Imperial College London

ProfessorElaineHolmes

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Professor of Chemical Biology
 
 
 
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Contact

 

+44 (0)20 7594 3220elaine.holmes

 
 
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Location

 

661Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

689 results found

Begum S, Johnson BZ, Morillon A-C, Yang R, Bong SH, Whiley L, Gray N, Fear VS, Cuttle L, Holland AJA, Nicholson JK, Wood FM, Fear MW, Holmes Eet al., 2022, Systemic long-term metabolic effects of acute non-severe paediatric burn injury., Sci Rep, Vol: 12

A growing body of evidence supports the concept of a systemic response to non-severe thermal trauma. This provokes an immunosuppressed state that predisposes paediatric patients to poor recovery and increased risk of secondary morbidity. In this study, to understand the long-term systemic effects of non-severe burns in children, targeted mass spectrometry assays for biogenic amines and tryptophan metabolites were performed on plasma collected from child burn patients at least three years post injury and compared to age and sex matched non-burn (healthy) controls. A panel of 12 metabolites, including urea cycle intermediates, aromatic amino acids and quinolinic acid were present in significantly higher concentrations in children with previous burn injury. Correlation analysis of metabolite levels to previously measured cytokine levels indicated the presence of multiple cytokine-metabolite associations in the burn injury participants that were absent from the healthy controls. These data suggest that there is a sustained immunometabolic imprint of non-severe burn trauma, potentially linked to long-term immune changes that may contribute to the poor long-term health outcomes observed in children after burn injury.

Journal article

U MRA, Shen EY-L, Cartlidge C, Alkhatib A, Thursz MR, Waked I, Gomaa AI, Holmes E, Sharma R, Taylor-Robinson SDet al., 2022, Optimised systematic review tool: Application to candidate biomarkers for the diagnosis of hepatocellular carcinoma, Cancer Epidemiology, Biomarkers and Prevention, Vol: 31, Pages: 1261-1274, ISSN: 1055-9965

This review aims to develop an appropriate review tool for systematically collating metabolites that are dysregulated in disease and applies the method to identify novel diagnostic biomarkers for hepatocellular carcinoma (HCC). Studies that analysed metabolites in blood or urine samples where HCC was compared with comparison groups (healthy, pre-cirrhotic liver disease, cirrhosis) were eligible. Tumour tissue was included to help differentiate primary and secondary biomarkers. Searches were conducted on Medline and EMBASE. A bespoke 'risk-of-bias' tool for metabolomic studies was developed adjusting for analytical quality. Discriminant metabolites for each sample type were ranked using a weighted score accounting for the direction and extent of change and the risk of bias of the reporting publication. A total of 84 eligible studies were included in the review (54 blood, 9 urine and 15 tissue), with six studying multiple sample types. High-ranking metabolites, based on their weighted score, comprised energy metabolites, bile acids, acylcarnitines and lysophosphocholines. This new review tool addresses an unmet need for incorporating quality of study design and analysis to overcome the gaps in standardisation of reporting of metabolomic data. Validation studies, standardised study designs and publications meeting minimal reporting standards are crucial for advancing the field beyond exploratory studies.

Journal article

Chan Q, Wren G, Lau CH, Ebbels T, Gibson R, Loo RL, Aljuraiban G, Posma J, Dyer A, Steffen L, Rodriguez B, Appel L, Daviglus M, Elliott P, Stamler J, Holmes E, Van Horn Let al., 2022, Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP), The American Journal of Clinical Nutrition, Vol: 116, Pages: 216-229, ISSN: 1938-3207

BackgroundAdherence to the Dietary Approaches to Stop Hypertension (DASH) diet enhances potassium intake and reduces sodium intake and blood pressure (BP), but the underlying metabolic pathways are unclear.ObjectiveAmong free-living populations, delineate metabolic signatures associated with the DASH diet adherence, 24-hr urinary sodium and potassium excretions and the potential metabolic pathways involved.Design24-hr urinary metabolic profiling by proton nuclear magnetic resonance spectroscopy was used to characterize the metabolic signatures associated with the DASH dietary pattern score (DASH score) and 24-hr excretion of sodium and potassium among participants in the United States (n=2,164) and United Kingdom (n= 496) enrolled in the International Study of Macro- and Micronutrients and Blood Pressure (INTERMAP). Multiple linear regression and cross-tabulation analyses were used to investigate the DASH-BP relation and its modulation by sodium and potassium. Potential pathways associated with DASH adherence, sodium and potassium excretion, and BP were identified using mediation analyses and metabolic reaction networks.ResultsAdherence to DASH diet was associated with urinary potassium excretion (correlation coefficient, r = 0.42, P<0.0001). In multivariable regression analyses, a five-point higher DASH score (range 7 to 35) was associated with a lower systolic BP by 1.35 mmHg (95% confidence interval: -1.95, -0.80, P=1.2 × 10−5); control of the model for potassium but not sodium attenuated the DASH-BP relation. Two common metabolites (hippurate and citrate) mediated the potassium-BP and DASH-BP relationships, while five metabolites (succinate, alanine, S-methyl cysteine sulfoxide, 4-hydroxyhippurate, phenylacetylglutamine) were found specific to the DASH-BP relation.ConclusionsGreater adherence to DASH diet is associated with lower BP and higher potassium intake across levels of sodium intake. The DASH diet recommends greater intake of fruits, veget

Journal article

Kean IRL, Wagner J, Wijeyesekera A, De Goffau M, Thurston S, Clark JA, White DK, Ridout J, Agrawal S, Kayani R, O'Donnell R, Ramnarayan P, Peters MJ, Klein N, Holmes E, Parkhill J, Baker S, Pathan Net al., 2022, Profiling gut microbiota and bile acid metabolism in critically ill children, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322

Journal article

Mujagic Z, Kasapi M, Jonkers DMAE, Garcia Perez I, Vork L, Weerts ZZRM, Serrano Contreras JI, Zhernakova A, Kurilshikov A, Scotcher J, Holmes E, Wijmenga C, Keszthelyi D, Nicholson J, Posma JM, Masclee AAMet al., 2022, Integrated fecal microbiome–metabolome signatures reflect stress and serotonin metabolism in irritable bowel syndrome, Gut Microbes, Vol: 14, Pages: 1-20, ISSN: 1949-0976

To gain insight into the complex microbiome-gut-brain axis in irritable bowel syndrome (IBS) several modalities of biological and clinical data must be combined. We aimed to identify profiles of faecal microbiota and metabolites associated with IBS and to delineate specific phenotypes of IBS that represent potential pathophysiological mechanisms. Faecal metabolites were measured using proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy and gut microbiome using Shotgun Metagenomic Sequencing (MGS) in a combined dataset of 142 IBS patients and 120 healthy controls (HC) with extensive clinical, biological and phenotype information. Data were analysed using support vector classification and regression and kernel t-SNE. Microbiome and metabolome profiles could distinguish IBS and HC with an area-under-the-receiver-operator-curve (AUC) of 77.3% and 79.5%, respectively, but this could be improved by combining microbiota and metabolites to 83.6%. No significant differences in predictive ability of the microbiome-metabolome data were observed between the three classical, stool pattern-based, IBS subtypes. However, unsupervised clustering showed distinct subsets of IBS patients based on faecal microbiome-metabolome data. These clusters could be related plasma levels of serotonin and its metabolite 5-hydroxyindoleacetate, effects of psychological stress on gastrointestinal symptoms, onset of IBS after stressful events, medical history of previous abdominal surgery, dietary caloric intake and IBS symptom duration. Furthermore, pathways in metabolic reaction networks were integrated with microbiota data, that reflect the host-microbiome interactions in IBS. The identified microbiome-metabolome signatures for IBS, associated with altered serotonin metabolism and unfavourable stress-response related to gastrointestinal symptoms, support the microbiota-gut-brain link in the pathogenesis of IBS.

Journal article

Sheridan D, Shawa I, Thomas EL, Felmlee DJ, Bridge SH, Neely D, Cobbold J, Holmes E, Bassendine MF, Taylor-Robinson Set al., 2022, Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis, Scientific Reports, Vol: 12, ISSN: 2045-2322

Background: Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis.Aims: We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism.Methods: We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR.Results: HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3.Conclusions: We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol lev

Journal article

Loo RL, Chan Q, Nicholson JK, Holmes Eet al., 2022, Balancing the equation: a natural history of trimethylamine and trimethylamine-N-oxide., Journal of Proteome Research, Vol: 21, Pages: 560-589, ISSN: 1535-3893

Trimethylamine (TMA) and its N-oxide (TMAO) are ubiquitous in prokaryote and eukaryote organisms as well as in the environment, reflecting their fundamental importance in evolutionary biology, and their diverse biochemical functions. Both metabolites have multiple biological roles including cell-signaling. Much attention has focused on the significance of serum and urinary TMAO in cardiovascular disease risk, yet this is only one of the many facets of a deeper TMA-TMAO partnership that reflects the significance of these metabolites in multiple biological processes spanning animals, plants, bacteria, and fungi. We report on analytical methods for measuring TMA and TMAO and attempt to critically synthesize and map the global functions of TMA and TMAO in a systems biology framework.

Journal article

Masuda R, Lodge S, Whiley L, Gray N, Lawler N, Nitschke P, Bong S-H, Kimhofer T, Loo RL, Boughton B, Zeng AX, Hall D, Schaefer H, Spraul M, Dwivedi G, Yeap BB, Diercks T, Bernardo-Seisdedos G, Mato JM, Lindon JC, Holmes E, Millet O, Wist J, Nicholson JKet al., 2022, Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection., Anal Chem

SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for in

Journal article

Martinez-Gili L, Gordon H, Blad W, McDonald JAK, Holmes E, Marchesi JR, Harbord Met al., 2022, Gut bacteria composition and familiality echo Inflammatory Bowel Disease type and pathological spectrum, 17th Congress of ECCO, Publisher: Oxford University Press, Pages: I601-I602, ISSN: 1873-9946

BackgroundInflammatory bowel disease (IBD) aetiology encompasses genetic and environmental factors. Twin studies provide valuable insights to the familial degree (shared genetics and environment) of observed phenotypes. We characterised the gut bacterial composition of twins with IBD to find taxa associated with disease and estimate their familiality.MethodsFaecal samples were collected from 88 monozygotic (MZ) and dizygotic (DZ) twin pairs concordant or discordant for Crohn’s disease (CD; 26 MZ; 19 DZ) or ulcerative colitis (UC; 16 MZ; 27 DZ). The 16S rRNA gene was sequenced and amplicon sequence variants (ASV) generated. ANCOM software was used to assess differences in IBD vs. non-IBD, stratifying by disease type (CD/UC) and adjusting for age, gender and smoking. Twin pair and zygosity were added as random effects to estimate familiality, defined as percentage of variation due to common environment and genetics. IBD-affected twins were used for differences in disease location or treatment. Participants reporting antibiotic/probiotic treatment within the last 3 months or with a stoma/pouch were not included. In UC, surgery-naive patients were compared to an excluded subset who underwent ileostomy or pouch surgery without any recent antibiotic courses.ResultsDisease concordance in MZ twins was higher in CD (54%) than UC (19%). Alpha diversity was lower in CD, but not UC, and in ileostomy and pouch vs. surgery-naive UC. Principal component analysis showed that CD-affected twins clustered apart from non-IBD ones (Figure 1A). Familiality was lower in CD, with 5% of ASVs having familiality > 50%, compared to 17% in UC (Figure 1B). Two Lachnospirales order ASVs were less abundant in UC, while 15 ASVs from Clostridia, Bacteroidia, Bacilli and Coriobacteriia classes differentiated CD from non-IBD. Firmicutes were higher in CD (β= 0.95; 95%CI [0.34,1.56]), while no phyla changed in UC. Veillonella, Barnesiella, Faecalimonas and Holdemania genera had opposite t

Conference paper

Nitschke P, Lodge S, Kimhofer T, Masuda R, Bong S-H, Hall D, Schäfer H, Spraul M, Pompe N, Diercks T, Bernardo-Seisdedos G, Mato JM, Millet O, Susic D, Henry A, El-Omar EM, Holmes E, Lindon JC, Nicholson JK, Wist Jet al., 2022, J-edited dIffusional proton nuclear magnetic resonance spectroscopic measurement of glycoprotein and supramolecular phospholipid biomarkers of inflammation in human serum., Analytical Chemistry, Vol: 94, Pages: 1333-1341, ISSN: 0003-2700

Proton nuclear magnetic resonance (NMR) N-acetyl signals (Glyc) from glycoproteins and supramolecular phospholipids composite peak (SPC) from phospholipid quaternary nitrogen methyls in subcompartments of lipoprotein particles) can give important systemic metabolic information, but their absolute quantification is compromised by overlap with interfering resonances from lipoprotein lipids themselves. We present a J-Edited DIffusional (JEDI) proton NMR spectroscopic approach to selectively augment signals from the inflammatory marker peaks Glyc and SPCs in blood serum NMR spectra, which enables direct integration of peaks associated with molecules found in specific compartments. We explore a range of pulse sequences that allow editing based on peak J-modulation, translational diffusion, and T2 relaxation time and validate them for untreated blood serum samples from SARS-CoV-2 infected patients (n = 116) as well as samples from healthy controls and pregnant women with physiological inflammation and hyperlipidemia (n = 631). The data show that JEDI is an improved approach to selectively investigate inflammatory signals in serum and may have widespread diagnostic applicability to disease states associated with systemic inflammation.

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

Adegbola SO, Sarafian M, Sahnan K, Pechlivanis A, Phillips RKS, Warusavitarne J, Faiz O, Haddow J, Knowles C, Tozer P, Holmes E, Hart Aet al., 2022, Lack of anti-TNF drugs levels in fistula tissue - a reason for nonresponse in Crohn's perianal fistulating disease?, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 18-26, ISSN: 0954-691X

Conference paper

Adegbola SO, Sarafian M, Sahnan K, Ding NS, Faiz OD, Warusavitarne J, Phillips RKS, Tozer PJ, Holmes E, Hart ALet al., 2021, Differences in amino acid and lipid metabolism distinguish Crohn's from idiopathic/cryptoglandular perianal fistulas by tissue metabonomic profiling and may offer clues to underlying pathogenesis, EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, Vol: 33, Pages: 1469-1479, ISSN: 0954-691X

Journal article

Wu Y, Posma JM, Holmes E, Chambers E, Frost G, Garcia Perez Iet al., 2021, Odd chain fatty acids are not robust biomarkers for dietary intake of fiber, Molecular Nutrition and Food Research, Vol: 65, Pages: 1-8, ISSN: 1613-4125

Prior investigation has suggested a positive association between increased colonic propionate production and circulating odd-chain fatty acids [(OCFAs; pentadecanoic acid (C15:0), heptadecanoic acid (C17:0)]. As the major source of propionate in humans is the microbial fermentation of dietary fiber, OCFAs have been proposed as candidate biomarkers of dietary fiber. The objective of this study is to critically assess the plausibility, robustness, reliability, dose-response, time-response aspects of OCFAs as potential biomarkers of fermentable fibers in two independent studies using a validated analytical method. OCFAs were first assessed in a fiber supplementation study, where 21 participants received 10g dietary fiber supplementation for 7 days with blood samples collected on the final day at a 420 minute study visit. OCFAs were then assessed in a highly controlled inpatient setting, which 19 participants consumed a high fiber (45.1g/day) and a low fiber diet (13.6g/day) for 4 days. Collectively in both studies, dietary intakes of fiber as fiber supplementations or having consumed a high fiber diet did not increase circulating levels of OCFAs. The dose and temporal relations were not observed. Current study has generated new insight on the utility of OCFAs as fiber biomarkers and highlighted the importance of critical assessment of candidate dietary biomarkers before application.

Journal article

Alsaleh M, Leftley Z, OConnor T, Hughes T, Barbera T, Koomson L, Zabron A, Reeves H, Cramp M, Ryder S, Greer S, Sithithaworn P, Khuntikeo N, Loilome W, Yongvanit P, Prince M, Cox IJ, Williams R, Wadsworth C, Holmes E, Nash K, Andrews R, Taylor-Robinson Set al., 2021, Mapping of population disparities in the cholangiocarcinoma urinary metabolome, Scientific Reports, Vol: 11, Pages: 1-12, ISSN: 2045-2322

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

Journal article

Blaise BJ, Correia GDS, Haggart GA, Surowiec I, Sands C, Lewis MR, Pearce JTM, Trygg J, Nicholson JK, Holmes E, Ebbels TMDet al., 2021, Statistical analysis in metabolic phenotyping, NATURE PROTOCOLS, Vol: 16, Pages: 4299-4326, ISSN: 1754-2189

Journal article

Gray N, Lawler NG, Zeng AX, Ryan M, Bong SH, Boughton BA, Bizkarguenaga M, Bruzzone C, Embade N, Wist J, Holmes E, Millet O, Nicholson JK, Whiley Let al., 2021, Diagnostic potential of the plasma lipidome in infectious disease: application to acute SARS-CoV-2 infection, Metabolites, Vol: 11, Pages: 1-17, ISSN: 2218-1989

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

Journal article

Masuda R, Lodge S, Nitschke P, Spraul M, Schaefer H, Bong S-H, Kimhofer T, Hall D, Loo RL, Bizkarguenaga M, Bruzzone C, Gil-Redondo R, Embade N, Mato JM, Holmes E, Wist J, Millet O, Nicholson JKet al., 2021, Integrative Modeling of Plasma Metabolic and Lipoprotein Biomarkers of SARS-CoV-2 Infection in Spanish and Australian COVID-19 Patient Cohorts, JOURNAL OF PROTEOME RESEARCH, Vol: 20, Pages: 4139-4152, ISSN: 1535-3893

Journal article

Thompson A, Bourke C, Robertson R, Shivakumar N, Edwards C, Preston T, Holmes E, Paul K, Gary F, Douglas Met al., 2021, Understanding the role of the gut in undernutrition: what can technology tell us?, Gut, Vol: 70, Pages: 1580-1594, ISSN: 0017-5749

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

Journal article

Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK, Hejndorf S, Ng YZ, Low JZY, Rossant J, Nechanitzky R, Holmes E, Nicholson JK, Tan E-K, Matthews PM, Pettersson Set al., 2021, Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor, Proceedings of the National Academy of Sciences, Vol: 118, Pages: 1-10, ISSN: 0027-8424

While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR−/−) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR–mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.

Journal article

Martinez-Gili L, Pechlivanis A, Begum S, Mells G, Holmes E, Jones Det al., 2021, Response failure to ursodeoxycholic acid treatment in primary biliary cholangitis is associated with a distinct stool and urine secondary bile acid profile, International Liver Congress (ILC2021), Publisher: ELSEVIER, Pages: S404-S405, ISSN: 0168-8278

Conference paper

Posma JM, Garcia-Perez I, Frost G, Aljuraiban GS, Chan Q, Van Horn L, Daviglus M, Stamler J, Holmes E, Elliott P, Nicholson JKet al., 2021, Nutriome-metabolome relationships provide insights into dietary intake and metabolism (vol 1, pg 426, 2020), NATURE FOOD, Vol: 2, Pages: 541-542

Journal article

Li J, 2021, Roux-en-Y Gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype, Microbiome, Vol: 9, ISSN: 2049-2618

BACKGROUND: Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations. METHODS: Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome. RESULTS: Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients' bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery. CONCLUSION: Altered bacterial composition and metabolism contribute to metabolic observations in biofluid

Journal article

Bergamaschi L, Mescia F, Turner L, Hanson AL, Kotagiri P, Dunmore BJ, Ruffieux H, De Sa A, Huhn O, Morgan MD, Gerber PP, Wills MR, Baker S, Calero-Nieto FJ, Doffinger R, Dougan G, Elmer A, Goodfellow IG, Gupta RK, Hosmillo M, Hunter K, Kingston N, Lehner PJ, Matheson NJ, Nicholson JK, Petrunkina AM, Richardson S, Saunders C, Thaventhiran JED, Toonen EJM, Weekes MP, Gottgens B, Toshner M, Hess C, Bradley JR, Lyons PA, Smith KGCet al., 2021, Longitudinal analysis reveals that delayed bystander CD8(+) T cell activation and early immune pathology distinguish severe COVID-19 from mild disease, IMMUNITY, Vol: 54, Pages: 1257-+, ISSN: 1074-7613

Journal article

Kimhofer T, Lodge S, Whiley L, Gray N, Loo RL, Lawler NG, Nitschke P, Bong S-H, Morrison DL, Begum S, Richards T, Yeap BB, Smith C, Smith KGC, Holmes E, Nicholson JKet al., 2021, Correction to "Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection"., J Proteome Res, Vol: 20

Journal article

Holmes E, Wist J, Masuda R, Lodge S, Nitschke P, Kimhofer T, Loo RL, Begum S, Boughton B, Yang R, Morillon A-C, Chin S-T, Hall D, Ryan M, Bong S-H, Gay M, Edgar DW, Lindon JC, Richards T, Yeap BB, Pettersson S, Spraul M, Schaefer H, Lawler NG, Gray N, Whiley L, Nicholson JKet al., 2021, Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome, Journal of Proteome Research, Vol: 20, Pages: 3315-3329, ISSN: 1535-3893

Journal article

Bergner R, Onida S, Velineni R, Spagou K, Gohel MS, Bouschbacher M, Bohbot S, Shalhoub J, Holmes E, Davies AHet al., 2021, Metabolic profiling reveals changes in serum predictive of venous ulcer healing, Annals of Surgery, ISSN: 0003-4932

Objective: The aim of this study was to identify potential biomarkers predictive of healing or failure to heal in a population with venous leg ulceration.Summary Background Data: Venous leg ulceration presents important physical, psychological, social and financial burdens. Compression therapy is the main treatment, but it can be painful and time-consuming, with significant recurrence rates. The identification of a reliable biochemical signature with the ability to identify nonhealing ulcers has important translational applications for disease prognostication, personalized health care and the development of novel therapies.Methods: Twenty-eight patients were assessed at baseline and at 20 weeks. Untargeted metabolic profiling was performed on urine, serum, and ulcer fluid, using mass spectrometry and nuclear magnetic resonance spectroscopy.Results: A differential metabolic phenotype was identified in healing (n = 15) compared to nonhealing (n = 13) venous leg ulcer patients. Analysis of the assigned metabolites found ceramide and carnitine metabolism to be relevant pathways. In this pilot study, only serum biofluids could differentiate between healing and nonhealing patients. The ratio of carnitine to ceramide was able to differentiate between healing phenotypes with 100% sensitivity, 79% specificity, and 91% accuracy.Conclusions: This study reports a metabolic signature predictive of healing in venous leg ulceration and presents potential translational applications for disease prognostication and development of targeted therapies.

Journal article

Calder N, Walsh K, Olupot-Olupot P, Ssenyondo T, Muhindo R, Brignardello J, Wang X, McKay E, Morrison D, Holmes E, Frost G, Maitland Ket al., 2021, Modifying gut integrity and microbiome in children with severe acute malnutrition using LEgume-Based Feeds [MIMBLE]: A pilot trial, Cell Reports Medicine, Vol: 2, Pages: 1-17, ISSN: 2666-3791

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

Journal article

Lawler NG, Gray N, Kimhofer T, Boughton B, Gay M, Yang R, Morillon A-C, Chin S-T, Ryan M, Begum S, Bong SH, Coudert JD, Edgar D, Raby E, Pettersson S, Richards T, Holmes E, Whiley L, Nicholson JKet al., 2021, Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses, Journal of Proteome Research, Vol: 20, Pages: 2796-2811, ISSN: 1535-3893

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

Journal article

Hoyles L, Mayneris-Perxachs J, Cardellini M, Latorre J, Davato F, Moreno-Navarette JM, Arnoriaga-Rodriquez M, Serino M, Abbott J, Barton RH, Puig J, Fernandez-Real X, Ricart W, Tomlinson C, Woodbridge M, Gentileschi P, Butcher SA, Holmes E, Nicholson JK, Perez-Brocal V, Moya A, McClain D, Burcelin R, Dumas M-E, Federici M, Fernandez-Real J-Met al., 2021, ­Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome, Microbiome, Vol: 9, Pages: 1-18, ISSN: 2049-2618

Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The

Journal article

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