, Pages: 1259-1267, ISSN: 0885-7490
Jackson FL, Georgakopoulou N, Kaluarachchi M, et al., 2016, Development of a pipeline for exploratory metabolic profiling of infant urine, Journal of Proteome Research, Vol: 15, Pages: 3432-3440, ISSN: 1535-3907
Numerous metabolic profiling pipelines have been developed to characterize the composition ofhuman biofluids and tissues, the vast majority of these being for studies in adults. To accommodatelimited sample volume and to take into account the compositional differences between adult andinfant biofluids, we developed and optimized sample handling and analytical procedures for studyingurine from newborns. A robust pipeline for metabolic profiling using NMR spectroscopy wasestablished, encompassing sample collection, preparation, spectroscopic measurement andcomputational analysis. Longitudinal samples were collected from five infants from birth until 14months of age. Methods of extraction, effects of freezing and sample dilution were assessed andurinary contaminants from breakdown of polymers in a range of diapers and cotton wool balls wereidentified and compared, including propylene glycol, acrylic acid and tert-butanol. Finally,assessment of urinary profiles obtained over the first few weeks of life revealed a dramatic change in composition, with concentrations of phenols, amino acids and betaine altering systematically overthe first few months of life. Therefore, neonatal samples require more stringent standardization ofexperimental design, sample handling and analysis compared to adult samples in order toaccommodate the variability and limited sample volume.
Amiot A, Dona AC, Wijeyesekera A, et al., 2015, H-1 NMR Spectroscopy of Fecal Extracts Enables Detection of Advanced Colorectal Neoplasia, JOURNAL OF PROTEOME RESEARCH, Vol: 14, Pages: 3871-3881, ISSN: 1535-3893
Holmes E, Wijeyesekera A, Taylor-Robinson SD, et al., 2015, The promise of metabolic phenotyping in gastroenterology and hepatology, Nature Reviews Gastroenterology & Hepatology, Vol: 12, Pages: 458-471, ISSN: 1759-5053
Disease risk and treatment response are determined, at the individual level, by a complex historyof genetic and environmental interactions, including those with our endogenous microbiomes. Personalizedhealth care requires a deep understanding of patient biology that can now be measured using a range of‘‑omics’ technologies. Patient stratification involves the identification of genetic and/or phenotypic diseasesubclasses that require different therapeutic strategies. Stratified medicine approaches to disease diagnosis,prognosis and therapeutic response monitoring herald a new dimension in patient care. Here, we explore thepotential value of metabolic profiling as applied to unmet clinical needs in gastroenterology and hepatology.We describe potential applications in a number of diseases, with emphasis on large-scale population studiesas well as metabolic profiling on the individual level, using spectrometric and imaging technologies that willleverage the discovery of mechanistic information and deliver novel health care solutions to improve clinicalpathway management.
Correia GDS, Ng KW, Wijeyesekera A, et al., 2015, Metabolic Profiling of Children Undergoing Surgery for Congenital Heart Disease, Critical Care Medicine, Vol: 43, Pages: 1467-1476, ISSN: 1530-0293
Inflammation and metabolism are closely interlinked.Both undergo significant dysregulation following surgery for congenitalheart disease, contributing to organ failure and morbidity.In this study, we combined cytokine and metabolic profilingto examine the effect of postoperative tight glycemic controlcompared with conventional blood glucose management onmetabolic and inflammatory outcomes in children undergoingcongenital heart surgery. The aim was to evaluate changes in keymetabolites following congenital heart surgery and to examinethe potential of metabolic profiling for stratifying patients in termsof expected clinical outcomes.Design: Laboratory and clinical study.Setting: University Hospital and Laboratory.Patients: Of 28 children undergoing surgery for congenital heartdisease, 15 underwent tight glycemic control postoperatively and13 were treated conventionally.Interventions: Metabolic profiling of blood plasma was undertakenusing proton nuclear magnetic resonance spectroscopy. A panel ofmetabolites was measured using a curve-fitting algorithm. Inflammatorycytokines were measured by enzyme-linked immunosorbentassay. The data were assessed with respect to clinical markers ofdisease severity (Risk Adjusted Congenital heart surgery score-1,Pediatric Logistic Organ Dysfunction, inotrope score, duration ofventilation and pediatric ICU-free days).Measurements and Main Results: Changes in metabolic andinflammatory profiles were seen over the time course from surgeryto recovery, compared with the preoperative state. Tight glycemiccontrol did not significantly alter the response profile. We identifiedeight metabolites (3-d-hydroxybutyrate, acetone, acetoacetate,citrate, lactate, creatine, creatinine, and alanine) associated withsurgical and disease severity. The strength of proinflammatoryresponse, particularly interleukin-8 and interleukin-6 concentrations,inversely correlated with PICU-free days at 28 days. The interleukin-6/interleukin-10ratio directly correlated wi
Chekmeneva E, Correia G, Denes J, et al., 2015, Development of nanoelectrospray high resolution isotope dilution mass spectrometry for targeted quantitative analysis of urinary metabolites: application to population profiling and clinical studies, Analytical Methods, Vol: 7, Pages: 5122-5133, ISSN: 1759-9679
An automated chip-based electrospray platform was used to develop a high-throughput nanoelectrospray high resolution mass spectrometry (nESI-HRMS) method for multiplexed parallel untargeted and targeted quantitative metabolic analysis of urine samples. The method was demonstrated to be suitable for metabolic analysis of large sample numbers and can be applied to large-scale epidemiological and stratified medicine studies. The method requires a small amount of sample (5 μL of injectable volume containing 250 nL of original sample), and the analysis time for each sample is three minutes per sample to acquire data in both negative and positive ion modes. Identification of metabolites was based on the high resolution accurate mass and tandem mass spectrometry using authentic standards. The method was validated for 8 targeted metabolites and was shown to be precise and accurate. The mean accuracy of individual measurements being 106% and the intra- and inter-day precision (expressed as relative standard deviations) were 9% and 14%, respectively. Selected metabolites were quantified by standard addition calibration using the stable isotope labelled internal standards in a pooled urine sample, to account for any matrix effect. The multiple point standard addition calibration curves yielded correlation coefficients greater than 0.99, and the linear dynamic range was more than three orders of magnitude. As a proof-of-concept the developed method was applied for targeted quantitative analysis of a set of 101 urine samples obtained from female participants with different pregnancy outcomes. In addition to the specifically targeted metabolites, several other metabolites were quantified relative to the internal standards. Based on the calculated concentrations, some metabolites showed significant differences according to different pregnancy outcomes. The acquired high resolution full-scan data were used for further untargeted fingerprinting and improved the differentiation of
Andreas NJ, Hyde MJ, Gomez-Romero M, et al., 2015, Multiplatform characterization of dynamic changes in breast milk during lactation., Electrophoresis, Vol: 36, Pages: 2269-2285, ISSN: 1522-2683
The multicomponent analysis of human breast milk (BM) by metabolic profiling is a new area of study applied to determining milk composition, and is capable of associating BM composition with maternal characteristics, and subsequent infant health outcomes. A multi-platform approach combining high-performance as well as ultra-performance liquid-chromatography (HPLC-MS and UPLC-MS), gas chromatography (GC-MS), capillary electrophoresis (CE-MS) coupled to mass spectrometry and (1) H NMR spectroscopy was used to comprehensively characterize metabolic profiles from seventy BM samples. A total of 710 metabolites spanning multiple molecular classes were defined. The utility of the individual and combined analytical platforms was explored in relation to numbers of metabolites identified, as well as the reproducibility of the methods. The greatest number of metabolites were identified by the single phase HPLC-MS method, whilst CE-MS uniquely profiled amino acids in detail and NMR was the most reproducible, whereas GC-MS targeted volatile compounds and short chain fatty acids. Dynamic changes in BM composition were characterized over the first 3 months of lactation. Metabolites identified as altering in abundance over lactation included fucose, di- and triacylglycerols and short chain fatty acids, known to be important for infant immunological, neurological and gastrointestinal development, as well as being an important source of energy. This extensive metabolic coverage of the dynamic BM metabolome provides a baseline for investigating the impact of maternal characteristics, as well as establishing the impact of environmental and dietary factors on the composition of BM, with a focus on the downstream health consequences this may have for infants. This article is protected by copyright. All rights reserved.
Obesity is a major public health problem worldwide. We used 24-hour urinary metabolic profiling by proton (1H) nuclear magnetic resonance (NMR) spectroscopy and ion exchange chromatography to characterize the metabolic signatures of adiposity in the U.S. (n = 1880) and UK (n = 444) cohorts of the INTERMAP (International Study of Macro- and Micronutrients and Blood Pressure) epidemiologic study. Metabolic profiling of urine samples collected over two 24-hour time periods 3 weeks apart showed reproducible patterns of metabolite excretion associated with adiposity. Exploratory analysis of the urinary metabolome using 1H NMR spectroscopy of the U.S. samples identified 29 molecular species, clustered in interconnecting metabolic pathways, that were significantly associated (P = 1.5 × 10−5 to 2.0 × 10−36) with body mass index (BMI); 25 of these species were also found in the UK validation cohort. We found multiple associations between urinary metabolites and BMI including urinary glycoproteins and N-acetyl neuraminate (related to renal function), trimethylamine, dimethylamine, 4-cresyl sulfate, phenylacetylglutamine and 2-hydroxyisobutyrate (gut microbial co-metabolites), succinate and citrate (tricarboxylic acid cycle intermediates), ketoleucine and the ketoleucine/leucine ratio (linked to skeletal muscle mitochondria and branched-chain amino acid metabolism), ethanolamine (skeletal muscle turnover), and 3-methylhistidine (skeletal muscle turnover and meat intake). We mapped the multiple BMI-metabolite relationships as part of an integrated systems network that describes the connectivities between the complex pathway and compartmental signatures of human adiposity.
Ladep NG, Dona AC, Lewis MR, et al., 2014, Discovery and Validation of Urinary Metabotypes for the Diagnosis of Hepatocellular Carcinoma in West Africans, HEPATOLOGY, Vol: 60, Pages: 1291-1301, ISSN: 0270-9139
Atkinson S, Wijeyesekera A, McPhail MJ, et al., 2014, UNTARGETED H-1-NMR SPECTROSCOPY DEMONSTRATES A UNIQUE METABOLIC PHENOTYPE OF ALCOHOLIC HEPATITIS, 49th Annual International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S170-S170, ISSN: 0168-8278
Klootwijk ED, Reichold M, Helip-Wooley A, et al., 2014, Mistargeting of peroxisomal EHHADH and inherited renal fanconi's syndrome, New England Journal of Medicine, Vol: 370, Pages: 129-138, ISSN: 0028-4793
BACKGROUNDIn renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown.METHODSWe clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance (1H-NMR) spectroscopy.RESULTSWe linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. 1H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency.CONCLUSIONSMistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Sevent
Stamler J, Brown IJ, Yap IKS, et al., 2013, Dietary and Urinary Metabonomic Factors Possibly Accounting for Higher Blood Pressure of Black Compared With White Americans Results of International Collaborative Study on Macro-/Micronutrients and Blood Pressure, HYPERTENSION, Vol: 62, Pages: 1074-1080, ISSN: 0194-911X
Ladep NG, Dona A, McPhail MJW, et al., 2013, URINARY METABOLIC PROFILE DISCRIMINATES HEPATOCELLULAR CARCINOMA BETTER THAN SERUM ALPHA FETOPROTEIN IN WEST AFRICANS, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S49-S49, ISSN: 0168-8278
Chan Q, Stamler J, Posma J, et al., 2013, Relationship of Coffee Consumption and its Urinary Biomarker to Blood Pressure: The Intermap Study, Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Garcia-Perez I, Villaseñor A, Wijeyesekera A, et al., 2012, Urinary metabolic phenotyping the slc26a6 (chloride-oxalate exchanger) null mouse model, Journal of Proteome Research, Vol: 11, Pages: 4425-4435, ISSN: 1535-3893
The prevalence of renal stone disease is increasing, although it remains higher in men than in women when matched for age. While still somewhat controversial, several studies have reported an association between renal stone disease and hypertension, but this may be confounded by a shared link with obesity. However, independent of obesity, hyperoxaluria has been shown to be associated with hypertension in stone-formers and the most common type of renal stone is composed of calcium oxalate. The chloride-oxalate exchanger slc26a6 (also known as CFEX or PAT-1), located in the renal proximal tubule, was originally thought to have an important role in sodium homeostasis and thereby blood pressure control, but it has recently been shown to have a key function in oxalate balance by mediating oxalate secretion in the gut. We have applied two orthogonal analytical platforms (NMR spectroscopy and capillary-electrophoresis with UV detection) in parallel to characterize the urinary metabolic signatures related to the loss of the renal chloride-oxalate exchanger in slc26a6 null mice. Clear metabolic differentiation between the urinary profiles of the slc26a6 null and the wild type mice were observed using both methods, with the combination of NMR and CE-UV providing extensive coverage of the urinary metabolome. Key discriminating metabolites included oxalate, m-hydroxyphenylpropionylsulfate (m-HPPS), trimethylamine-N-oxide, glycolate and scyllo-inositol (higher in CFEX null mice) and hippurate, taurine, trimethylamine, and citrate (lower in slc26a6 null mice). In addition to the reduced efficiency of anion transport, several of these metabolites (hippurate, m-HPPS, methylamines) reflect alteration in gut microbial co-metabolic activities. Gender-related metabotypes were also observed in both wild type and slc26a6 null groups. Other urinary chemicals that showed a gender-specific pattern included trimethylamine, trimethylamine-N-oxide, citrate, spermidine, guanidinoacetate, and 2-
Wijeyesekera A, Selman C, Barton RH, et al., 2012, Metabotyping of Long-Lived Mice using H-1 NMR Spectroscopy, Journal of Proteome Research, Vol: 11, Pages: 2224-2235, ISSN: 1535-3893
Significant advances in understanding aging have been achieved through studying model organisms with extended healthy lifespans. Employing 1H NMR spectroscopy, we characterized the plasma metabolic phenotype (metabotype) of three long-lived murine models: 30% dietary restricted (DR), insulin receptor substrate 1 null (Irs1–/–), and Ames dwarf (Prop1df/df). A panel of metabolic differences were generated for each model relative to their controls, and subsequently, the three long-lived models were compared to one another. Concentrations of mobile very low density lipoproteins, trimethylamine, and choline were significantly decreased in the plasma of all three models. Metabolites including glucose, choline, glycerophosphocholine, and various lipids were significantly reduced, while acetoacetate, d-3-hydroxybutyrate and trimethylamine-N-oxide levels were increased in DR compared to ad libitum fed controls. Plasma lipids and glycerophosphocholine were also decreased in Irs1–/– mice compared to controls, as were methionine and citrate. In contrast, high density lipoproteins and glycerophosphocholine were increased in Ames dwarf mice, as were methionine and citrate. Pairwise comparisons indicated that differences existed between the metabotypes of the different long-lived mice models. Irs1–/– mice, for example, had elevated glucose, acetate, acetone, and creatine but lower methionine relative to DR mice and Ames dwarfs. Our study identified several potential candidate biomarkers directionally altered across all three models that may be predictive of longevity but also identified differences in the metabolic signatures. This comparative approach suggests that the metabolic networks underlying lifespan extension may not be exactly the same for each model of longevity and is consistent with multifactorial control of the aging process.
Wijeyesekera A, Clarke PA, Bictash M, et al., 2012, Quantitative UPLC-MS/MS analysis of the gut microbial co-metabolites phenylacetylglutamine, 4-cresyl sulphate and hippurate in human urine: INTERMAP Study, ANALYTICAL METHODS, Vol: 4, Pages: 65-72, ISSN: 1759-9660
Kestelooty H, Tzoulaki I, Brown IJ, et al., 2011, Relation of Urinary Calcium and Magnesium Excretion to Blood Pressure The International Study of Macro- and Micro-Nutrients and Blood Pressure and the International Cooperative Study on Salt, Other Factors, and Blood Pressure, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 174, Pages: 44-51, ISSN: 0002-9262
Yap IKS, Brown IJ, Chan Q, et al., 2010, Metabolome-Wide Association Study Identifies Multiple Biomarkers that Discriminate North and South Chinese Populations at Differing Risks of Cardiovascular Disease INTERMAP Study, JOURNAL OF PROTEOME RESEARCH, Vol: 9, Pages: 6647-6654, ISSN: 1535-3893
Selman C, Kerrison ND, Cooray A, et al., 2006, Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice, PHYSIOLOGICAL GENOMICS, Vol: 27, Pages: 187-200, ISSN: 1094-8341
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