Imperial College London

Emeritus ProfessorJeremyNicholson

Faculty of MedicineDepartment of Surgery & Cancer

Emeritus Professor of Biological Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 3195j.nicholson Website

 
 
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Assistant

 

Ms Wendy Torto +44 (0)20 7594 3225

 
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Location

 

Office no. 665Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

978 results found

Sands C, Wolfer A, DS Correia G, Sadawi N, Ahmed A, Jimenez B, Lewis M, Glen R, Nicholson J, Pearce Jet al., The nPYc-Toolbox, a Python module for the pre-processing, quality-control, and analysis of metabolic profiling datasets, Bioinformatics, ISSN: 1367-4803

Journal article

Nye LC, Williams JP, Munjoma NC, Letertre MPM, Coen M, Bouwmeester R, Martens L, Swann JR, Nicholson JK, Plumb RS, McCullagh M, Gethings LA, Lai S, Langridge JI, Vissers JPC, Wilson IDet al., 2019, A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry: Application to the characterisation of metabolites in rat urine., J Chromatogr A

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.

Journal article

Whiley L, Chekmeneva E, Berry DJ, Jimenez B, Yuen AHY, Salam A, Hussain H, Witt M, Takats Z, Nicholson JK, Lewis MRet al., 2019, Systematic isolation and structure elucidation of urinary metabolites optimized for the analytical-scale molecular profiling laboratory, Analytical Chemistry, ISSN: 0003-2700

Annotation and identification of metabolite biomarkers is critical for their biological interpretation in metabolic phenotyping studies, presenting a significant bottleneck in the successful implementation of untargeted metabolomics. Here, a systematic multi-step protocol was developed for the purification and de novo structural elucidation of urinary metabolites. The protocol is most suited for instances where structure elucidation and metabolite annotation are critical for the downstream biological interpretation of metabolic phenotyping studies. First, a bulk urine pool was desalted using ion-exchange resins enabling large-scale fractionation using precise iterations of analytical scale chromatography. Primary urine fractions were collected and assembled into a “fraction bank” suitable for long-term laboratory storage. Secondary and tertiary fractionations exploited differences in selectivity across a range of reversed-phase chemistries, achieving the purification of metabolites of interest yielding an amount of material suitable for chemical characterisation. To exemplify the application of the systematic workflow in a diverse set of cases, four metabolites with a range of physico-chemical properties were selected and purified from urine and subjected to chemical formula and structure elucidation by respective magnetic resonance mass spectrometry (MRMS) and NMR analyses. Their structures were fully assigned as teterahydropentoxyline, indole-3-acetic-acid-O-glucuronide, p-cresol glucuronide, and pregnanediol-3-glucuronide. Unused effluent was collected, dried and returned to the fraction bank, demonstrating the viability of the system for repeat use in metabolite annotation with a high degree of efficiency.

Journal article

Lees HJ, Swann JR, Poucher S, Holmes E, Wilson ID, Nicholson JKet al., 2019, Obesity and cage environment modulate metabolism in the Zucker rat: a multiple biological matrix approach to characterizing metabolic phenomena, Journal of Proteome Research, Vol: 18, Pages: 2160-2174, ISSN: 1535-3893

Obesity and its comorbidities are increasing worldwide imposing a heavy socioeconomic burden. The effects of obesity on the metabolic profiles of tissues (liver, kidney, pancreas), urine, and the systemic circulation were investigated in the Zucker rat model using 1H NMR spectroscopy coupled to multivariate statistical analysis. The metabolic profiles of the obese ( fa/ fa) animals were clearly differentiated from the two phenotypically lean phenotypes, ((+/+) and ( fa/+)) within each biological compartment studied, and across all matrices combined. No significant differences were observed between the metabolic profiles of the genotypically distinct lean strains. Obese Zucker rats were characterized by higher relative concentrations of blood lipid species, cross-compartmental amino acids (particularly BCAAs), urinary and liver metabolites relating to the TCA cycle and glucose metabolism; and lower amounts of urinary gut microbial-host cometabolites, and intermatrix metabolites associated with creatine metabolism. Further to this, the obese Zucker rat metabotype was defined by significant metabolic alterations relating to disruptions in the metabolism of choline across all compartments analyzed. The cage environment was found to have a significant effect on urinary metabolites related to gut-microbial metabolism, with additional cage-microenvironment trends also observed in liver, kidney, and pancreas. This study emphasizes the value in metabotyping multiple biological matrices simultaneously to gain a better understanding of systemic perturbations in metabolism, and also underscores the need for control or evaluation of cage environment when designing and interpreting data from metabonomic studies in animal models.

Journal article

Katsidzira L, Ocvirk S, Wilson A, Li J, Mahachi CB, Soni D, DeLany J, Nicholson JK, Zoetendal EG, O'Keefe SJDet al., 2019, Differences in fecal gut microbiota, short-chain fatty acids and bile acids link colorectal cancer risk to dietary changes associated with urbanization among Zimbabweans, Nutrition and Cancer, ISSN: 0163-5581

The incidence of colorectal cancer (CRC) is gradually rising in sub-Saharan Africa. This may be due to dietary changes associated with urbanization, which may induce tumor-promoting gut microbiota composition and function. We compared fecal microbiota composition and activity in 10 rural and 10 urban Zimbabweans for evidence of a differential CRC risk. Dietary intake was assessed by a food frequency questionnaire. Fecal microbiota composition, metabolomic profile, functional microbial genes were analyzed, and bile acids and short chain fatty acids quantified. Animal protein intake was higher among urban volunteers, but carbohydrate and fiber intake were similar. Bacteria related to Blautia obeum, Streptococcus bovis, and Subdoligranulum variabile were higher in urban residents, whereas bacteria related to Oscillospira guillermondii and Sporobacter termitidis were higher in rural volunteers. Fecal levels of primary bile acids, cholic acid, and chenodeoxycholic acid (P < 0.05), and secondary bile acids, deoxycholic acid (P < 0.05) and ursodeoxycholic acid (P < 0.001) were higher in urban residents. Fecal levels of acetate and propionate, but not butyrate, were higher in urban residents. The gut microbiota composition and activity among rural and urban Zimbabweans retain significant homogeneity (possibly due to retention of dietary fiber), but urban residents have subtle changes, which may indicate a higher CRC risk.

Journal article

Whiley LW, Nye L, Grant I, Andreas N, Chappell K, Sarafian MHS, Misra R, Plumb R, Lewis M, Nicholson J, Holmes E, Swann J, Wilson Iet al., 2019, Ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionization quantification of tryptophan metabolites and markers of gut health in serum and plasmaapplication to clinical and epidemiology cohorts, Analytical Chemistry, Vol: 91, Pages: 5207-5216, ISSN: 0003-2700

A targeted ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionization (UHPLC-ESI-MS/MS) method has been developed for the quantification of tryptophan and its downstream metabolites from the kynurenine and serotonin pathways. The assay coverage also includes markers of gut health and inflammation, including citrulline and neopterin. The method was designed in 96-well plate format for application in multiday, multiplate clinical and epidemiology population studies. A chromatographic cycle time of 7 min enables the analysis of two 96-well plates in 24 h. To protect chromatographic column lifespan, samples underwent a two-step extraction, using solvent protein precipitation followed by delipidation via solid-phase extraction (SPE). Analytical validation reported accuracy of each analyte <20% for the lowest limit of quantification and <15% for all other quality control (QC) levels. The analytical precision for each analyte was 2.1–12.9%. To test the applicability of the method to multiplate and multiday preparations, a serum pool underwent periodic repeat analysis during a run consisting of 18 plates. The % CV (coefficient of variation) values obtained for each analyte were <15%. Additional biological testing applied the assay to samples collected from healthy control participants and two groups diagnosed with inflammatory bowel disease (IBD) (one group treated with the anti-inflammatory 5-aminosalicylic acid (5-ASA) and one group untreated), with results showing significant differences in the concentrations of picolinic acid, kynurenine, and xanthurenic acid. The short analysis time and 96-well plate format of the assay makes it suitable for high-throughput targeted UHPLC-ESI-MS/MS metabolomic analysis in large-scale clinical and epidemiological population studies.

Journal article

Neves AL, Rodriguez-Martinez A, Ayala R, Posma JM, Abellona U MR, Chilloux J, Nicholson JK, Dumas M-E, Hoyles Let al., 2019, A network-based data-mining approach to investigate indole-related microbiota-host co-metabolism, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Motivation</jats:title><jats:p>Indoles have been shown to play a significant role in cardiometabolic disorders. While some individual bacterial species are known to produce indole-adducts, to our best knowledge no studies have made use of publicly available genome data to identify prokaryotes, specifically those associated with the human gut microbiota, contributing to the indole metabolic network.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Here, we propose a computational strategy, comprising the integration of KEGG and BLAST, to identify prokaryote-specific metabolic reactions relevant for the production of indoles, as well as to predict new members of the human gut microbiota potentially involved in these reactions. By identifying relevant prokaryotic species for further validation studies <jats:italic>in vitro</jats:italic>, this strategy represents a useful approach for those interrogating the metabolism of other gut-derived microbial metabolites relevant to human health.</jats:p></jats:sec><jats:sec><jats:title>Availability</jats:title><jats:p>All R scripts and files (gut microbial dataset, FASTA protein sequences, BLASTP output files) are available from <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/AndreaRMICL/Microbial_networks">https://github.com/AndreaRMICL/Microbial_networks</jats:ext-link>.</jats:p></jats:sec><jats:sec><jats:title>Contact</jats:title><jats:p>ARM: <jats:email>andrea.rodriguez-martinez13@imperial.ac.uk</jats:email>; LH: <jats:email>lesley.hoyles@ntu.ac.uk</jats:email>.</jats:p></jats:sec>

Working paper

Brial F, Le Lay A, Hedjazi L, Tsang T, Fearnside JF, Otto GW, Alzaid F, Wilder SP, Venteclef N, Cazier J-B, Nicholson JK, Day C, Burt AD, Gut IG, Lathrop M, Dumas M-E, Gauguier Det al., 2019, Systems genetics of hepatic metabolome reveals octopamine as a target for non-alcoholic fatty liver disease treatment, Scientific Reports, Vol: 9, ISSN: 2045-2322

Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. To disentangle etiological relationships between these conditions and identify genetically-determined metabolites involved in NAFLD processes, we mapped 1H nuclear magnetic resonance (NMR) metabolomic and disease-related phenotypes in a mouse F2 cross derived from strains showing resistance (BALB/c) and increased susceptibility (129S6) to these diseases. Quantitative trait locus (QTL) analysis based on single nucleotide polymorphism (SNP) genotypes identified diet responsive QTLs in F2 mice fed control or high fat diet (HFD). In HFD fed F2 mice we mapped on chromosome 18 a QTL regulating liver micro- and macrovesicular steatosis and inflammation, independently from glucose intolerance and adiposity, which was linked to chromosome 4. Linkage analysis of liver metabolomic profiling data identified a QTL for octopamine, which co-localised with the QTL for liver histopathology in the cross. Functional relationship between these two QTLs was validated in vivo in mice chronically treated with octopamine, which exhibited reduction in liver histopathology and metabolic benefits, underlining its role as a mechanistic biomarker of fatty liver with potential therapeutic applications.

Journal article

Poynter L, Mirnezami R, Galea D, Veselkov K, Nicholson J, Takats Z, Darzi A, Kinross J, Mirnezami Aet al., 2019, Network mapping of molecular biomarkers influencing radiation response in rectal cancer, Clinical Colorectal Cancer, ISSN: 1533-0028

IntroductionPre-operative radiotherapy (RT) has an important role in the management of locally advanced rectal cancer (RC). Tumour regression following RT shows marked variability and robust molecular methods are needed with which to predict likely response. The aim of this study was to review the current published literature and employ Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC.MethodsA systematic review of electronic bibliographic databases (MEDLINE, Embase) was performed for original articles published between 2000 and 2015. Biomarkers were then classified according to biological function and incorporated into a hierarchical GO tree. Both significant and non-significant results were included in the analysis. Significance was binarized based on uni- and multivariate statistics. Significance scores were calculated for each biological domain (or node), and a direct acyclic graph was generated for intuitive mapping of biological pathways and markers involved in rectal cancer radiation response.Results72 individual biomarkers, across 74 studies, were identified through review. On highest order classification, molecular biomarkers falling within the domains of response to stress, cellular metabolism and pathways inhibiting apoptosis were found to be the most influential in predicting radiosensitivity.ConclusionsHomogenising biomarker data from original articles using controlled GO terminology demonstrates that cellular mechanisms of response to radiotherapy in RC - in particular the metabolic response to radiotherapy - may hold promise in developing radiotherapeutic biomarkers with which to predict, and in the future modulate, radiation response.

Journal article

Gray N, Plumb RS, Wilson ID, Nicholson JKet al., 2019, A validated UPLC-MS/MS assay for the quantification of amino acids and biogenic amines in rat urine., J Chromatogr B Analyt Technol Biomed Life Sci, Vol: 1106-1107, Pages: 50-57

A UPLC-MS/MS assay, employing a reversed-phase separation, has been applied to the analysis of a number of common amino acids and biogenic amines in rat urine. Analytes were derivatised, using 6‑aminoquinolyl‑N‑hydroxysuccinimidyl carbamate (AccQTag Ultra™). Derivatisation with this reagent, by increasing the hydrophobicity of the analytes, enables better retention by improving reversed-phase chromatographic properties and also improves ionisation efficiency to enhance MS-detection. The method allows for the determination of 38 amino compounds in 7.5 min, including baseline resolution of critical isomers. The assay has been validated for the absolute quantification of 29 amino compounds in rat urine, over a concentration range of 0.6-200 μM, for the purpose of exploratory metabolite phenotyping. Acceptable linearity (R2 > 0.995) and intra- and inter-day accuracy (<20.7%) and precision (<20.1%) for these analytes was achieved. The limits of detection ranged from 1.2-12 fmol on column with 20 μL of sample. The remaining nine amines examined were not accurately quantified by this method but can be monitored for relative/fold change in biological samples. The use of the method is exemplified by the monitoring of changes in healthy male Sprague-Dawley rat urinary amino acid concentrations over a 7-day period.

Journal article

McGill D, Chekmeneva E, Lindon J, Takats Z, Nicholson Jet al., 2019, Application of novel Solid Phase Extraction-NMR protocols for metabolic profiling of human urine, Faraday Discussions, ISSN: 1359-6640

Metabolite identification and annotation procedures are necessary for the discovery of biomarkers indicative of phenotypes or disease states, but these processes can be bottlenecked by the sheer complexity of biofluids containing thousands of different compounds. Here we describe low-cost novel SPE-NMR protocols utilising different cartridges and conditions, on both natural and artifical urine mixtures, which produce unique retention profiles useful to metabolic profiling. We find that different SPE methods applied to biofluids such as urine can be used to selectively retain metabolites based on compound taxonomy or other key functional groups, reducing peak overlap through concentration and fractionation of unknowns and hence promising greater control over the metabolite annotation/identification process.

Journal article

Inglese P, Correia G, Takats Z, Nicholson JK, Glen RCet al., 2019, SPUTNIK: an R package for filtering of spatially related peaks in mass spectrometry imaging data, Bioinformatics, Vol: 35, Pages: 178-180, ISSN: 1367-4803

Summary: SPUTNIK is an R package consisting of a series of tools to filter mass spectrometry imaging peaks characterized by a noisy or unlikely spatial distribution. SPUTNIK can produce mass spectrometry imaging datasets characterized by a smaller but more informative set of peaks, reduce the complexity of subsequent multi-variate analysis and increase the interpretability of the statistical results. Availability: SPUTNIK is freely available online from CRAN repository and at https://github.com/paoloinglese/SPUTNIK. The package is distributed under the GNU General Public License version 3 and is accompanied by example files and data. Supplementary information: Supplementary data are available at Bioinformatics online.

Journal article

Adesina-Georgiadis KN, Gray N, Plumb RS, Thompson DF, Holmes E, Nicholson JK, Wilson IDet al., 2018, The metabolic fate and effects of 2-bromophenol in male Sprague-Dawley rats, Xenobiotica, ISSN: 0049-8254

1. The metabolic fate and urinary excretion of 2-bromophenol, a phenolic metabolite of bromobenzene, was investigated in male Sprague Dawley rats following single intraperitoneal doses at either 0, 100 or 200 mg/kg. 2. Urine was collected for seven days and samples analysed using 1H NMR spectroscopy, inductively coupled plasma (ICP)MS, and UPLC-MS. 3. 1H NMR spectroscopy of the urine samples showed that, at these doses, 2-bromophenol had little effect on endogenous metabolite profiles, supporting histopathology and clinical chemistry data which showed no changes associated with the administration of 2-bromophenol at these doses. 4. The use of ICP-MS Provided a means for the selective detection and quantification of bromine-containing species and showed that between 15 and 30% of the dose was excreted via the urine over the 7 days of the study for both the 100 and 200 mg doses respectively. 6. The bulk of the excretion of Br-containing material had occurred by 8 hr post administration. UPLC-MS of urine revealed a number of metabolites of 2-bromophenol, with 2-bromophenol glucuronide and 2-bromophenol sulphate identified as the major species. A number of minor hydroxylated metabolites were also detected as their glucuronide, sulphate or O-methyl conjugates. There was no evidence for the production of reactive metabolites.

Journal article

Harbaum L, Ghataorhe P, Wharton J, Jimenez B, Howard L, Gibbs S, Nicholson J, Rhodes C, Wilkins Met al., 2018, Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension, Thorax, ISSN: 1468-3296

Background Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.Objective To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH.Methods Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation.Results Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein–kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed.Conclusion Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.

Journal article

Rodriguez-Martinez A, Ayala R, Posma JM, Harvey N, Jiménez B, Sonomura K, Sato T-A, Matsuda F, Zalloua P, Gauguier D, Nicholson JK, Dumas M-Eet al., 2018, pJRES Binning Algorithm (JBA): a new method to facilitate the recovery of metabolic information from pJRES 1H NMR spectra, Bioinformatics, ISSN: 1367-4803

Motivation: Data processing is a key bottleneck for 1H NMR-based metabolic profiling of complex biological mixtures, such as biofluids. These spectra typically contain several thousands of signals, corresponding to possibly few hundreds of metabolites. A number of binning-based methods have been proposed to reduce the dimensionality of 1D 1H NMR datasets, including statistical recoupling of variables (SRV). Here, we introduce a new binning method, named JBA ("pJRES Binning Algorithm"), which aims to extend the applicability of SRV to pJRES spectra. Results: The performance of JBA is comprehensively evaluated using 617 plasma 1H NMR spectra from the FGENTCARD cohort. The results presented here show that JBA exhibits higher sensitivity than SRV to detect peaks from low-abundance metabolites. In addition, JBA allows a more efficient removal of spectral variables corresponding to pure electronic noise, and this has a positive impact on multivariate model building. Availability: The algorithm is implemented using the MWASTools R/Bioconductor package. Supplementary information: Supplementary data are available at Bioinformatics online.

Journal article

Jimenez B, Holmes E, Heude C, Tolson RFM, Harvey N, Lodge SL, Chetwynd AJ, Cannet C, Fang F, Pearce JTM, Lewis MR, Viant MR, Lindon JC, Spraul M, Schaefer H, Nicholson JKet al., 2018, Quantitative lipoprotein subclass and low molecular weight metabolite analysis in human serum and plasma by 1H NMR spectroscopy in a multilaboratory trial, Analytical Chemistry, Vol: 90, Pages: 11962-11971, ISSN: 0003-2700

We report an extensive 600 MHz NMR trial of a quantitative lipoprotein and small molecule measurements in human blood serum and plasma. Five centers with eleven 600 MHz NMR spectrometers were used to analyze 98 samples including: 20 QCs, 37 commercially sourced, paired serum and plasma samples and 2 National Institute of Science and Technology, NIST, reference material 1951c replicates. Samples were analyzed using rigorous protocols for sample preparation and experimental acquisition. A commercial lipoprotein subclass analysis was used to quantify 105 lipoprotein subclasses and 24 low molecular weight metabolites from the nuclear magnetic resonance, NMR, spectra. For all spectrometers, the instrument specific variance in measuring internal quality controls, QCs, was lower than the percentage described by the National Cholesterol Education Program, NCEP, criteria for lipid testing (triglycerides<2.7%, cholesterol<2.8%; LDL-cholesterol<2.8%; HDL-cholesterol<2.3%), showing exceptional reproducibility for direct quantitation of lipoproteins in both matrices. The average RSD for the 105 lipoprotein parameters in the 11 instruments was 4.6% and 3.9% for the two NIST samples while it was 38% and 40% for the 37 commercially sourced plasmas and sera, respectively, showing negligible analytical compared to biological variation. The coefficient of variance, CV, obtained for the quantification of the small molecules across the 11 spectrometers was below 15% for 20 out of the 24 metabolites analyzed. This study provides further evidence of the suitability of NMR for high-throughput lipoprotein subcomponent analysis and small molecule quantitation with the exceptional reproducibility required for clinical and other regulatory settings.

Journal article

Chekmeneva E, Dos Santos Correia G, Gomez Romero M, Stamler J, Chan Q, Elliott P, Nicholson J, Holmes Eet al., 2018, Ultra performance liquid chromatography-high resolution mass spectrometry and direct infusion-high resolution mass spectrometry for combined exploratory and targeted metabolic profiling of human urine, Journal of Proteome Research, Vol: 17, Pages: 3492-3502, ISSN: 1535-3893

The application of metabolic phenotyping to epidemiological studies involving thousands of biofluid samples presents a challenge for the selection of analytical platforms that meet the requirements of high-throughput precision analysis and cost-effectiveness. Here, direct infusion nanoelectrospray (DI-nESI)- was compared to an ultra-performance (UPLC)-high resolution mass spectrometry (HRMS) method for metabolic profiling of an exemplary set of 132 human urine samples from a large epidemiological cohort. Both methods were developed and optimised to allow simultaneous collection of high resolution urinary metabolic profiles and quantitative data for a selected panel of 35 metabolites. The total run time for measuring the sample set in both polarities by UPLC-HRMS was of 5 days compared to 9 hours by DI-nESI-HRMS. To compare the classification ability of the two MS methods we performed exploratory analysis of the full-scan HRMS profiles to detect sex-related differences in biochemical composition. Although metabolite identification is less specific in DI-nESI-HRMS, the significant features responsible for discrimination between sexes were mostly the same in both MS-based platforms. Using the quantitative data we showed that 10 metabolites have strong correlation (Pearson’s r > 0.9 and Passing-Bablok regression slope 0.8-1.3) and good agreement assessed by Bland-Altman plots between UPLC-HRMS and DI-nESI-HRMS and thus, can be measured using a cheaper and less sample- and time-consuming method. Only five metabolites showed weak correlation (Pearson’s r< 0.4) and poor agreement due to the overestimation of the results by DI-nESI-HRMS, and the rest of metabolites showed acceptable correlation between the two methods.

Journal article

Abellona MRU, Mark P, Ladep N, Oleribe O, Reeves H, Greer S, Prince M, Ryder SD, Nash K, Cramp ME, Thursz MR, Nicholson J, Taylor-Robinson S, Ndow G, D'Alessandro U, Njie R, Okeke E, Holmes E, Lemoine Met al., 2018, Elucidating Serum and Urinary Hepatocellular Carcinoma Diagnostic Biomarker Panels: Insight from the United Kingdom and West Africa, Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 37A-38A, ISSN: 0270-9139

Conference paper

Hoyles L, Fernandez-Real J-M, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Luque JL, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Moreno-Navarrete JM, Benhamed F, Azalbert V, Blasco-Baque V, Puig J, Xifra G, Ricart W, Tomlinson C, Woodbridge M, Cardellini M, Davato F, Cardolini I, Porzio O, Gentileschi P, Lopez F, Foufelle F, Butcher SA, Holmes E, Nicholson JK, Postic C, Burcelin R, Dumas M-Eet al., 2018, Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women (vol 24, pg 1070, 2018), NATURE MEDICINE, Vol: 24, Pages: 1628-1628, ISSN: 1078-8956

Journal article

Dumas M-E, Chilloux J, Myridakis A, Hoyles L, Everard A, Plovier H, Cani P, Brial F, Gauguier D, Smyth D, Zhang L, Liu Pet al., 2018, Microbiome inhibition of IRAK-4 by trimethylamine mediates metabolic and immune benefits in high fat diet-induced insulin resistance, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S267-S268, ISSN: 0012-186X

Conference paper

Domingo-Almenara X, Montenegro-Burke JR, Ivanisevic J, Thomas A, Sidibe J, Teav T, Guijas C, Aisporna AE, Rinehart D, Hoang L, Nordstrom A, Gomez-Romero M, Whiley L, Lewis MR, Nicholson JK, Benton HP, Siuzdak Get al., 2018, CMS-MRM and METLIN-MRM: a cloud library and public resource for targeted analysis of small molecules, NATURE METHODS, Vol: 15, Pages: 681-+, ISSN: 1548-7091

Journal article

Izzi-Engbeaya CN, Comninos AN, Clarke S, Abbara A, Lewis M, Holmes E, Nicholson J, Tan T, Rutter G, Dhillo Wet al., 2018, The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans, Diabetes, Obesity and Metabolism, ISSN: 1462-8902

AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

Journal article

Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Latorre Luque J, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Moreno-Navarrete JM, Rayah F, Azalbert V, Blasco-Baque V, Puig J, Xifra G, Ricart W, Tomlinson C, Woodbridge M, Cardellini M, Davato F, Cardolini I, Porzio O, Gentilieschi P, Lopez F, Foufelle F, Butcher SA, Holmes E, Nicholson JK, Postic C, Burcelin R, Dumas MEet al., 2018, Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1080-1080, ISSN: 1078-8956

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.

Journal article

McDonald JAK, Kimhofer T, West K, Coales I, Holmes E, Marchesi J, Nicholson Jet al., Role of the gut microbiota in autism spectrum disorder, ISME17, Publisher: Nature Publishing Group

Conference paper

McDonald JAK, Mullish BH, Pechlivanis A, Li JV, Nicholson JK, Holmes E, Thursz MR, Marchesi JRet al., 2018, 24 - A novel route to controlling Clostridioides Difficile growth via short chain fatty acid and bile acid modulation, Digestive Diseases Week, Publisher: Elsevier, Pages: S8-S8, ISSN: 0016-5085

Conference paper

Hoyles L, Jiménez-Pranteda MJ, Chilloux J, Brial F, Myridakis A, Aranias T, Magnan C, Gibson GR, Sanderson JD, Nicholson JK, Gauguier D, McCartney AL, Dumas MEet al., 2018, Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota, Microbiome, Vol: 6, ISSN: 2049-2618

Background:The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). However, little is known about the use of trimethylamine N-oxide (TMAO) by this consortium of microbes.Results:A feeding study using deuterated TMAO in C57BL6/J mice demonstrated microbial conversion of TMAO to TMA, with uptake of TMA into the bloodstream and its conversion to TMAO. Microbial activity necessary to convert TMAO to TMA was suppressed in antibiotic-treated mice, with deuterated TMAO being taken up directly into the bloodstream. In batch-culture fermentation systems inoculated with human faeces, growth of Enterobacteriaceae was stimulated in the presence of TMAO. Human-derived faecal and caecal bacteria (n = 66 isolates) were screened on solid and liquid media for their ability to use TMAO, with metabolites in spent media analysed by 1H-NMR. As with the in vitro fermentation experiments, TMAO stimulated the growth of Enterobacteriaceae; these bacteria produced most TMA from TMAO. Caecal/small intestinal isolates of Escherichia coli produced more TMA from TMAO than their faecal counterparts. Lactic acid bacteria produced increased amounts of lactate when grown in the presence of TMAO but did not produce large amounts of TMA. Clostridia (sensu stricto), bifidobacteria, and coriobacteria were significantly correlated with TMA production in the mixed fermentation system but did not produce notable quantities of TMA from TMAO in pure culture.Conclusions:Reduction of TMAO by the gut microbiota (predominantly Enterobacteriaceae) to TMA followed by host uptake of TMA into the bloodstream from the intestine and its conversion back to TMAO by host hepatic enzymes is an example of metabolic retroconversion. TMAO influences microbial metabolism depending on isolation source and taxon of gut bacterium. Correlation of metabolomic and abundance data from mixed microbiota fermenta

Journal article

Hoyles L, Snelling T, Umlai UK, Nicholson JK, Carding SR, Glen RC, McArthur Set al., 2018, Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier, Microbiome, Vol: 6, ISSN: 2049-2618

Background: Gut microbiota composition and function are symbiotically linked with host health, and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognized mechanisms exist by which the microbiome influences the gut--brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesized interactions between circulating gut-derived microbial metabolites and the blood--brain barrier (BBB) also contribute to the gut--brain axis. Propionate, produced from dietary substrates by colonic bacteria, stimulates intestinal gluconeogenesis and is associated with reduced stress behaviours, but its potential endocrine role has not been addressed. Results: After demonstrating expression of the propionate receptor FFAR3 on human brain endothelium, we examined the impact of a physiologically relevant propionate concentration (1 μM) on BBB properties in vitro. Propionate inhibited pathways associated with non-specific microbial infections via a CD14-dependent mechanism, suppressed expression of LRP-1 and protected the BBB from oxidative stress via NRF2 (NFE2L2) signaling. Conclusions: Together, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut--brain axis that warrants further attention.

Journal article

Hoyles L, Snelling T, Umlai U-K, Nicholson J, Carding S, Glen R, McArthur Set al., 2018, Propionate has protective and anti-inflammatory effects on the blood–brain barrier, Alzheimer's Research UK Research Conference 2018

Propionate is a short-chain fatty acid (SCFA) produced by the human gut microbiota from dietary substrates, and is biologically active via the G protein coupled receptors FFAR2 and FFAR3. It is taken up from the gut and reaches systemic circulation in micromolar quantities. The blood–brain barrier (BBB) is the major interface between the circulation and central nervous system. FFAR3 is expressed on the vascular endothelium and a likely target for propionate in the BBB. We hypothesized exposure of the BBB to propionate influences barrier integrity and function.Methods and materialsWe investigated the in vitro effects of a physiologically relevant concentration (1 μM) of propionate upon the human immortalised cerebromicrovascular endothelial cell line hCMEC/D3. FFAR3 was present on these cells. We, therefore, performed an unbiased transcriptomic analysis of confluent hCMEC/D3 monolayers treated or not for 24 h with 1 μM propionate, supported by in vitro validation of key findings and assessment of functional endothelial permeability barrier properties.ResultsPropionate treatment had a significant (PFDR < 0.1) effect on the expression of 1136 genes. It inhibited several inflammation-associated pathways: TLR-specific signalling, NFkappaB signalling, and cytosolic DNA-sensing. Functional validation of these findings confirmed the down-regulation of TLR signalling by propionate, achieved primarily through down-regulation of endothelial CD14 expression. Accordingly, propionate prevented LPS-induced increases in paracellular permeability to 70 kDa FITC-dextran and loss of transendothelial electrical resistance. Propionate activated the NFE2L2 (NRF2)-driven protective response against oxidative stress. Confirming these data, propionate limited free reactive oxygen species induction by the mitochondrial respiratory inhibitor rotenone. ConclusionsOur data strongly suggest the SCFA propionate contributes to maintaining BBB integrity and protecting against inflamm

Poster

McArthur S, Carvalho A, Fonseca S, Snelling T, Nicholson J, Glen R, Carding S, Hoyles Let al., 2018, Effects of gut-derived trimethylamines on the blood–brain barrier, Alzheimer's Research UK Research Conference 2018

Introduction: The gut microbiota and its metabolites exert significant effects on host health, with disturbances to composition and function associated with conditions including obesity, type II diabetes and, more recently, Alzheimer’s disease (AD). Communication between microbes and the host can take a number of forms, but central to all of them is a role for gut-derived microbial metabolites, with trimethylamine N-oxide (TMAO) and its precursor trimethylamine (TMA) being important examples. TMA produced by gut bacteria is converted to TMAO in the liver by flavin monooxygenases whereupon it enters the circulation. TMAO was recently identified as potentially important in genetic pathways associated with AD, and has been shown to influence peripheral vascular function. Given these links, the key position of the cerebral vasculature as the major interface between circulating molecules and the brain, and evidence that deficits in blood–brain barrier (BBB) function occur early in AD, we investigated the effects of TMAO and TMA on key BBB properties in vitro and in vivo.Materials and Methods: Male C57Bl/6 mice (n=4-5) were used to examine the effect of TMAO treatment (1.8 mg/kg, 2 h, dose equivalent to circulating human concentrations) upon BBB permeability in vivo, assessed by Evans’ blue dye extravasation. TMA was not investigated as the average mouse plasma concentration of this methylamine is substantially greater than that seen in humans (TMAO-to-TMA ratio 1:10 in mice, 10:1 in humans).Human hCMEC/D3 cerebromicrovascular cells were used as an in vitro model of the BBB to investigate the effects of 24 h treatment with human physiologically relevant doses of TMAO (40 μM) and TMA (0.4 μM), studying (i) functional barrier properties of cell monolayers and (ii) gene expression. Results: Administration of TMAO to mice enhanced BBB integrity above baseline after 2 h treatment (p<0.05). Similarly, in vitro exposure of hCMEC/D3 cells to TMAO enhanc

Poster

Hoyles L, Snelling T, Umlai U-K, Nicholson J, Carding S, Glen R, McArthur Set al., 2018, Microbiome–host interactions: protective effects of propionate upon the blood–brain barrier

Breakdown of foodstuffs by the gut microbiota results in the production of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate. SFCAs are potent bioactive molecules, providing energy for intestinal cells, enhancing satiety and positively influencing metabolic health. They also influence the gut–brain axis. The gut microbiota and/or its bioactive molecules contribute to maintaining the integrity of the blood–brain barrier (BBB), the primary defensive structure of the brain. Propionate is produced by the gut microbiota from the breakdown of glucans found in whole grains, mushrooms and yeast products. It is found in the blood at ≤1 μM. At this physiologically relevant concentration, propionate enhances BBB integrity, mitigating against deleterious inflammatory and oxidative stimuli known to contribute to neurological and psychological diseases. Therefore, there is the potential that dietary supplementation with glucan-containing products may offer protection of the brain against detrimental stimuli.

Working paper

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