Publications by authors named "Elaine Holmes"

399 Publications

The impact of bariatric surgery on serum tryptophan-kynurenine pathway metabolites.

Sci Rep 2022 Jan 7;12(1):294. Epub 2022 Jan 7.

Department of Surgery & Cancer, Imperial College London, South Kensington, London, UK.

This study aims to explore the immediate effects of bariatric surgery on serum tryptophan-kynurenine pathway metabolites in individuals with type 2 diabetes and BMI > 30. With the goal of providing insight into the link between tryptophan pathway metabolites, type 2 diabetes, and chronic obesity-induced inflammation. This longitudinal study included 20 participants. Half were diagnosed with type 2 diabetes. 11 and 9 underwent RYGB and SG respectively. Blood samples were obtained at pre-operative and 3 months post-operative timepoints. Tryptophan and downstream metabolites of the kynurenine pathway were quantified with an ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionisation method. At 3 months post-operation, RYGB led to significant reductions in tryptophan, kynurenic acid and xanthurenic acid levels when compared to baseline. Significant reductions of the same metabolites after surgery were also observed in individuals with T2D irrespective of surgical procedure. These metabolites were significantly correlated with serum HbA1c levels and BMI. Bariatric surgery, in particular RYGB reduces serum levels of tryptophan and its downstream kynurenine metabolites. These metabolites are associated with T2D and thought to be potentially mechanistic in the systemic processes of obesity induced inflammation leading to insulin resistance. Its reduction after surgery is associated with an improvement in glycaemic control (HbA1c).
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http://dx.doi.org/10.1038/s41598-021-03833-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741964PMC
January 2022

J-Edited DIffusional Proton Nuclear Magnetic Resonance Spectroscopic Measurement of Glycoprotein and Supramolecular Phospholipid Biomarkers of Inflammation in Human Serum.

Anal Chem 2022 01 5;94(2):1333-1341. Epub 2022 Jan 5.

Australian National Phenome Centre and Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Western Australia 6150, Australia.

Proton nuclear magnetic resonance (NMR) -acetyl signals (Glyc) from glycoproteins and supramolecular phospholipids composite peak (SPC) from phospholipid quaternary nitrogen methyls in subcompartments of lipoprotein particles) can give important systemic metabolic information, but their absolute quantification is compromised by overlap with interfering resonances from lipoprotein lipids themselves. We present a J-Edited DIffusional (JEDI) proton NMR spectroscopic approach to selectively augment signals from the inflammatory marker peaks Glyc and SPCs in blood serum NMR spectra, which enables direct integration of peaks associated with molecules found in specific compartments. We explore a range of pulse sequences that allow editing based on peak J-modulation, translational diffusion, and relaxation time and validate them for untreated blood serum samples from SARS-CoV-2 infected patients ( = 116) as well as samples from healthy controls and pregnant women with physiological inflammation and hyperlipidemia ( = 631). The data show that JEDI is an improved approach to selectively investigate inflammatory signals in serum and may have widespread diagnostic applicability to disease states associated with systemic inflammation.
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http://dx.doi.org/10.1021/acs.analchem.1c04576DOI Listing
January 2022

The rationale and design of a Mediterranean diet accompanied by time restricted feeding to optimise the management of type 2 diabetes: The MedDietFast randomised controlled trial.

Nutr Metab Cardiovasc Dis 2022 Jan 7;32(1):220-230. Epub 2021 Oct 7.

School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia. Electronic address:

Background And Aims: Substantial scientific evidence supports the effectiveness of a Mediterranean diet (MedDiet) in managing type 2 diabetes mellitus (T2DM). Potential benefits of time restricted feeding (TRF) in T2DM are unknown. The MedDietFast trial aims to investigate the efficacy of a MedDiet with or without TRF compared to standard care diet in managing T2DM.

Methods And Results: 120 adults aged 20-75 with a body mass index (BMI) of 20-35 kg/m and T2DM will be randomised in a 3-arm parallel design to follow an ad libitum MedDiet with or without 12-h TRF or the standard Australian Dietary Guidelines (ADG) for 24 weeks. All groups will receive dietary counselling fortnightly for 12 weeks and monthly thereafter. The primary outcome is changes in HbA1c from baseline to 12 and 24 weeks. Secondary outcomes include fasting blood glucose, insulin, blood lipids, weight loss, insulin resistance index (HOMA), Glucagon-like peptide 1 (GLP-1) and high-sensitivity C- reactive protein (hs-CRP). Data on medical history, anthropometry, wellbeing, MedDiet adherence and satiety will be measured at a private clinic via self-report questionnaires at baseline, 6, 12 and 24 weeks. Additionally, specimens (blood, urine and stool) will be collected at all time points for future omics analysis.

Conclusion: The MedDietFast trial will examine the feasibility and effectiveness of a MedDiet with/without TRF in T2DM patients. Potential synergistic effects of a MedDiet with TRF will be evaluated. Future studies will generate microbiomic and metabolomic data for translation of findings into simple and effective management plans for T2DM patients.

Trial Registration: Australia and New Zealand Clinical Trials Register, ACTRN12619000246189.
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http://dx.doi.org/10.1016/j.numecd.2021.09.031DOI Listing
January 2022

Mapping of population disparities in the cholangiocarcinoma urinary metabolome.

Sci Rep 2021 10 28;11(1):21286. Epub 2021 Oct 28.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W2 INY, UK.

Phenotypic diversity in urinary metabolomes of different geographical populations has been recognized recently. In this study, urinary metabolic signatures from Western (United Kingdom) and South-East Asian (Thai) cholangiocarcinoma patients were characterized to understand spectral variability due to host carcinogenic processes and/or exogenous differences (nutritional, environmental and pharmaceutical). Urinary liquid chromatography mass spectroscopy (LC-MS) spectral profiles from Thai (healthy = 20 and cholangiocarcinoma = 14) and UK cohorts (healthy = 22 and cholangiocarcinoma = 10) were obtained and modelled using chemometric data analysis. Healthy metabolome disparities between the two distinct populations were primarily related to differences in dietary practices and body composition. Metabolites excreted due to drug treatment were dominant in urine specimens from cholangiocarcinoma patients, particularly in Western individuals. Urine from participants with sporadic (UK) cholangiocarcinoma contained greater levels of a nucleotide metabolite (uridine/pseudouridine). Higher relative concentrations of 7-methylguanine were observed in urine specimens from Thai cholangiocarcinoma patients. The urinary excretion of hippurate and methyladenine (gut microbial-host co-metabolites) showed a similar pattern of lower levels in patients with malignant biliary tumours from both countries. Intrinsic (body weight and body composition) and extrinsic (xenobiotic metabolism) factors were the main causes of disparities between the two populations. Regardless of the underlying aetiology, biological perturbations associated with cholangiocarcinoma urine metabolome signatures appeared to be influenced by gut microbial community metabolism. Dysregulation in nucleotide metabolism was associated with sporadic cholangiocarcinoma, possibly indicating differences in mitochondrial energy production pathways between cholangiocarcinoma tumour subtypes. Mapping population-specific metabolic disparities may aid in interpretation of disease processes and identification of candidate biomarkers.
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http://dx.doi.org/10.1038/s41598-021-00530-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553759PMC
October 2021

Odd Chain Fatty Acids Are Not Robust Biomarkers for Dietary Intake of Fiber.

Mol Nutr Food Res 2021 Nov 22;65(22):e2100316. Epub 2021 Oct 22.

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.

Scope: Prior investigation has suggested a positive association between increased colonic propionate production and circulating odd-chain fatty acids (OCFAs; pentadecanoic acid [C15:0], heptadecanoic acid [C17:0]). As the major source of propionate in humans is the microbial fermentation of dietary fiber, OCFAs have been proposed as candidate biomarkers of dietary fiber. The objective of this study is to critically assess the plausibility, robustness, reliability, dose-response, time-response aspects of OCFAs as potential biomarkers of fermentable fibers in two independent studies using a validated analytical method.

Methods And Results: OCFAs are first assessed in a fiber supplementation study, where 21 participants received 10 g dietary fiber supplementation for 7 days. OCFAs are then assessed in a highly controlled inpatient setting, which 19 participants consumed a high fiber (45.1 g per day) and a low fiber diet (13.6 g per day) for 4 days. Collectively in both studies, dietary intakes of fiber as fiber supplementations or having consumed a high fiber diet do not increase circulating levels of OCFAs. The dose and temporal relations are not observed.

Conclusion: Current study has generated new insight on the utility of OCFAs as fiber biomarkers and highlighted the importance of critical assessment of candidate biomarkers before application.
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http://dx.doi.org/10.1002/mnfr.202100316DOI Listing
November 2021

Diagnostic Potential of the Plasma Lipidome in Infectious Disease: Application to Acute SARS-CoV-2 Infection.

Metabolites 2021 Jul 20;11(7). Epub 2021 Jul 20.

Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia.

Improved methods are required for investigating the systemic metabolic effects of SARS-CoV-2 infection and patient stratification for precision treatment. We aimed to develop an effective method using lipid profiles for discriminating between SARS-CoV-2 infection, healthy controls, and non-SARS-CoV-2 respiratory infections. Targeted liquid chromatography-mass spectrometry lipid profiling was performed on discovery (20 SARS-CoV-2-positive; 37 healthy controls; 22 COVID-19 symptoms but SARS-CoV-2negative) and validation (312 SARS-CoV-2-positive; 100 healthy controls) cohorts. Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) and Kruskal-Wallis tests were applied to establish discriminant lipids, significance, and effect size, followed by logistic regression to evaluate classification performance. OPLS-DA reported separation of SARS-CoV-2 infection from healthy controls in the discovery cohort, with an area under the curve (AUC) of 1.000. A refined panel of discriminant features consisted of six lipids from different subclasses (PE, PC, LPC, HCER, CER, and DCER). Logistic regression in the discovery cohort returned a training ROC AUC of 1.000 (sensitivity = 1.000, specificity = 1.000) and a test ROC AUC of 1.000. The validation cohort produced a training ROC AUC of 0.977 (sensitivity = 0.855, specificity = 0.948) and a test ROC AUC of 0.978 (sensitivity = 0.948, specificity = 0.922). The lipid panel was also able to differentiate SARS-CoV-2-positive individuals from SARS-CoV-2-negative individuals with COVID-19-like symptoms (specificity = 0.818). Lipid profiling and multivariate modelling revealed a signature offering mechanistic insights into SARS-CoV-2, with strong predictive power, and the potential to facilitate effective diagnosis and clinical management.
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http://dx.doi.org/10.3390/metabo11070467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306636PMC
July 2021

The effects of sustained fitness improvement on the gut microbiome: A longitudinal, repeated measures case-study approach.

Transl Sports Med 2021 Mar 13;4(2):174-192. Epub 2020 Dec 13.

APC Microbiome Ireland National University of Ireland Cork Ireland.

The athlete gut microbiome differs from that of non-athletes in its composition and metabolic function. Short-term fitness improvement in sedentary adults does not replicate the microbiome characteristics of athletes. The objective of this study was to investigate whether sustained fitness improvement leads to pronounced alterations in the gut microbiome. This was achieved using a repeated-measures, case-study approach that examined the gut microbiome of two initially unfit volunteers undertaking progressive exercise training over a 6-month period. Samples were collected every two weeks, and microbiome, metabolome, diet, body composition, and cardiorespiratory fitness data were recorded. Training culminated in both participants completing their respective goals (a marathon or Olympic-distance triathlon) with improved body composition and fitness parameters. Increases in gut microbiota α-diversity occurred with sustained training and fluctuations occurred in response to training events (eg, injury, illness, and training peaks). Participants' BMI reduced during the study and was significantly associated with increased urinary measurements of N-methyl nicotinate and hippurate, and decreased phenylacetylglutamine. These results suggest that sustained fitness improvements support alterations to gut microbiota and physiologically-relevant metabolites. This study provides longitudinal analysis of the gut microbiome response to real-world events during progressive fitness training, including intercurrent illness and injury.
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http://dx.doi.org/10.1002/tsm2.215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317196PMC
March 2021

Statistical analysis in metabolic phenotyping.

Nat Protoc 2021 09 28;16(9):4299-4326. Epub 2021 Jul 28.

Division of Systems Medicine, Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, UK.

Metabolic phenotyping is an important tool in translational biomedical research. The advanced analytical technologies commonly used for phenotyping, including mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy, generate complex data requiring tailored statistical analysis methods. Detailed protocols have been published for data acquisition by liquid NMR, solid-state NMR, ultra-performance liquid chromatography (LC-)MS and gas chromatography (GC-)MS on biofluids or tissues and their preprocessing. Here we propose an efficient protocol (guidelines and software) for statistical analysis of metabolic data generated by these methods. Code for all steps is provided, and no prior coding skill is necessary. We offer efficient solutions for the different steps required within the complete phenotyping data analytics workflow: scaling, normalization, outlier detection, multivariate analysis to explore and model study-related effects, selection of candidate biomarkers, validation, multiple testing correction and performance evaluation of statistical models. We also provide a statistical power calculation algorithm and safeguards to ensure robust and meaningful experimental designs that deliver reliable results. We exemplify the protocol with a two-group classification study and data from an epidemiological cohort; however, the protocol can be easily modified to cover a wider range of experimental designs or incorporate different modeling approaches. This protocol describes a minimal set of analyses needed to rigorously investigate typical datasets encountered in metabolic phenotyping.
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http://dx.doi.org/10.1038/s41596-021-00579-1DOI Listing
September 2021

Integrative Modeling of Plasma Metabolic and Lipoprotein Biomarkers of SARS-CoV-2 Infection in Spanish and Australian COVID-19 Patient Cohorts.

J Proteome Res 2021 08 12;20(8):4139-4152. Epub 2021 Jul 12.

Australian National Phenome Centre, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia.

Quantitative plasma lipoprotein and metabolite profiles were measured on an autonomous community of the Basque Country (Spain) cohort consisting of hospitalized COVID-19 patients ( = 72) and a matched control group ( = 75) and a Western Australian (WA) cohort consisting of ( = 17) SARS-CoV-2 positives and ( = 20) healthy controls using 600 MHz H nuclear magnetic resonance (NMR) spectroscopy. Spanish samples were measured in two laboratories using one-dimensional (1D) solvent-suppressed and T-filtered methods with in vitro diagnostic quantification of lipoproteins and metabolites. SARS-CoV-2 positive patients and healthy controls from both populations were modeled and cross-projected to estimate the biological similarities and validate biomarkers. Using the top 15 most discriminatory variables enabled construction of a cross-predictive model with 100% sensitivity and specificity (within populations) and 100% sensitivity and 82% specificity (between populations). Minor differences were observed between the control metabolic variables in the two cohorts, but the lipoproteins were virtually indistinguishable. We observed highly significant infection-related reductions in high-density lipoprotein (HDL) subfraction 4 phospholipids, apolipoproteins A1 and A2,that have previously been associated with negative regulation of blood coagulation and fibrinolysis. The Spanish and Australian diagnostic SARS-CoV-2 biomarkers were mathematically and biologically equivalent, demonstrating that NMR-based technologies are suitable for the study of the comparative pathology of COVID-19 via plasma phenotyping.
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http://dx.doi.org/10.1021/acs.jproteome.1c00458DOI Listing
August 2021

Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor.

Proc Natl Acad Sci U S A 2021 07;118(27)

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;

While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene knockout (KO) mutant unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of , , and genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
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http://dx.doi.org/10.1073/pnas.2021091118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271728PMC
July 2021

Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype.

Microbiome 2021 06 14;9(1):139. Epub 2021 Jun 14.

Division of Digestive Disease, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK.

Background: Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations.

Methods: Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome.

Results: Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients' bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery.

Conclusion: Altered bacterial composition and metabolism contribute to metabolic observations in biofluids of patients following RYGB surgery. The impact of these changes on the functional clinical outcomes requires further investigation. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01086-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201742PMC
June 2021

Understanding the role of the gut in undernutrition: what can technology tell us?

Gut 2021 Jun 8. Epub 2021 Jun 8.

Stable Isotope Biochemistry Laboratory, Scottish Universities Environmental Research Centre, East Kilbride, UK

Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)-a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability-is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.
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http://dx.doi.org/10.1136/gutjnl-2020-323609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292602PMC
June 2021

Modifying gut integrity and microbiome in children with severe acute malnutrition using legume-based feeds (MIMBLE): A pilot trial.

Cell Rep Med 2021 May 18;2(5):100280. Epub 2021 May 18.

Imperial Centre for Pediatrics and Child Health, Imperial College, St Mary's Campus Norfolk Place, London W2 1PG, UK.

Case fatality among African children with severe acute malnutrition remains high. We report a 3-arm pilot trial in 58 Ugandan children, comparing feeds targeting disordered gastrointestinal function containing cowpea (CpF, n = 20) or inulin (InF, n = 20) with conventional feeds (ConF, n = 18). Baseline measurements of gut permeability (lactulose:mannitol ratio 1.19 ± SD 2.00), inflammation (fecal calprotectin 539.0 μg/g, interquartile range [IQR] 904.8), and satiety (plasma polypeptide YY 62.6 pmol/l, IQR 110.3) confirm gastrointestinal dysfunction. By day 28, no differences are observable in proportion achieving weight gain >5 g/kg/day (87%, 92%, 86%; p > 0.05), mortality (16%, 30%, 17%; p > 0.05), or edema resolution (83%, 54%, 91%; p > 0.05) among CpF, InF, and ConF. Decreased fecal bacterial richness from day 1 (abundance-based coverage estimator [ACE] 53.2) to day 7 (ACE 40.8) is observed only in ConF (p = 0.025). relative abundance increases from day 7 (5.8% ± 8.6%) to day 28 (10.9% ± 8.7%) in CpF (corrected p = 1.000). Legume-enriched feeds support aspects of gut function and the microbiome. Trial registration PACTR201805003381361.
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http://dx.doi.org/10.1016/j.xcrm.2021.100280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149470PMC
May 2021

Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome.

J Proteome Res 2021 06 19;20(6):3315-3329. Epub 2021 May 19.

Australian National Phenome Centre, Health Futures Institute, Murdoch University, Harry Perkins Building, 5 Robin Warren Drive, Perth, WA 6150, Australia.

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients ( = 27) were compared with controls ( = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients ( = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine ( = 3.6 × 10 versus controls) and reduced glutamine/glutamate ratio ( = 6.95 × 10 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower ( = 4.2 × 10) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.
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http://dx.doi.org/10.1021/acs.jproteome.1c00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147448PMC
June 2021

Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome.

Microbiome 2021 05 7;9(1):104. Epub 2021 May 7.

Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Girona, Spain.

Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.

Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient's mice. In line with the results in humans, transplantation from 'high ferritin donors' resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient's mice.

Conclusions: Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01052-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106161PMC
May 2021

Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses.

J Proteome Res 2021 05 16;20(5):2796-2811. Epub 2021 Mar 16.

Australian National Phenome Centre, Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia.

We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) ( = 10) or SARS-CoV-2 (-) ( = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer's ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.
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http://dx.doi.org/10.1021/acs.jproteome.1c00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986977PMC
May 2021

Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection.

Anal Chem 2021 03 12;93(8):3976-3986. Epub 2021 Feb 12.

Australian National Phenome Center, and Center for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth WA6150, Australia.

We have applied nuclear magnetic resonance spectroscopy based plasma phenotyping to reveal diagnostic molecular signatures of SARS-CoV-2 infection combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls ( = 26) with SARS-CoV-2 negative non-hospitalized respiratory patients and hospitalized respiratory patients ( = 23 and 11 respectively) with SARS-CoV-2 rRT-PCR positive respiratory patients ( = 17, with longitudinal sampling time-points). DIRE data were modelled using principal component analysis and orthogonal projections to latent structures discriminant analysis (O-PLS-DA), with statistical cross-validation indices indicating excellent model generalization for the classification of SARS-CoV-2 positivity for all comparator groups (area under the receiver operator characteristic curve = 1). DIRE spectra show biomarker signal combinations conferred by differential concentrations of metabolites with selected molecular mobility properties. These comprise the following: (a) composite -acetyl signals from α-1-acid glycoprotein and other glycoproteins (designated GlycA and GlycB) that were elevated in SARS-CoV-2 positive patients [ = 2.52 × 10 (GlycA) and 1.25 × 10 (GlycB) controls], (b) two diagnostic supramolecular phospholipid composite signals that were identified (SPC-A and SPC-B) from the -N-(CH) choline headgroups of lysophosphatidylcholines carried on plasma glycoproteins and from phospholipids in high-density lipoprotein subfractions (SPC-A) together with a phospholipid component of low-density lipoprotein (SPC-B). The integrals of the summed SPC signals (SPC) were reduced in SARS-CoV-2 positive patients relative to both controls ( = 1.40 × 10) and SARS-CoV-2 negative patients ( = 4.52 × 10) but were not significantly different between controls and SARS-CoV-2 negative patients. The identity of the SPC signal components was determined using one and two dimensional diffusional, relaxation, and statistical spectroscopic experiments. The SPC/GlycA ratios were also significantly different for control SARS-CoV-2 positive patients ( = 1.23 × 10) and for SARS-CoV-2 negatives positives ( = 1.60 × 10). Thus, plasma SPC and SPC/GlycA are proposed as sensitive molecular markers for SARS-CoV-2 positivity that could effectively augment current COVID-19 diagnostics and may have value in functional assessment of the disease recovery process in patients with long-term symptoms.
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http://dx.doi.org/10.1021/acs.analchem.0c04952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908063PMC
March 2021

Roux-en-Y gastric bypass surgery in Zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss.

Gut Microbes 2021 Jan-Dec;13(1):1-20

Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College London London, UK.

Mechanisms of Roux-en-Y gastric bypass (RYGB) surgery are not fully understood. This study aimed to investigate weight loss-independent bacterial and metabolic changes, as well as the absorption of bacterial metabolites and bile acids through the hepatic portal system following RYGB surgery. Three groups of obese Zucker () rats were included: RYGB (n = 11), sham surgery and body weight matched with RYGB (Sham-BWM, n = 5), and sham surgery fed (Sham-obese, n = 5). Urine and feces were collected at multiple time points, with portal vein and peripheral blood obtained at the end of the study. Metabolic phenotyping approaches and 16S rRNA gene sequencing were used to determine the biochemical and bacterial composition of the samples, respectively. RYGB surgery-induced distinct metabolic and bacterial disturbances, which were independent of weight loss through caloric restriction. RYGB resulted in lower absorption of phenylalanine and choline, and higher urinary concentrations of host-bacterial co-metabolites (e.g., phenylacetylglycine, indoxyl sulfate), together with higher fecal trimethylamine, suggesting enhanced bacterial aromatic amino acid and choline metabolism. Short chain fatty acids (SCFAs) were lower in feces and portal vein blood from RYGB group compared to Sham-BWM, accompanied with lower abundances of , and known to contain SCFA producers, indicating reduced bacterial fiber fermentation. Fecal γ-amino butyric acid (GABA) was found in higher concentrations in RYGB than that in Sham groups and could play a role in the metabolic benefits associated with RYGB surgery. While no significant difference in urinary BA excretion, RYGB lowered both portal vein and circulating BA compared to Sham groups. These findings provide a valuable resource for how dynamic, multi-systems changes impact on overall metabolic health, and may provide potential therapeutic targets for developing downstream non-surgical treatment for metabolic disease.
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http://dx.doi.org/10.1080/19490976.2021.1875108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872092PMC
January 2022

Lack of anti-TNF drugs levels in fistula tissue - a reason for nonresponse in Crohn's perianal fistulating disease?

Eur J Gastroenterol Hepatol 2022 Jan;34(1):18-26

Robin Phillips Fistula Research Unit, St Mark's Hospital & Academic Institute, Harrow, Middlesex.

Introduction: Anti-TNF therapy is recommended as treatment for patients with Crohn´s perianal fistulas. However, a significant proportion of patients have a sub-optimal response to anti-TNF therapy. Higher serum levels of anti-TNF agents have been associated with improved outcomes in perianal Crohn's disease. Currently, it is unknown whether anti-TNF agent levels can be detected in tissue from fistula tracts themselves and whether this is associated with response.

Aims And Methods: We undertook a pilot study to measure fistula tissue levels of anti-TNF medication (infliximab and adalimumab). We used a previously validated targeted proteomic technique, employing ultraperformance liquid chromatography-mass spectrometry, to detect/quantify anti-TNF drugs. Biopsies were obtained from fistula tracts of patients with Crohn's disease on maintenance treatment; with idiopathic (cryptoglandular) fistula tissues used as negative controls as well as positive controls (by spiking the latter tissues with anti-TNF drugs).

Results: Tissue was sampled from the fistula tracts of seven patients with Crohn's perianal disease (five patients were on adalimumab and two patients were on infliximab). The anti-TNF drugs, infliximab and adalimumab, were not detected in fistula samples from any of the Crohn's patients despite detection in 'spiked' positive control samples.

Conclusion: Absence of detection of the anti-TNF drugs in fistula tissue raises the question on the role of tissue penetrance of anti-TNF drugs in response to therapy. Further work is required in a larger number of patients to validate the findings observed and investigate if any correlation exists between tissue and serum levels of anti-TNF and clinical outcome.

Summary: Predicting response in Crohn's fistula patients on biologic therapy is difficult with no reliable biomarkers. This pilot study uses targeted proteomics to investigate the potential role of tissue drug levels in acting as a biomarker of treatment response.
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http://dx.doi.org/10.1097/MEG.0000000000002032DOI Listing
January 2022

Neuroendocrine Neoplasms: Identification of Novel Metabolic Circuits of Potential Diagnostic Utility.

Cancers (Basel) 2021 Jan 20;13(3). Epub 2021 Jan 20.

Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, UK.

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36-85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine--oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.
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http://dx.doi.org/10.3390/cancers13030374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864182PMC
January 2021

Low Volume in Vitro Diagnostic Proton NMR Spectroscopy of Human Blood Plasma for Lipoprotein and Metabolite Analysis: Application to SARS-CoV-2 Biomarkers.

J Proteome Res 2021 02 23;20(2):1415-1423. Epub 2021 Jan 23.

Australian National Phenome Centre, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia.

The utility of low sample volume in vitro diagnostic (IVDr) proton nuclear magnetic resonance (H NMR) spectroscopic experiments on blood plasma for information recovery from limited availability or high value samples was exemplified using plasma from patients with SARS-CoV-2 infection and normal controls. H NMR spectra were obtained using solvent-suppressed 1D, spin-echo (CPMG), and 2-dimensional J-resolved (JRES) spectroscopy using both 3 mm outer diameter SampleJet NMR tubes (100 μL plasma) and 5 mm SampleJet NMR tubes (300 μL plasma) under in vitro diagnostic conditions. We noted near identical diagnostic models in both standard and low volume IVDr lipoprotein analysis (measuring 112 lipoprotein parameters) with a comparison of the two tubes yielding values ranging between 0.82 and 0.99 for the 40 paired lipoprotein parameters samples. Lipoprotein measurements for the 3 mm tubes were achieved without time penalty over the 5 mm tubes as defined by biomarker recovery for SARS-CoV-2. Overall, biomarker pattern recovery for the lipoproteins was extremely similar, but there were some small positive offsets in the linear equations for several variables due to small shimming artifacts, but there was minimal degradation of the biological information. For the standard untargeted 1D, CPMG, and JRES NMR experiments on the same samples, the reduced signal-to-noise was more constraining and required greater scanning times to achieve similar differential diagnostic performance (15 min per sample per experiment for 3 mm 1D and CPMG, compared to 4 min for the 5 mm tubes). We conclude that the 3 mm IVDr method is fit-for-purpose for quantitative lipoprotein measurements, allowing the preparation of smaller volumes for high value or limited volume samples that is common in clinical studies. If there are no analytical time constraints, the lower volume experiments are equally informative for untargeted profiling.
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http://dx.doi.org/10.1021/acs.jproteome.0c00815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857136PMC
February 2021

NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines.

J Proteome Res 2021 02 11;20(2):1382-1396. Epub 2021 Jan 11.

Australian National Phenome Centre, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Western Australia 6150, Australia.

To investigate the systemic metabolic effects of SARS-CoV-2 infection, we analyzed H NMR spectroscopic data on human blood plasma and co-modeled with multiple plasma cytokines and chemokines (measured in parallel). Thus, 600 MHz H solvent-suppressed single-pulse, spin-echo, and 2D J-resolved spectra were collected on plasma recorded from SARS-CoV-2 rRT-PCR-positive patients ( = 15, with multiple sampling timepoints) and age-matched healthy controls ( = 34, confirmed rRT-PCR negative), together with patients with COVID-19/influenza-like clinical symptoms who tested SARS-CoV-2 negative ( = 35). We compared the single-pulse NMR spectral data with diagnostic research (IVDr) information on quantitative lipoprotein profiles (112 parameters) extracted from the raw 1D NMR data. All NMR methods gave highly significant discrimination of SARS-CoV-2 positive patients from controls and SARS-CoV-2 negative patients with individual NMR methods, giving different diagnostic information windows on disease-induced phenoconversion. Longitudinal trajectory analysis in selected patients indicated that metabolic recovery was incomplete in individuals without detectable virus in the recovery phase. We observed four plasma cytokine clusters that expressed complex differential statistical relationships with multiple lipoproteins and metabolites. These included the following: cluster 1, comprising MIP-1β, SDF-1α, IL-22, and IL-1α, which correlated with multiple increased LDL and VLDL subfractions; cluster 2, including IL-10 and IL-17A, which was only weakly linked to the lipoprotein profile; cluster 3, which included IL-8 and MCP-1 and were inversely correlated with multiple lipoproteins. IL-18, IL-6, and IFN-γ together with IP-10 and RANTES exhibited strong positive correlations with LDL1-4 subfractions and negative correlations with multiple HDL subfractions. Collectively, these data show a distinct pattern indicative of a multilevel cellular immune response to SARS CoV-2 infection interacting with the plasma lipoproteome giving a strong and characteristic immunometabolic phenotype of the disease. We observed that some patients in the respiratory recovery phase and testing virus-free were still metabolically highly abnormal, which indicates a new role for these technologies in assessing full systemic recovery.
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http://dx.doi.org/10.1021/acs.jproteome.0c00876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805607PMC
February 2021

Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer's disease.

Alzheimers Res Ther 2021 01 9;13(1):20. Epub 2021 Jan 9.

UK Dementia Research Institute, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK.

Background: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer's disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls.

Methods: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations.

Results: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine.

Conclusions: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.
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http://dx.doi.org/10.1186/s13195-020-00741-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797094PMC
January 2021

Differences in amino acid and lipid metabolism distinguish Crohn's from idiopathic/cryptoglandular perianal fistulas by tissue metabonomic profiling and may offer clues to underlying pathogenesis.

Eur J Gastroenterol Hepatol 2021 12;33(12):1469-1479

Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex.

Introduction: Few studies have investigated perianal fistula etiopathogenesis, and although the cryptoglandular theory is widely accepted in idiopathic cases, in Crohn's disease, it is thought to involve the interplay between microbiological, immunological and genetic factors. A pilot study was conducted to assess for metabolic variations in Crohn's perianal fistula tissue that might differ from that of idiopathic (cryptoglandular) perianal fistula tissue as a comparator. The goal was to identify any potential biomarkers of disease, which may improve the understanding of pathogenesis.

Aims And Methods: Fistula tract biopsies were obtained from 30 patients with idiopathic perianal fistula and 20 patients with Crohn's anal fistula. Two different assays were used in an ultra-high-performance liquid chromatography system coupled with a mass spectrometric detector to achieve broad metabolome coverage. Univariate and multivariate statistical data analyses were used to identify differentiating metabolic features corresponding to the perianal fistula phenotype (i.e. Crohn's disease vs. idiopathic).

Results: Significant orthogonal partial least squares discriminant analysis predictive models (validated with cross-validated-analysis of variance P value <0.05) differentiated metabolites from tissue samples from Crohn's vs. idiopathic anal fistula patients using both metabolic profiling platforms. A total of 41 metabolites were identified, suggesting alterations in pathways, including amino acid, carnitine and lipid metabolism.

Conclusion: Metabonomics may reveal biomarkers of Crohn's perianal fistula. Further work in larger numbers is required to validate the findings of these studies as well as cross-correlation with microbiome work to better understand the impact of host-gut/environment interactions in the pathophysiology of Crohn's and idiopathic perianal fistulas and identify novel therapeutic targets.
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http://dx.doi.org/10.1097/MEG.0000000000001976DOI Listing
December 2021

Urinary metabolic phenotyping for Alzheimer's disease.

Sci Rep 2020 12 10;10(1):21745. Epub 2020 Dec 10.

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.

Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer's Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer's Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer's Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer's Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer's pathology in previous studies.
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http://dx.doi.org/10.1038/s41598-020-78031-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730184PMC
December 2020

A simultaneous exploratory and quantitative amino acid and biogenic amine metabolic profiling platform for rapid disease phenotyping via UPLC-QToF-MS.

Talanta 2021 Feb 7;223(Pt 2):121872. Epub 2020 Nov 7.

Australian National Phenome Centre, Health Futures Institute, Murdoch University, Harry Perkins South Building, Perth, WA, 6150, Australia; Center for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Murdoch Perth, WA, 6150, Australia; The Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia. Electronic address:

Metabolic phenotyping using mass spectrometry (MS) is being applied to ever increasing sample numbers in clinical and epidemiology studies. High-throughput and robust methods are being developed for the accurate measurement of metabolites associated with disease. Traditionally, quantitative assays have utilized triple quadrupole (QQQ) MS based methods; however, the use of such focused methods removes the ability to perform discovery-based metabolic phenotyping. An integrated workflow for the hybrid simultaneous quantification of 34 biogenic amines in combination with full scan high-resolution accurate mass (HRAM) exploratory metabolic phenotyping is presented. Primary and secondary amines are derivatized with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate prior to revered-phase liquid chromatographic separation and mass spectrometric detection. Using the HRAM-MS data, retrospective phenotypic data mining could be performed, demonstrating the versatility of HRAM-MS instrumentation in a clinical and molecular epidemiological environment. Quantitative performance was assessed using two MS detector platforms: Waters TQ-XS (QQQ; n = 3) and Bruker Impact II QToF (HRAMS-MS; n = 2) and three human biofluids (plasma, serum and urine). Finally, each platform was assessed using a certified external reference sample (NIST SRM 1950 plasma). Intra- and inter-day accuracy and precision were comparable between the QQQ and QToF instruments (<15%), with excellent linearity (R > 0.99) over the quantification range of 1-400 μmol L. Quantitative values were comparable across all instruments for human plasma, serum and urine samples, and calculated concentrations were verified against certified reference values for NIST SRM 1950 plasma as an external reference. As a real-life biological exemplar, the method was applied to plasma samples obtained from SARS-CoV-2 positive patients versus healthy controls. Both the QQQ and QToF approaches were equivalent in being able to correctly classify SARS-CoV-2 positivity. Critically, the use of HRAM full scan data was also assessed for retrospective exploratory mining of data to extract additional biogenic amines of biomarker interest beyond the 34 quantified targets.
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http://dx.doi.org/10.1016/j.talanta.2020.121872DOI Listing
February 2021

Metabolic Signatures of Gestational Weight Gain and Postpartum Weight Loss in a Lifestyle Intervention Study of Overweight and Obese Women.

Metabolites 2020 Dec 4;10(12). Epub 2020 Dec 4.

Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK.

Background: Overweight and obesity amongst women of reproductive age are increasingly common in developed economies and are shown to adversely affect birth outcomes and both childhood and adulthood health risks in the offspring. Metabolic profiling in conditions of overweight and obesity in pregnancy could potentially be applied to elucidate the molecular basis of the adverse effects of gestational weight gain (GWG) and postpartum weight loss (WL) on future risks for cardiovascular disease (CVD) and other chronic diseases.

Methods: Biofluid samples were collected from 114 ethnically diverse pregnant women with body mass index (BMI) between 25 and 40 kg/m from Chicago (US), as part of a randomized lifestyle intervention trial (Maternal Offspring Metabolics: Family Intervention Trial; NCT01631747). At 15 weeks, 35 weeks of gestation, and at 1 year postpartum, the blood plasma lipidome and metabolic profile of urine samples were analyzed by liquid chromatography mass spectrometry (LC-MS) and H nuclear magnetic resonance spectroscopy (H NMR) respectively.

Results: Urinary 4-deoxyerythronic acid and 4-deoxythreonic acid were found to be positively correlated to BMI. Seventeen plasma lipids were found to be associated with GWG and 16 lipids were found to be associated with WL, which included phosphatidylinositols (PI), phosphatidylcholines (PC), lysophospholipids (lyso-), sphingomyelins (SM) and ether phosphatidylcholine (PC-O). Three phospholipids found to be positively associated with GWG all contained palmitate side-chains, and amongst the 14 lipids that were negatively associated with GWG, seven were PC-O. Six of eight lipids found to be negatively associated with WL contained an 18:2 fatty acid side-chain.

Conclusions: Maternal obesity was associated with characteristic urine and plasma metabolic phenotypes, and phospholipid profile was found to be associated with both GWG and postpartum WL in metabolically healthy pregnant women with overweight/obesity. Postpartum WL may be linked to the reduction in the intake of linoleic acid/conjugated linoleic acid food sources in our study population.
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http://dx.doi.org/10.3390/metabo10120498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761920PMC
December 2020

Metabolomic Analysis in Inflammatory Bowel Disease: A Systematic Review.

J Crohns Colitis 2021 May;15(5):813-826

Department of Metabolism Digestion and Reproduction, Imperial College London, UK.

Background And Aims: The inflammatory bowel diseases [IBD], Crohn's disease and ulcerative colitis, are chronic, idiopathic gastrointestinal diseases. Although their precise aetiology is unknown, it is thought to involve a complex interaction between genetic predisposition and an abnormal host immune response to environmental exposures, probably microbial. Microbial dysbiosis has frequently been documented in IBD. Metabolomics [the study of small molecular intermediates and end products of metabolism in biological samples] provides a unique opportunity to characterize disease-associated metabolic changes and may be of particular use in quantifying gut microbial metabolism. Numerous metabolomic studies have been undertaken in IBD populations, identifying consistent alterations in a range of molecules across several biological matrices. This systematic review aims to summarize these findings.

Methods: A comprehensive, systematic search was carried out using Medline and Embase. All studies were reviewed by two authors independently using predefined exclusion criteria. Sixty-four relevant papers were assessed for quality and included in the review.

Results: Consistent metabolic perturbations were identified, including increases in levels of branched chain amino acids and lipid classes across stool, serum, plasma and tissue biopsy samples, and reduced levels of microbially modified metabolites in both urine [such as hippurate] and stool [such as secondary bile acids] samples.

Conclusions: This review provides a summary of metabolomic research in IBD to date, highlighting underlying themes of perturbed gut microbial metabolism and mammalian-microbial co-metabolism associated with disease status.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa227DOI Listing
May 2021

Author Correction: Metabolism of the predominant human milk oligosaccharide fucosyllactose by an infant gut commensal.

Sci Rep 2020 Oct 9;10(1):17265. Epub 2020 Oct 9.

APC Microbiome Ireland, University College Cork, Western Road, Cork, Ireland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-73762-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547093PMC
October 2020
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