Imperial College London

Dr Matthew R. Lewis

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Senior Research Officer
 
 
 
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Contact

 

matthew.lewis

 
 
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Location

 

660Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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107 results found

Valdivia-Garcia MA, Chappell KE, Camuzeaux S, Olmo-Garcia L, van der Sluis VH, Radhakrishnan ST, Stephens H, Bouri S, Braz LMDC, Williams HT, Lewis MR, Frost G, Li Jet al., 2022, Improved quantitation of short-chain carboxylic acids in human biofluids using 3-nitrophenylhydrazine derivatization and liquid chromatography with tandem mass spectrometry (LC-MS/MS), JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 221, ISSN: 0731-7085

Journal article

Kowalka AM, Alexiadou K, Cuenco J, Clarke RE, Minnion J, Williams EL, Bech P, Purkayastha S, Ahmed AR, Takats Z, Whitwell HJ, Romero MG, Bloom SR, Camuzeaux S, Lewis MR, Khoo B, Tan TM-Met al., 2022, The post-prandial secretion of Peptide YY<sub>1-36</sub> and <sub>3-36</sub> in obesity is differentially increased after gastric bypass versus sleeve gastrectomy., Clin Endocrinol (Oxf)

OBJECTIVES: Peptide tyrosine tyrosine (PYY) exists as two species, PYY<sub>1-36</sub> and PYY<sub>3-36</sub> <sup>,</sup> with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY<sub>1-36</sub> and PYY<sub>3-36</sub> secretion are not known as previous studies have used non-specific immunoassays to measure total PYY. Our objective was to characterise the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and post-prandial PYY<sub>1-36</sub> and PYY<sub>3-36</sub> secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. DESIGN AND SUBJECTS: Observational study in 10 healthy non-obese volunteers and 30 participants with obesity who underwent RYGB (n=24) or SG (n=6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardised mixed meal test (MMT) before and 1 year after surgery. The outcome measure was PYY<sub>1-36</sub> and PYY<sub>3-36</sub> concentration. RESULTS: Pre-surgery, the fasting and post-prandial levels of PYY<sub>1-36</sub> and PYY<sub>3-36</sub> were low, with minimal responses to the MMT, and these did not differ from healthy non-obese volunteers. The postprandial secretion of both PYY<sub>1-36</sub> and PYY<sub>3-36</sub> at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared to SG. CONCLUSIONS: There appears to be no difference in PYY secretion between non-obese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased post-prandial secretion of PYY<sub>1-36</sub> and PYY<sub>3-36</sub> , which may account for long-term differences in efficacy and adverse effects between the two types of surgery. This article is

Journal article

Dehghan A, Pinto RC, Karaman I, Huang J, Durainayagam BR, Ghanbari M, Nazeer A, Zhong Q, Liggi S, Whiley L, Mustafa R, Kivipelto M, Solomon A, Ngandu T, Kanekiyo T, Aikawa T, Radulescu CI, Barnes SJ, Graça G, Chekmeneva E, Camuzeaux S, Lewis MR, Kaluarachchi MR, Ikram MA, Holmes E, Tzoulaki I, Matthews PM, Griffin JL, Elliott Pet al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proc Natl Acad Sci U S A, Vol: 119

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Journal article

Mullish BH, Martinez Gili L, Chekmeneva E, Dos Santos Correia GDS, Lewis MR, Horneffer-van der Sluis V, Roberts LA, McDonald JAK, Pechlivanis A, Walters JRF, McClure EL, Marchesi JR, Allegretti JRet al., 2022, Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection, Alimentary Pharmacology and Therapeutics, ISSN: 0269-2813

Background:Factors influencing recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools predicting recurrence are lacking. Perturbations in bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis.Aims:To define stool BA dynamics in patients with primary CDI and explore signatures predicting recurrenceMethodsWeekly stool samples were collected from patients with primary CDI from the last day of anti-CDI therapy until recurrence or, otherwise, through 8 weeks post-completion. Ultra-high performance liquid chromatography-mass spectrometry was used to profile BAs; stool bile salt hydrolase (BSH) activity was measured to determine primary BA bacterial deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in patients with recurrence versus those without, and to assess faecal BAs as predictive markers for recurrence.Results:Twenty (36%) of 56 patients (median age: 57, 64% male) had recurrence; 80% of recurrences occurred within the first 9 days post-antibiotic treatment. Principal component analysis of stool BA profiles demonstrated clustering by recurrence status and post-treatment timepoint. Longitudinal faecal BA trajectories showed recovery of secondary BAs and their derivatives only in patients without recurrence. BSH activity increased over time only among non-relapsing patients (β = 0.056; likelihood ratio test p = 0.018). A joint longitudinal-survival model identified five stool BAs with area under the receiver operating characteristic curve >0.73 for predicting recurrence within 9 days post-CDI treatment.Conclusions:Gut BA metabolism dynamics differ in primary CDI patients between those developing recurrence and those who do not. Individual BAs show promise as potential novel biomarkers to predict CDI recurrence.

Journal article

Takis PG, Vuckovic I, Tan T, Denic A, Lieske JC, Lewis MR, Macura Set al., 2022, NMRpQuant: an automated software for large scale urinary total protein quantification by one-dimensional 1H NMR profiles, Bioinformatics, Vol: 38, Pages: 4437-4439, ISSN: 1367-4803

Summary1H nuclear magnetic resonance (NMR) spectroscopy is an established bioanalytical technology for metabolic profiling of biofluids in both clinical and large-scale population screening applications. Recently, urinary protein quantification has been demonstrated using the same 1D 1H NMR experimental data captured for metabolic profiling. Here, we introduce NMRpQuant, a freely available platform that builds on these findings with both novel and further optimized computational NMR approaches for rigorous, automated protein urine quantification. The results are validated by interlaboratory comparisons, demonstrating agreement with clinical/biochemical methodologies, pointing at a ready-to-use tool for routine protein urinalyses.Availability and implementationNMRpQuant was developed on MATLAB programming environment. Source code and Windows/macOS compiled applications are available at https://github.com/pantakis/NMRpQuant, and working examples are available at https://doi.org/10.6084/m9.figshare.18737189.v1.

Journal article

Gadgil MD, Kanaya AM, Sands C, Chekmeneva E, Lewis MR, Kandula NR, Herrington DMet al., 2022, Diet Patterns Are Associated with Circulating Metabolites and Lipid Profiles of South Asians in the United States, JOURNAL OF NUTRITION, ISSN: 0022-3166

Journal article

Alexander J, Mullish B, Danckert N, Liu Z, Saifuddin A, Torkizadeh M, Ibraheim H, Miguens-Blanco J, Bewshea C, Nice R, Lin S, Prabhudev H, Sands C, Lewis M, Teare J, Hart A, Kennedy N, Ahmad T, Marchesi J, Powell Net al., 2022, COVID-19 VACCINATION RESPONSE IN IMMUNOSUPPRESSED PATIENTS WITH IBD IS ASSOCIATED WITH ALTERED GUT MICROBIOTA FUNCTION, Publisher: BMJ PUBLISHING GROUP, Pages: A36-A36, ISSN: 0017-5749

Conference paper

Kragsnaes MS, Blanco JM, Chekmeneva E, Salam A, Lewis MR, Kjeldsen J, Horn HC, Munk HL, Pedersen JK, Marchesi J, Ellingsen Tet al., 2022, INCREASED INTESTINAL PERMEABILITY IN PATIENTS WITH PSORIATIC ARTHRITIS CLASSIFIED AS TREATMENT FAILURES DURING THE 26-WEEK FLORA TRIAL, Publisher: BMJ PUBLISHING GROUP, Pages: 868-868, ISSN: 0003-4967

Conference paper

Wilshaw J, Boswood A, Chang YM, Sands CJ, Camuzeaux S, Lewis MR, Xia D, Connolly DJet al., 2022, Evidence of altered fatty acid metabolism in dogs with naturally occurring valvular heart disease and congestive heart failure, Metabolomics, Vol: 18, ISSN: 1573-3882

IntroductionMyxomatous mitral valve disease (MMVD) is the most common cardiac condition in adult dogs. The disease progresses over several years and affected dogs may develop congestive heart failure (HF). Research has shown that myocardial metabolism is altered in cardiac disease, leading to a reduction in β-oxidation of fatty acids and an increased dependence upon glycolysis.ObjectivesThis study aimed to evaluate whether a shift in substrate use occurs in canine patients with MMVD; a naturally occurring model of human disease.MethodsClient-owned dogs were longitudinally evaluated at a research clinic in London, UK and paired serum samples were selected from visits when patients were in ACVIM stage B1: asymptomatic disease without cardiomegaly, and stage C: HF. Samples were processed using ultra-performance liquid chromatography mass spectrometry and lipid profiles were compared using mixed effects models with false discovery rate adjustment. The effect of disease stage was evaluated with patient breed entered as a confounder. Features that significantly differed were screened for selection for annotation efforts using reference databases.ResultsDogs in HF had altered concentrations of lipid species belonging to several classes previously associated with cardiovascular disease. Concentrations of certain acylcarnitines, phospholipids and sphingomyelins were increased after individuals had developed HF, whilst some ceramides and lysophosphatidylcholines decreased.ConclusionsThe canine metabolome appears to change as MMVD progresses. Findings from this study suggest that in HF myocardial metabolism may be characterised by reduced β-oxidation. This proposed explanation warrants further research.

Journal article

Alexander JL, Mullish BH, Danckert NP, Liu Z, Saifuddin A, Torkizadeh M, Ibraheim H, Blanco JM, Roberts LA, Bewshea CM, Nice R, Lin S, Prabhudev H, Sands C, Sluis VH-VD, Lewis M, Sebastian S, Lees CW, Teare JP, Hart A, Goodhand JR, Kennedy NA, Marchesi JR, Ahmad T, Powell Net al., 2022, The gut microbiota and metabolome is associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients

<jats:title>Abstract</jats:title> <jats:p>Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination. Forty-three infliximab-treated patients with IBD were recruited (30 Crohn’s disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.021). <jats:italic>Bilophila</jats:italic> abundance was associated with better serological response, while <jats:italic>Streptococcus</jats:italic> was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R<jats:sup>2</jats:sup>X 0.25, R&l

Journal article

Correia GDS, Takis PG, Sands CJ, Kowalka AM, Tan T, Turtle L, Ho A, Semple MG, Openshaw PJM, Baillie JK, Takáts Z, Lewis MRet al., 2022, 1H NMR Signals from urine excreted protein are a source of bias in probabilistic quotient normalization, Analytical Chemistry, Vol: 94, Pages: 6919-6923, ISSN: 0003-2700

Normalization to account for variation in urinary dilution is crucial for interpretation of urine metabolic profiles. Probabilistic quotient normalization (PQN) is used routinely in metabolomics but is sensitive to systematic variation shared across a large proportion of the spectral profile (>50%). Where 1H nuclear magnetic resonance (NMR) spectroscopy is employed, the presence of urinary protein can elevate the spectral baseline and substantially impact the resulting profile. Using 1H NMR profile measurements of spot urine samples collected from hospitalized COVID-19 patients in the ISARIC 4C study, we determined that PQN coefficients are significantly correlated with observed protein levels (r2 = 0.423, p < 2.2 × 10–16). This correlation was significantly reduced (r2 = 0.163, p < 2.2 × 10–16) when using a computational method for suppression of macromolecular signals known as small molecule enhancement spectroscopy (SMolESY) for proteinic baseline removal prior to PQN. These results highlight proteinuria as a common yet overlooked source of bias in 1H NMR metabolic profiling studies which can be effectively mitigated using SMolESY or other macromolecular signal suppression methods before estimation of normalization coefficients.

Journal article

Inglese P, Huang HX, Wu V, Lewis MR, Takats Zet al., 2022, Mass recalibration for desorption electrospray ionization mass spectrometry imaging using endogenous reference ions, BMC Bioinformatics, Vol: 23, Pages: 1-17, ISSN: 1471-2105

BackgroundMass spectrometry imaging (MSI) data often consist of tens of thousands of mass spectra collected from a sample surface. During the time necessary to perform a single acquisition, it is likely that uncontrollable factors alter the validity of the initial mass calibration of the instrument, resulting in mass errors of magnitude significantly larger than their theoretical values. This phenomenon has a two-fold detrimental effect: (a) it reduces the ability to interpret the results based on the observed signals, (b) it can affect the quality of the observed signal spatial distributions.ResultsWe present a post-acquisition computational method capable of reducing the observed mass drift by up to 60 ppm in biological samples, exploiting the presence of typical molecules with a known mass-to-charge ratio. The procedure, tested on time-of-flight and Orbitrap mass spectrometry analyzers interfaced to a desorption electrospray ionization (DESI) source, improves the molecular annotation quality and the spatial distributions of the detected ions.ConclusionThe presented method represents a robust and accurate tool for performing post-acquisition mass recalibration of DESI-MSI datasets and can help to increase the reliability of the molecular assignment and the data quality.

Journal article

Climaco Pinto R, Karaman I, Lewis MR, Hällqvist J, Kaluarachchi M, Graça G, Chekmeneva E, Durainayagam B, Ghanbari M, Ikram MA, Zetterberg H, Griffin J, Elliott P, Tzoulaki I, Dehghan A, Herrington D, Ebbels Tet al., 2022, Finding correspondence between metabolomic features in untargeted liquid chromatography-mass spectrometry metabolomics datasets., Analytical Chemistry, Vol: 94, Pages: 5493-5503, ISSN: 0003-2700

Integration of multiple datasets can greatly enhance bioanalytical studies, for example, by increasing power to discover and validate biomarkers. In liquid chromatography-mass spectrometry (LC-MS) metabolomics, it is especially hard to combine untargeted datasets since the majority of metabolomic features are not annotated and thus cannot be matched by chemical identity. Typically, the information available for each feature is retention time (RT), mass-to-charge ratio (m/z), and feature intensity (FI). Pairs of features from the same metabolite in separate datasets can exhibit small but significant differences, making matching very challenging. Current methods to address this issue are too simple or rely on assumptions that cannot be met in all cases. We present a method to find feature correspondence between two similar LC-MS metabolomics experiments or batches using only the features' RT, m/z, and FI. We demonstrate the method on both real and synthetic datasets, using six orthogonal validation strategies to gauge the matching quality. In our main example, 4953 features were uniquely matched, of which 585 (96.8%) of 604 manually annotated features were correct. In a second example, 2324 features could be uniquely matched, with 79 (90.8%) out of 87 annotated features correctly matched. Most of the missed annotated matches are between features that behave very differently from modeled inter-dataset shifts of RT, MZ, and FI. In a third example with simulated data with 4755 features per dataset, 99.6% of the matches were correct. Finally, the results of matching three other dataset pairs using our method are compared with a published alternative method, metabCombiner, showing the advantages of our approach. The method can be applied using M2S (Match 2 Sets), a free, open-source MATLAB toolbox, available at https://github.com/rjdossan/M2S.

Journal article

Lippa KA, Aristizabal-Henao JJ, Beger RD, Bowden JA, Broeckling C, Beecher C, Clay Davis W, Dunn WB, Flores R, Goodacre R, Gouveia GJ, Harms AC, Hartung T, Jones CM, Lewis MR, Ntai I, Percy AJ, Raftery D, Schock TB, Sun J, Theodoridis G, Tayyari F, Torta F, Ulmer CZ, Wilson I, Ubhi BKet al., 2022, Reference materials for MS-based untargeted metabolomics and lipidomics: a review by the metabolomics quality assurance and quality control consortium (mQACC), Metabolomics, Vol: 18, ISSN: 1573-3882

IntroductionThe metabolomics quality assurance and quality control consortium (mQACC) is enabling the identification, development, prioritization, and promotion of suitable reference materials (RMs) to be used in quality assurance (QA) and quality control (QC) for untargeted metabolomics research.ObjectivesThis review aims to highlight current RMs, and methodologies used within untargeted metabolomics and lipidomics communities to ensure standardization of results obtained from data analysis, interpretation and cross-study, and cross-laboratory comparisons. The essence of the aims is also applicable to other ‘omics areas that generate high dimensional data.ResultsThe potential for game-changing biochemical discoveries through mass spectrometry-based (MS) untargeted metabolomics and lipidomics are predicated on the evolution of more confident qualitative (and eventually quantitative) results from research laboratories. RMs are thus critical QC tools to be able to assure standardization, comparability, repeatability and reproducibility for untargeted data analysis, interpretation, to compare data within and across studies and across multiple laboratories. Standard operating procedures (SOPs) that promote, describe and exemplify the use of RMs will also improve QC for the metabolomics and lipidomics communities.ConclusionsThe application of RMs described in this review may significantly improve data quality to support metabolomics and lipidomics research. The continued development and deployment of new RMs, together with interlaboratory studies and educational outreach and training, will further promote sound QA practices in the community.

Journal article

Sliz E, Shin J, Ahmad S, Williams DM, Frenzel S, Gauss F, Harris SE, Henning A-K, Hernandez MV, Hu Y-H, Jimenez B, Sargurupremraj M, Sudre C, Wang R, Wittfeld K, Yang Q, Wardlaw JM, Volzke H, Vernooij MW, Schott JM, Richards M, Proitsi P, Nauck M, Lewis MR, Launer L, Hosten N, Grabe HJ, Ghanbari M, Deary IJ, Cox SR, Chaturvedi N, Barnes J, Rotter J, Debette S, Ikram MA, Fornage M, Paus T, Seshadri S, Pausova Zet al., 2022, Circulating metabolome and white matter hyperintensities in women and men, Circulation, Vol: 145, Pages: 1040-1052, ISSN: 0009-7322

Background:White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites.Methods:We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment–stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance–weighted method. Associations with false discovery rate (FDR)–adjusted P values (PFDR)<0.05 were considered significant.Results:In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10−7) and in both the pooled sample (PFDR.full.adj=1.66×10−4) and statin-untreated (PFDR.full.adj=1.65×10−6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingo

Journal article

Gadgil MD, Sarkar M, Sands C, Lewis MR, Herrington DM, Kanaya AMet al., 2022, Associations of NAFLD with circulating ceramides and impaired glycemia, DIABETES RESEARCH AND CLINICAL PRACTICE, Vol: 186, ISSN: 0168-8227

Journal article

Närhi F, Moonesinghe SR, Shenkin SD, Drake TM, Mulholland RH, Donegan C, Dunning J, Fairfield CJ, Girvan M, Hardwick HE, Ho A, Leeming G, Nguyen-Van-Tam JS, Pius R, Russell CD, Shaw CA, Spencer RG, Turtle L, Openshaw PJM, Baillie JK, Harrison EM, Semple MG, Docherty AB, ISARIC4C investigatorset al., 2022, Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study., The Lancet Digital Health, Vol: 4, Pages: e220-e234, ISSN: 2589-7500

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70-0·89], p=0·0001, for 70-79 years; 0·52 [0·46-0·58], p<0·0001, for >80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75-80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant wom

Journal article

Mehta R, Chekmeneva E, Jackson H, Sands C, Mills E, Arancon D, Li HK, Arkell P, Rawson T, Hammond R, Amran M, Haber A, Cooke G, Noursadeghi M, Kaforou M, Lewis M, Takats Z, Sriskandan Set al., 2022, Antiviral metabolite 3’-Deoxy-3’,4’-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19, Med, Vol: 3, Pages: 204-215.e6, ISSN: 2666-6340

Background:There is a critical need for rapid viral infection diagnostics to enable prompt case identification in pandemic settings and support targeted antimicrobial prescribing.Methods:Using untargeted high-resolution liquid chromatography coupled with mass spectrometry, we compared the admission serum metabolome of emergency department patients with viral infections including COVID-19, bacterial infections, inflammatory conditions, and healthy controls. Sera from an independent cohort of emergency department patients admitted with viral or bacterial infections underwent profiling to validate findings. Associations between whole-blood gene expression and the identified metabolite of interest were examined.Findings:3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum. When comparing 60 viral to 101 non-viral cases in the discovery cohort, ddhC was the most differentially abundant metabolite, generating an area under the receiver operating characteristic curve (AUC) of 0.954 (95% CI: 0.923-0.986). In the validation cohort, ddhC was again the most significantly differentially abundant metabolite when comparing 40 viral to 40 bacterial cases, generating an AUC of 0.81 (95% CI 0.708-0.915). Transcripts of viperin and CMPK2, enzymes responsible for ddhCTP synthesis, were amongst the five genes most highly correlated to ddhC abundance.Conclusions:The antiviral precursor molecule ddhC is detectable in serum and an accurate marker for acute viral infection. Interferon-inducible genes viperin and CMPK2 are implicated in ddhC production in vivo. These findings highlight a future diagnostic role for ddhC in viral diagnosis, pandemic preparedness, and acute infection management.

Journal article

Gritti F, David M, Brothy P, Lewis MRet al., 2022, Model of retention time and density of gradient peak capacity for improved LC-MS method optimization: Application to metabolomics, ANALYTICA CHIMICA ACTA, Vol: 1197, ISSN: 0003-2670

Journal article

Graca G, Cai Y, Lau C-H, Vorkas PA, Lewis MR, Want EJ, Herrington D, Ebbels Tet al., 2022, Automated annotation of untargeted all-ion fragmentation LC-MS metabolomics data with MetaboAnnotatoR, Analytical Chemistry, Vol: 94, Pages: 3446-3455, ISSN: 0003-2700

Untargeted metabolomics and lipidomics LC-MS experiments produce complex datasets, usually containing tens of thousands of features from thousands of metabolites whose annotation requires additional MS/MS experiments and expert knowledge. All-ion fragmentation (AIF) LC-MS/MS acquisition provides fragmentation data at no additional experimental time cost. However, analysis of such datasets requires reconstruction of parent fragment relationships and annotation of the resulting pseudo-MS/MS spectra. Here we propose a novel approach for automated annotation of isotopologues, adducts and in-source fragments from AIF LC-MS datasets by combining correlation-based parent-fragment linking with molecular fragment matching. Our workflow focuses on a subset of features rather than trying to annotate the full dataset, saving time and simplifying the process. We demonstrate the workflow in three human serum datasets containing 599 features manually annotated by experts. Precision and recall values of 82- 92% and 82-85% respectively, were obtained for features found in the highest-rank scores (1-5). These results equal or outperform those obtained using MS-DIAL software, the current state-of-the-art for AIF data annotation. Further validation for other biological matrices and different instrument types showed variable precision (60-89%) and recall (10-88%) particularly for datasets dominated by non-lipid metabolites. The workflow is freely available as an open-source R package, MetaboAnnotatoR, together with the fragment libraries from Github (https://github.com/gggraca/MetaboAnnotatoR).

Journal article

Mehta R, Chekmeneva E, Jackson H, Sands C, Mills E, Arancon D, Li HK, Arkell P, Rawson TM, Hammond R, Amran M, Haber A, Cooke GS, Noursadeghi M, Kaforou M, Lewis MR, Takats Z, Sriskandan Set al., 2022, Antiviral metabolite 3'-deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19., Med (New York, N.Y.), Vol: 3, Pages: 204-215.e6, ISSN: 2666-6359

<h4>Background</h4>There is a critical need for rapid viral infection diagnostics to enable prompt case identification in pandemic settings and support targeted antimicrobial prescribing.<h4>Methods</h4>Using untargeted high-resolution liquid chromatography coupled with mass spectrometry, we compared the admission serum metabolome of emergency department patients with viral infections (including COVID-19), bacterial infections, inflammatory conditions, and healthy controls. Sera from an independent cohort of emergency department patients admitted with viral or bacterial infections underwent profiling to validate findings. Associations between whole-blood gene expression and the identified metabolite of interest were examined.<h4>Findings</h4>3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum. When comparing 60 viral with 101 non-viral cases in the discovery cohort, ddhC was the most significantly differentially abundant metabolite, generating an area under the receiver operating characteristic curve (AUC) of 0.954 (95% CI: 0.923-0.986). In the validation cohort, ddhC was again the most significantly differentially abundant metabolite when comparing 40 viral with 40 bacterial cases, generating an AUC of 0.81 (95% CI 0.708-0.915). Transcripts of viperin and <i>CMPK2</i>, enzymes responsible for ddhCTP synthesis, were among the five genes most highly correlated with ddhC abundance.<h4>Conclusions</h4>The antiviral precursor molecule ddhC is detectable in serum and an accurate marker for acute viral infection. Interferon-inducible genes viperin and <i>CMPK2</i> are implicated in ddhC production <i>in vivo</i>. These findings highlight a future diagnostic role for ddhC in viral diagnosis, pandemic preparedness, and acute infection management.<h4>Funding</h

Journal article

Harshfield EL, Sands CJ, Tuladhar AM, de Leeuw F-E, Lewis MR, Markus HSet al., 2022, Metabolomic profiling in small vessel disease identifies multiple associations with disease severity, BRAIN, Vol: 145, Pages: 2461-2471, ISSN: 0006-8950

Journal article

Jones B, Sands C, Alexiadou K, Minnion J, Tharakan G, Behary P, Ahmed A, Purkayastha S, Lewis M, Bloom S, Li J, Tan Tet al., 2022, The metabolomic effects of tripeptide gut hormone infusion compared to Roux-en-Y gastric bypass and caloric restriction, Journal of Clinical Endocrinology and Metabolism, Vol: 107, Pages: e767-e782, ISSN: 0021-972X

Context: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis, and are thought to contribute to the glucose-lowering effects of bariatric surgery. Objective: To establish the metabolomic effects of a combined infusion of GLP-1, OXM and PYY (tripeptide “GOP”) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). Design and setting: Sub-analysis of a single-blind, randomised, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. Patients and interventions: 25 obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n=14) or 0.9% saline control (SAL; n=11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. Main outcome measures: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modelling approaches to identify similarities and differences between the effects of each intervention. Results: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. Conclusions: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.

Journal article

Albreht A, Hussain H, Jimenez B, Armstrong A, Whiley L, Witt M, Lewis M, Chekmeneva Eet al., 2022, Structure elucidation and mitigation of endogenous interferences in LC-MS-based metabolic profiling of urine, Analytical Chemistry, Vol: 94, ISSN: 0003-2700

Liquid chromatography mass spectrometry (LC-MS) is the main workhorse of metabolomics owing to its high degree of analytical sensitivity and specificity when measuring diverse chemistry in complex biological samples. LC-MS-based metabolic profiling of human urine, a biofluid of primary interest for clinical and biobank studies, is not widely considered to be compromised by the presence of endogenous interferences and is often accomplished using a simple “dilute-and-shoot” approach. Yet, it is our experience that broad obscuring signals are routinely observed in LC-MS metabolic profiles and represent interferences which lack consideration in the relevant metabolomics literature. In this work we chromatographically isolated the interfering metabolites from human urine and unambiguously identified them via de novo structure elucidation as two separate proline-containing dipeptides: N,N,N-trimethyl-L-alanine-L-proline betaine (L,L-TMAP) and N,N-dimethyl-L-proline-L-proline betaine (L,L-DMPP), the latter reported here for the first time. Offline LC-MS/MS, MRMS, and NMR spectroscopy were essential components of this workflow for the full chemical and spectroscopic characterization of these metabolites and for establishing the co-existence of cis and trans isomers of both dipeptides in solution. Analysis of these definitive structures highlighted intramolecular ionic interactions as responsible for slow interconversion between these isomeric forms resulting in their unusually broad elution profiles. Proposed mitigation strategies, aimed at increasing the quality of LC-MS-based urine metabolomics data, include modification of the column temperature and mobile phase pH to reduce the chromatographic footprint of these dipeptides, thereby reducing their interfering effect on the underlying metabolic profiles. Alternatively, sample dilution and internal standardization methods may be employed to reduce or account for the observed effects of ionization suppression on

Journal article

Yeung KTD, Penney N, Whiley L, Ashrafian H, Lewis M, Purkayastha S, Darzi A, Holmes Eet al., 2022, The impact of bariatric surgery on serum tryptophan-kynurenine pathway metabolites, Scientific Reports, Vol: 12, ISSN: 2045-2322

Objectives: 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. Methods: 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 three 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. Results: 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. Conclusions: 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).

Journal article

Inglese P, Huang X, Wu V, Lewis M, Takats Zet al., 2021, Mass recalibration for desorption electrospray ionization mass spectrometry imaging using endogenous reference ions, Publisher: Cold Spring Harbor Laboratory

BackgroundMass spectrometry imaging (MSI) data often consist of tens of thousands of mass spectra collected from a sample surface. During the time necessary to perform a single acquisition, it is likely that uncontrollable factors alter the validity of the initial mass calibration of the instrument, resulting in mass errors of magnitude significantly larger than their theoretical values. This phenomenon has a two-fold detrimental effect: a) it reduces the ability to interpret the results based on the observed signals, b) it can affect the quality of the observed signal spatial distributions. ResultsWe present a post-acquisition computational method capable of reducing the observed mass drift by up to 60 ppm in biological samples, exploiting the presence of typical molecules with a known mass-to-charge ratio. The procedure, tested on time-of-flight (TOF) and Orbitrap mass spectrometry analyzers interfaced to a desorption electrospray ionization (DESI) source, improves the molecular annotation quality and the spatial distributions of the detected ions.ConclusionThe presented method represents a robust and accurate tool for performing post-acquisition mass recalibration of DESI-MSI datasets and can help to increase the reliability of the molecular assignment and the data quality.

Working paper

Ferreira MR, Sands CJ, Li J, Andreyev JN, Chekmeneva E, Gulliford S, Marchesi J, Lewis MR, Dearnaley DPet al., 2021, Impact of pelvic radiation therapy for prostate cancer on global metabolic profiles and microbiota-driven gastrointestinal late side effects: a longitudinal observational study, International Journal of Radiation: Oncology - Biology - Physics, Vol: 111, Pages: 1204-1213, ISSN: 0360-3016

PurposeRadiation therapy to the prostate and pelvic lymph nodes (PLNRT) is part of the curative treatment of high-risk prostate cancer. Yet, the broader influence of radiation therapy on patient physiology is poorly understood. We conducted comprehensive global metabolomic profiling of urine, plasma, and stools sampled from patients undergoing PLNRT for high-risk prostate cancer.Methods and MaterialsSamples were taken from 32 patients at 6 timepoints: baseline, 2 to 3 and 4 to 5 weeks of PLNRT; and 3, 6, and 12 months after PLNRT. We characterized the global metabolome of urine and plasma using 1H nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography-mass spectrometry, and of stools with nuclear magnetic resonance. Linear mixed-effects modeling was used to investigate metabolic changes between timepoints for each biofluid and assay and determine metabolites of interest.ResultsMetabolites in urine, plasma and stools changed significantly after PLNRT initiation. Metabolic profiles did not return to baseline up to 1 year post-PLNRT in any biofluid. Molecules associated with cardiovascular risk were increased in plasma. Pre-PLNRT fecal butyrate levels directly associated with increasing gastrointestinal side effects, as did a sharper fall in those levels during and up to 1 year postradiation therapy, mirroring our previous results with metataxonomics.ConclusionsWe showed for the first time that an overall metabolic effect is observed in patients undergoing PLNRT up to 1 year posttreatment. These metabolic changes may effect on long-term morbidity after treatment, which warrants further investigation.

Journal article

Takis P, Lewis M, 2021, PROCESSING 1H-NMR SPECTRAL DATA

Patent

Wickenhagen A, Sugrue E, Lytras S, Kuchi S, Noerenberg M, Turnbull ML, Loney C, Herder V, Allan J, Jarmson I, Cameron-Ruiz N, Varjak M, Pinto RM, Lee JY, Iselin L, Palmalux N, Stewart DG, Swingler S, Greenwood EJD, Crozier TWM, Gu Q, Davies EL, Clohisey S, Wang B, Maranhao Costa FT, Santana MF, de Lima Ferreira LC, Murphy L, Fawkes A, Meynert A, Grimes G, Filho JLDS, Marti M, Hughes J, Stanton RJ, Wang ECY, Ho A, Davis I, Jarrett RF, Castello A, Robertson DL, Semple MG, Openshaw PJM, Palmarini M, Lehner PJ, Baillie JK, Rihn SJ, Wilson SJet al., 2021, A prenylated dsRNA sensor protects against severe COVID-19, Science, Vol: 374, Pages: 1-18, ISSN: 0036-8075

Journal article

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