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

975 results found

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., J Proteome Res, Vol: 18, Pages: 2160-2174

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., Nutr Cancer, Pages: 1-12

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 L, Nye LC, Grant I, Andreas N, Chappell KE, Sarafian MH, Misra R, Plumb RS, Lewis MR, Nicholson JK, Holmes E, Swann JR, Wilson IDet 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

JOURNAL ARTICLE

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

Abstract Motivation 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. Results 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 in vitro , this strategy represents a useful approach for those interrogating the metabolism of other gut-derived microbial metabolites relevant to human health. Availability All R scripts and files (gut microbial dataset, FASTA protein sequences, BLASTP output files) are available from https://github.com/AndreaRMICL/Microbial_networks . Contact ARM: andrea.rodriguez-martinez13@imperial.ac.uk ; LH: lesley.hoyles@ntu.ac.uk .

WORKING PAPER

Harbaum L, Ghataorhe P, Wharton J, Jiménez B, Howard LSG, Gibbs JSR, Nicholson JK, Rhodes CJ, Wilkins MRet al., 2019, Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension., Thorax, Vol: 74, Pages: 380-389

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

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

JOURNAL ARTICLE

Poynter L, Galea D, Veselkov K, Mirnezami A, Kinross J, Nicholson J, Takáts Z, Darzi A, Mirnezami Ret al., 2019, Network Mapping of Molecular Biomarkers Influencing Radiation Response in Rectal Cancer., Clin Colorectal Cancer

Preoperative radiotherapy (RT) plays an important role in the management of locally advanced rectal cancer (RC). Tumor regression after RT shows marked variability, and robust molecular methods are needed to help predict likely response. The aim of this study was to review the current published literature and use Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC. A 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 nonsignificant results were included in the analysis. Significance was binarized on the basis of univariate 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 RC radiation response. Seventy-two individual biomarkers across 74 studies were identified. 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. Homogenizing biomarker data from original articles using controlled GO terminology demonstrated that cellular mechanisms of response to RT in RC-in particular the metabolic response to RT-may hold promise in developing radiotherapeutic biomarkers to help 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

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

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, Pages: 1-8

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 1 H NMR spectroscopy, inductively coupled plasma (ICP)MS, and UPLC-MS. 3. 1 H 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 in this study. 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 7 days of the study for both the 100 and 200 mg doses, respectively. 5. The bulk of the excretion of Br-containing material had occurred by 8 h 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

Izzi-Engbeaya C, Comninos AN, Clarke SA, Jomard A, Yang L, Jones S, Abbara A, Narayanaswamy S, Eng PC, Papadopoulou D, Prague JK, Bech P, Godsland IF, Bassett P, Sands C, Camuzeaux S, Gomez-Romero M, Pearce JTM, Lewis MR, Holmes E, Nicholson JK, Tan T, Ratnasabapathy R, Hu M, Carrat G, Piemonti L, Bugliani M, Marchetti P, Johnson PR, Hughes SJ, James Shapiro AM, Rutter GA, Dhillo WSet al., 2018, The effects of kisspeptin on beta-cell function, serum metabolites and appetite in humans, DIABETES OBESITY & METABOLISM, Vol: 20, Pages: 2800-2810, ISSN: 1462-8902

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

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 RF, 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 H-1 NMR Spectroscopy in a Multilaboratory Trial, ANALYTICAL CHEMISTRY, Vol: 90, Pages: 11962-11971, ISSN: 0003-2700

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

Chekmeneva E, Correia GDS, Gomez-Romero M, Stamler J, Chan Q, Elliott P, Nicholson JK, 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

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

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

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

Hoyles L, Fernandez-Real J-M, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Latorre Luque J, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Maria Moreno-Navarrete J, 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, NATURE MEDICINE, Vol: 24, Pages: 1070-+, ISSN: 1078-8956

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

Athersuch TJ, Antoine DJ, Boobis AR, Coen M, Daly AK, Possamai L, Nicholson JK, Wilson IDet al., 2018, Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective, TOXICOLOGY RESEARCH, Vol: 7, Pages: 347-357, ISSN: 2045-452X

JOURNAL ARTICLE

McDonald JA, Mullish BH, Pechlivanis A, Li JV, Nicholson JK, Holmes E, Thursz MR, Marchesi Jet al., 2018, A NOVEL ROUTE TO CONTROLLING CLOSTRIDIOIDES DIFFICILE GROWTH VIA SHORT CHAIN FATTY ACID AND BILE ACID MODULATION, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S8-S8, ISSN: 0016-5085

CONFERENCE PAPER

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

JOURNAL ARTICLE

Posma JM, Garcia-Perez I, Ebbels TMD, Lindon JC, Stamler J, Elliott P, Holmes E, Nicholson JKet al., 2018, Optimized Phenotypic Biomarker Discovery and Confounder Elimination via Covariate-Adjusted Projection to Latent Structures from Metabolic Spectroscopy Data, JOURNAL OF PROTEOME RESEARCH, Vol: 17, Pages: 1586-1595, ISSN: 1535-3893

JOURNAL ARTICLE

Hoyles L, Snelling T, Umlai U-K, 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

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

Veselkov K, Sleeman J, Claude E, Vissers JPC, Galea D, Mroz A, Laponogov I, Towers M, Tonge R, Mirnezami R, Takats Z, Nicholson JK, Langridge JIet al., 2018, BASIS: High-performance bioinformatics platform for processing of large-scale mass spectrometry imaging data in chemically augmented histology, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322

JOURNAL ARTICLE

Loo RL, Zou X, Appel LJ, Nicholson JK, Holmes Eet al., 2018, Characterization of metabolic responses to healthy diets and association with blood pressure: application to the Optimal Macronutrient Intake Trial for Heart Health (OmniHeart), a randomized controlled study, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 107, Pages: 323-334, ISSN: 0002-9165

JOURNAL ARTICLE

Rodriguez-Martinez A, Posma JM, Ayala R, Neves AL, Anwar M, Petretto E, Emanueli C, Gauguier D, Nicholson JK, Dumas M-Eet al., 2018, MWASTools: an R/bioconductor package for metabolome-wide association studies, BIOINFORMATICS, Vol: 34, Pages: 890-892, ISSN: 1367-4803

JOURNAL ARTICLE

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