Imperial College London

Dr. Jia Li

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3230jia.li

 
 
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Location

 

101Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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95 results found

Taylor H, Serrano-Contreras JI, McDonald JAK, Epstein J, Fell JM, Seoane RC, Li JV, Marchesi JR, Hart ALet al., 2020, Multiomic features associated with mucosal healing and inflammation in paediatric Crohn's disease., Aliment Pharmacol Ther

BACKGROUND: The gastrointestinal microbiota has an important role in mucosal immune homoeostasis and may contribute to maintaining mucosal healing in Crohn's disease (CD). AIM: To identify changes in the microbiota, metabolome and protease activity associated with mucosal healing in established paediatric CD. METHODS: Twenty-five participants aged 3-18 years with CD, disease duration of over 6 months, and maintenance treatment with biological therapy were recruited. They were divided into a low calprotectin group (faecal calprotectin <100 μg/g, "mucosal healing," n = 11), and a high calprotectin group (faecal calprotectin >100 μg/g, "mucosal inflammation," n = 11). 16S gene-based metataxonomics, 1 H-NMR spectroscopy-based metabolic profiling and protease activity assays were performed on stool samples. RESULTS: Relative abundance of Dialister species was six times greater in the low calprotectin group (q = 0.00999). Alpha and beta diversity, total protease activity and inferred metagenomic profiles did not differ between groups. Pentanoate (valerate) and lysine were principal discriminators in a machine-learning model which differentiated high and low calprotectin samples using NMR spectra (R2 0.87, Q2 0.41). Mean relative concentration of pentanoate was 1.35-times greater in the low calprotectin group (95% CI 1.03-1.68, P = 0.036) and was positively correlated with Dialister. Mean relative concentration of lysine was 1.54-times greater in the high calprotectin group (95% CI 1.05-2.03, P = 0.028). CONCLUSIONS: This multiomic study identified an increase in Dialister species and pentanoate, and a decrease in lysine, in patients with "mucosal healing." It supports further investigation of these as potential novel therapeutic targets in CD.

Journal article

Vonhof EV, Piotto M, Holmes E, Lindon JC, Nicholson JK, Li JVet al., 2020, Improved Spatial Resolution of Metabolites in Tissue Biopsies Using High-Resolution Magic-Angle-Spinning Slice Localization NMR Spectroscopy., Anal Chem, Vol: 92, Pages: 11516-11519

High-resolution magic-angle-spinning 1H NMR spectroscopy (HR-MAS NMR) is a well-established technique for assessing the biochemical composition of intact tissue samples. In this study, we utilized a method based on HR-MAS NMR spectroscopy with slice localization (SLS) to achieve spatial resolution of metabolites. The obtained 7 slice spectra from each of the model samples (i.e., chicken thigh muscle with skin and murine renal biopsy including medulla (M) and cortex (C)) showed distinct metabolite compositions. Furthermore, we analyzed previously acquired 1H HR-MAS NMR spectra of separated cortex and medulla samples using multivariate statistical methods. Concentrations of glycerophosphocholine (GPC) were found to be significantly higher in the renal medulla compared to the cortex. Using GPC as a biomarker, we identified the tissue slices that were predominantly the cortex or medulla. This study demonstrates that HR-MAS SLS combined with multivariate statistics has the potential for identifying tissue heterogeneity and detailed biochemical characterization of complex tissue samples.

Journal article

West K, Kanu C, Maric T, McDonald J, Nicholson J, Li J, Johnson M, Holmes E, Savvidou Met al., 2020, Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery, Gut, Vol: 69, Pages: 1452-1459, ISSN: 0017-5749

Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development.DesignA parallel metabonomic (1H NMR spectroscopy) and gut bacterial (16S rRNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared to women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed.ResultsPrevious malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p-cresol sulfate, indoxyl sulfate and p-hydroxyphenylacetate), and a shift in the gut microbiota. Urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (P=0.001) and was also elevated in urine of neonates born from these mothers (P=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight.ConclusionMetabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.

Journal article

Hu C, Liu Z, Zhao H, Wu L, Lian Q, Ma D, Li JVet al., 2020, A biochemical comparison of the lung, colonic, brain, renal, and ovarian cancer cell lines using 1H-NMR spectroscopy, Bioscience Reports, Vol: 40, ISSN: 0144-8463

Cancer cell lines are very often used for cancer research. However, continuous genetic instability-induced heterogeneity of cell lines can hinder the reproducibility of cancer research. Molecular profiling approaches including transcriptomics, chromatin modification profiling and proteomics are used to evaluate the phenotypic characteristics of cell lines. However, these do not reflect the metabolic function at the molecular level. Metabolic phenotyping is a powerful tool to profile the biochemical composition of cell lines. In this study, 1H-NMR spectroscopy-based metabolic phenotyping was used to detect metabolic differences among 5 cancer cell lines, namely, lung (A549), colonic (Caco2), brain (H4), renal (RCC), and ovarian (SKOV3) cancer cells. The concentrations of choline, creatine, lactate, alanine, fumarate and succinate varied remarkably among different cell types.The significantly higher intracellular concentrations of glutathione, myo-inositol, and phosphocholine were found in the SKOV3 cell line relative to other cell lines. Glutamate is higher in both SKOV3 and RCC cells compared to other cell lines. For cell culture media analysis, isopropanol was found to be the highest in RCC media, followed by A549 and SKOV3 media, while acetone was the highest in A549, followed by RCC and SKOV3. These results demonstrated that 1H-NMR-based metabolic phenotyping approach allows us to characterize specific metabolic signatures of cancer cell lines and provides phenotypical information of cellular metabolism.

Journal article

Guo Y, Li Y, Zhang Y, Fang S, Xu X, Zhao A, Zhang J, Li J, Ma D, Jia W, Jiang Wet al., 2020, Post-operative delirium associated with metabolic alterations following hemi-arthroplasty in older patients, AGE AND AGEING, Vol: 49, Pages: 88-95, ISSN: 0002-0729

Journal article

Ritler D, Rufener R, Li JV, Kämpfer U, Müller J, Bühr C, Schürch S, Lundström-Stadelmann Bet al., 2019, In vitro metabolomic footprint of the Echinococcus multilocularis metacestode., Sci Rep, Vol: 9

Alveolar echinococcosis (AE) is a zoonotic disease that is deadly if left untreated. AE is caused by the larval metacestode stage of the cestode Echinococcus multilocularis. Better knowledge on the host-parasite interface could yield novel targets for improvement of the treatment against AE. We analyzed culture media incubated with in vitro grown E. multilocularis metacestodes by 1H nuclear magnetic resonance spectroscopy to identify the unknown metabolic footprint of the parasite. Moreover, we quantitatively analyzed all amino acids, acetate, glucose, lactate, and succinate in time-course experiments using liquid chromatography and enzymatic assays. The E. multilocularis metacestodes consumed glucose and, surprisingly, threonine and produced succinate, acetate, and alanine as major fermentation products. The metabolic composition of vesicle fluid (VF) from in vitro grown E. multilocularis metacestodes was different from parasite-incubated culture medium with respect to the abundance, but not the spectrum, of metabolites, and some metabolites, in particular amino acids, accumulated in the VF. Overall, this study presents the first characterization of the in vitro metabolic footprint of E. multilocularis metacestodes and VF composition, and it provides the basis for analyses of potentially targetable pathways for future drug development.

Journal article

Ocvirk S, Wilson AS, Posma JM, Li JV, Koller KR, Day GM, Flanagan CA, Otto JE, Sacco PE, Sacco FD, Sapp FR, Wilson AS, Newton K, Brouard F, DeLany JP, Behnning M, Appolonia CN, Soni D, Bhatti F, Methé B, Fitch A, Morris A, Gaskins HR, Kinross J, Nicholson JK, Thomas TK, O'Keefe SJDet al., 2019, A prospective cohort analysis of gut microbial co-metabolism in Alaska Native and rural African people at high and low risk of colorectal cancer, American Journal of Clinical Nutrition, Vol: 111, Pages: 406-419, ISSN: 0002-9165

BACKGROUND: Alaska Native (AN) people have the world's highest recorded incidence of sporadic colorectal cancer (CRC) (∼91:100,000), whereas rural African (RA) people have the lowest risk (<5:100,000). Previous data supported the hypothesis that diet affected CRC risk through its effects on the colonic microbiota that produce tumor-suppressive or -promoting metabolites. OBJECTIVES: We investigated whether differences in these metabolites may contribute to the high risk of CRC in AN people. METHODS: A cross-sectional observational study assessed dietary intake from 32 AN and 21 RA healthy middle-aged volunteers before screening colonoscopy. Analysis of fecal microbiota composition by 16S ribosomal RNA gene sequencing and fecal/urinary metabolites by 1H-NMR spectroscopy was complemented with targeted quantification of fecal SCFAs, bile acids, and functional microbial genes. RESULTS: Adenomatous polyps were detected in 16 of 32 AN participants, but not found in RA participants. The AN diet contained higher proportions of fat and animal protein and less fiber. AN fecal microbiota showed a compositional predominance of Blautia and Lachnoclostridium, higher microbial capacity for bile acid conversion, and low abundance of some species involved in saccharolytic fermentation (e.g., Prevotellaceae, Ruminococcaceae), but no significant lack of butyrogenic bacteria. Significantly lower concentrations of tumor-suppressive butyrate (22.5 ± 3.1 compared with 47.2 ± 7.3 SEM µmol/g) coincided with significantly higher concentrations of tumor-promoting deoxycholic acid (26.7 ± 4.2 compared with 11 ± 1.9 µmol/g) in AN fecal samples. AN participants had lower quantities of fecal/urinary metabolites than RA participants and metabolite profiles correlated with the abundance of distinct microbial genera in feces. The main microbial and metabolic CRC-associated markers were not significantly altered in

Journal article

Jukes CA, Ijaz UZ, Buckley A, Spencer J, Irvine J, Candlish D, Li J, Marchesi JR, Douce Get al., 2019, Bile salt metabolism is not the only factor contributing to Clostridioides (Clostridium) difficile disease severity in the murine model of disease, Gut Microbes, Vol: 11, Pages: 481-496, ISSN: 1949-0976

Susceptibility of patients to antibiotic-associated C. difficile disease is intimately associated with specific changes to gut microbiome composition. In particular, loss of microbes that modify bile salt acids (BSA) play a central role; primary bile acids stimulate spore germination whilst secondary bile acids limit C. difficile vegetative growth. To determine the relative contribution of bile salt (BS) metabolism on C. difficile disease severity, we treated mice with three combinations of antibiotics prior to infection. Mice given clindamycin alone became colonized but displayed no tissue pathology while severe disease, exemplified by weight loss and inflammatory tissue damage occurred in animals given a combination of five antibiotics and clindamycin. Animals given only the five antibiotic cocktails showed only transient colonization and no disease. C. difficile colonization was associated with a reduction in bacterial diversity, an inability to amplify bile salt hydrolase (BSH) sequences from fecal DNA and a relative increase in primary bile acids (pBA) in cecal lavages from infected mice. Further, the link between BSA modification and the microbiome was confirmed by the isolation of strains of Lactobacillus murinus that modified primary bile acids in vitro, thus preventing C. difficile germination. Interestingly, BSH activity did not correlate with disease severity which appeared linked to alternations in mucin, which may indirectly lead to increased exposure of the epithelial surface to inflammatory signals. These data confirm the role of microbial metabolic activity in protection of the gut and highlights the need for greater understanding the function of bacterial communities in disease prevention.

Journal article

Sabino AR, Tavares SS, Riffel A, Li J, Oliveira DJA, Feres CIMA, Henrique L, Oliveira JS, Correia GDS, Sabino AR, Nascimento TG, Hawkes G, Santana AEG, Holmes E, Bento ESet al., 2019, H-1 NMR metabolomic approach reveals chlorogenic acid as a response of sugarcane induced by exposure to Diatraea saccharalis, INDUSTRIAL CROPS AND PRODUCTS, Vol: 140, ISSN: 0926-6690

Journal article

Cameron SJS, Alexander JL, Bolt F, Burke A, Ashrafian H, Teare J, Marchesi JR, Kinross J, Li JV, Takats Zet al., 2019, Evaluation of direct from sample metabolomics of human feces using rapid evaporative ionization mass spectrometry, Analytical Chemistry, Vol: 91, Pages: 13448-13457, ISSN: 0003-2700

Mass spectrometry is a powerful tool in the investigation of the human fecal metabolome. However, current approaches require time-consuming sample preparation, chromatographic separations, and consequently long analytical run times. Rapid evaporative ionization mass spectrometry (REIMS) is a method of ambient ionization mass spectrometry and has been utilized in the metabolic profiling of a diverse range of biological materials, including human tissue, cell culture lines, and microorganisms. Here, we describe the use of an automated, high-throughput REIMS robotic platform for direct analysis of human feces. Through the analysis of fecal samples from five healthy male participants, REIMS analytical parameters were optimized and used to assess the chemical information obtainable using REIMS. Within the fecal samples analyzed, bile acids, including primary, secondary, and conjugate species, were identified, and phospholipids of possible bacterial origin were detected. In addition, the effect of storage conditions and consecutive freeze/thaw cycles was determined. Within the REIMS mass spectra, the lower molecular weight metabolites, such as fatty acids, were shown to be significantly affected by storage conditions for prolonged periods at temperatures above −80 °C and consecutive freeze/thaw cycles. However, the complex lipid region was shown to be unaffected by these conditions. A further cohort of 50 fecal samples, collected from patients undergoing bariatric surgery, were analyzed using the optimized REIMS parameters and the complex lipid region mass spectra used for multivariate modeling. This analysis showed a predicted separation between pre- and post-surgery specimens, suggesting that REIMS analysis can detect biological differences, such as microbiome-level differences, which have traditionally been reliant upon methods utilizing extensive sample preparations and chromatographic separations and/or DNA sequencing.

Journal article

Ferreira MR, Andreyev HJN, Mohammed K, Truelove L, Gowan SM, Li J, Gulliford SL, Marchesi JR, Dearnaley DPet al., 2019, Microbiota- and Radiotherapy-Induced Gastrointestinal Side-Effects (MARS) Study: A Large Pilot Study of the Microbiome in Acute and Late-Radiation Enteropathy, CLINICAL CANCER RESEARCH, Vol: 25, Pages: 6487-6500, ISSN: 1078-0432

Journal article

Nahok K, Li JV, Phetcharaburanin J, Abdul H, Wongkham C, Thanan R, Silsirivanit A, Anutrakulchai S, Selmi C, Cha'on Uet al., 2019, Monosodium Glutamate (MSG) renders alkalinizing properties and Its urinary metabolic markers of MSG consumption in rats, Biomolecules, Vol: 9, ISSN: 2218-273X

Monosodium glutamate (MSG) is widely used as a flavor enhancer and its effects on human health are still debated. We aimed to investigate whether MSG can act as alkalinizing agent in murine models and if its metabolites are biomarkers of MSG consumption. For this purpose, adult male Wistar rats were given water added with 1 g% MSG or three types of control water, including sodium chloride (NaCl) and sodium bicarbonate (NaHCO3). At 14 days, urinary pH, electrolytes, urinary metabolites and ion-exchanger gene expression were determined. The results revealed that MSG-treated rats had significantly more alkaline urine and higher levels of urinary sodium and bicarbonate similar to NaHCO3 controls. These changes correlated with a lower expression of ion-exchanger genes, namely, CAII, NBC1, and AE1, which are involved in bicarbonate kidney reabsorption. The urinary metabolic profiles also revealed similar patterns for the MSG and NaHCO3 groups. In conclusion, MSG exhibits similar properties to NaHCO3, an alkalinizing agent, with regard to inducing alkaline urine, reducing bicarbonate kidney reabsorption, and generating a specific urinary metabolic pattern. We believe that these observations will be useful to further study the MSG effects in humans.

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, Vol: 71, Pages: 1313-1324, 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

McDonald JAK, Mullish BH, Pechlivanis A, Liu Z, Brignardello J, Kao D, Holmes E, Li JV, Clarke TB, Thursz MR, Marchesi JRet al., 2018, Inhibiting growth of clostridioides difficile by restoring valerate, produced by the intestinal microbiota, Gastroenterology, Vol: 155, Pages: 1495-1507.e15, ISSN: 0016-5085

Background & AimsFecal microbiota transplantation (FMT) is effective for treating recurrent Clostridioides difficile infection (CDI), but there are concerns about its long-term safety. Understanding the mechanisms of the effects of FMT could help us design safer, targeted therapies. We aimed to identify microbial metabolites that are important for C difficile growth.MethodsWe used a CDI chemostat model as a tool to study the effects of FMT in vitro. The following analyses were performed: C difficile plate counts, 16S rRNA gene sequencing, 1H-NMR spectroscopy, and UPLC mass spectrometry bile acid profiling. FMT mixtures were prepared using fresh fecal samples provided by donors enrolled in an FMT program in the United Kingdom. Results from chemostat experiments were validated using human stool samples, C difficile batch cultures, and C57BL/6 mice with CDI. Human stool samples were collected from 16 patients with recurrent CDI and healthy donors (n=5) participating in an FMT trial in Canada.ResultsIn the CDI chemostat model, clindamycin decreased valerate and deoxycholic acid concentrations and increased C difficile total viable counts (TVC) and valerate precursors, taurocholic acid, and succinate concentrations. After we stopped adding clindamycin, levels of bile acids and succinate recovered, whereas levels of valerate and valerate precursors did not. In the CDI chemostat model, FMT increased valerate concentrations and decreased C difficile TVC (94% reduction), spore counts (86% reduction), and valerate precursor concentrations—concentrations of bile acids were unchanged. In stool samples from patients with CDI, valerate was depleted before FMT, but restored after FMT. C difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid is required for germination but had no effect on vegetative growth. C difficile TVC were decreased by 95% in mice with CDI given glycerol trivalerate compared to phosphate-buffered sali

Journal article

Li JV, 2018, Functional Microbiomics, Methods, Vol: 149, Pages: 1-2, ISSN: 1046-2023

Journal article

Liu Z, Xia B, Saric J, Utzinger J, Holmes E, Keiser J, Li JVet al., 2018, Effects of vancomycin and ciprofloxacin on the NMRI mouse metabolism, Journal of Proteome Research, Vol: 17, Pages: 3565-3573, ISSN: 1535-3893

The reduction in gut microbiota diversity is associated with a range of human diseases. Overuse of antibiotics has been associated with a diminished gut-microbial diversity in humans and may promote microbiota-associated negative effects to physical health, such as the metabolic syndrome-cluster of diseases and mental illnesses. There is a pressing need to deepen the understanding of the effects of antibiotics at the biochemical level. The current study investigated metabolic effects of two widely prescribed antibiotics–vancomycin and ciprofloxacin–on biofluids and brain tissue samples of NMRI female mice using a 1H nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling approach. While both antibiotics significantly affected the host metabolic signatures of urine and feces, only ciprofloxacin induced metabolic changes in plasma. Metabolic perturbations were pronounced 1 day post-treatment, reverting back to baseline at day 20 post-treatment. Both antibiotics induced changes in the choline metabolism, host-microbial cometabolites, short chain fatty acid production, and protein/purine degradation. The metabolic profiles of brain tissue aqueous extracts did not show any antibiotics-related changes by day 20 post-treatment. The data suggest that the metabolic disruptions in biofluids caused by antibiotics are reversed by day 20 post-treatment when compared to the pre-treatment profiles.

Journal article

McDonald JAK, Mullish BH, Pechlivanis A, Liu Z, Brignardello J, Kao D, Holmes E, Li JV, Clarke TB, Thursz MR, Marchesi JRet al., 2018, A novel route for controlling Clostridioides difficile growth via bile acid and short chain fatty acid modulation, ISME17

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

Li JV, Saric J, Sabrina D, 2018, 1H NMR-based Metabolic Profiling in Infectious Disease Research, NMR-based Metabolomics, Editors: Keun, Publisher: Royal Society of Chemistry, ISBN: 9781849736435

This chapter highlights the application of 1H NMR spectroscopy-based metabolic profiling in infection research, specifically on HIV/AIDS, tuberculosis, malaria and the neglected tropical diseases, such as Schistosomiasis. We describe the use of this approach to investigate the metabolic responses of the host to infectious agents in both in vivo and in vitro models, as well in natural human infections. These metabolic signatures hold significant promise in leading to early and robust diagnosis of a range infectious diseases, including parasitic infections, where often a unique set of metabolites has been found to be associated with infection. In addition, metabolic profiling, together with measures of immune responses and gut microbial composition, provides mechanistic insight into the pathogen–host interactions through the immune–gut microbiota–metabolic axis.

Book chapter

Vorkas PA, Abellona U MR, Li JV, 2018, Tissue Multiplatform-Based Metabolomics/Metabonomics for Enhanced Metabolome Coverage., Pages: 239-260

The use of tissue as a matrix to elucidate disease pathology or explore intervention comes with several advantages. It allows investigation of the target alteration directly at the focal location and facilitates the detection of molecules that could become elusive after secretion into biofluids. However, tissue metabolomics/metabonomics comes with challenges not encountered in biofluid analyses. Furthermore, tissue heterogeneity does not allow for tissue aliquoting. Here we describe a multiplatform, multi-method workflow which enables metabolic profiling analysis of tissue samples, while it can deliver enhanced metabolome coverage. After applying a dual consecutive extraction (organic followed by aqueous), tissue extracts are analyzed by reversed-phase (RP-) and hydrophilic interaction liquid chromatography (HILIC-) ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS) and nuclear magnetic resonance (NMR) spectroscopy. This pipeline incorporates the required quality control features, enhances versatility, allows provisional aliquoting of tissue extracts for future guided analyses, expands the range of metabolites robustly detected, and supports data integration. It has been successfully employed for the analysis of a wide range of tissue types.

Book chapter

Glaysher M, Mohanaruban A, Prechtl CG, Goldstone AP, Miras AD, Lord J, Chhina N, Falaschetti E, Johnson NA, Al-Najim W, smith C, Li JV, Patel M, Ahmed AR, Moore M, Poulter NR, Bloom S, Darzi A, Le Roux C, Byrne JP, teare Jet al., 2017, A randomised controlled trial of a duodenal-jejunal bypass sleeve device (EndoBarrier) compared with standard medical therapy for the management of obese subjects with type 2 diabetes mellitus, BMJ Open, Vol: 7, ISSN: 2044-6055

Introduction The prevalence of obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), is increasing. Exclusion of the foregut, as occurs in Roux-en-Y gastric bypass, has a key role in the metabolic improvements that occur following bariatric surgery, which are independent of weight loss. Endoscopically placed duodenal-jejunal bypass sleeve devices, such as the EndoBarrier (GI Dynamics, Lexington, Massachusetts, USA), have been designed to create an impermeable barrier between chyme exiting the stomach and the mucosa of the duodenum and proximal jejunum. The non-surgical and reversible nature of these devices represents an attractive therapeutic option for patients with obesity and T2DM by potentially improving glycaemic control and reducing their weight.Methods and analysis In this multicentre, randomised, controlled, non-blinded trial, male and female patients aged 18–65 years with a body mass index 30–50 kg/m2 and inadequately controlled T2DM on oral antihyperglycaemic medications (glycosylated haemoglobin (HbA1c) 58–97 mmol/mol) will be randomised in a 1:1 ratio to receive either the EndoBarrier device (n=80) for 12 months or conventional medical therapy, diet and exercise (n=80). The primary outcome measure will be a reduction in HbA1c by 20% at 12 months. Secondary outcome measures will include percentage weight loss, change in cardiovascular risk factors and medications, quality of life, cost, quality-adjusted life years accrued and adverse events. Three additional subgroups will investigate the mechanisms behind the effect of the EndoBarrier device, looking at changes in gut hormones, metabolites, bile acids, microbiome, food hedonics and preferences, taste, brain reward system responses to food, eating and addictive behaviours, body fat content, insulin sensitivity, and intestinal tissue gene expression.

Journal article

Anwar MA, Adesina-Georgiadis KN, Spagou K, Vorkas PA, Li JV, Shalhoub J, Holmes E, Davies AHet al., 2017, A comprehensive characterisation of the metabolic profile of varicose veins; implications in elaborating plausible cellular pathways for disease pathogenesis, Scientific Reports, Vol: 7, ISSN: 2045-2322

Metabolic phenotypes reflect both the genetic and environmental factors which contribute to the development of varicose veins (VV). This study utilises analytical techniques to provide a comprehensive metabolic picture of VV disease, with the aim of identifying putative cellular pathways of disease pathogenesis. VV (n = 80) and non-VV (n = 35) aqueous and lipid metabolite extracts were analysed using 600 MHz 1H Nuclear Magnetic Resonance spectroscopy and Ultra-Performance Liquid Chromatography Mass Spectrometry. A subset of tissue samples (8 subjects and 8 controls) were analysed for microRNA expression and the data analysed with mirBase (www.mirbase.org). Using Multivariate statistical analysis, Ingenuity pathway analysis software, DIANALAB database and published literature, the association of significant metabolites with relevant cellular pathways were understood. Higher concentrations of glutamate, taurine, myo-inositol, creatine and inosine were present in aqueous extracts and phosphatidylcholine, phosphatidylethanolamine and sphingomyelin in lipid extracts in the VV group compared with non-VV group. Out of 7 differentially expressed miRNAs, spearman correlation testing highlighted correlation of hsa-miR-642a-3p, hsa-miR-4459 and hsa-miR-135a-3p expression with inosine in the vein tissue, while miR-216a-5p, conversely, was correlated with phosphatidylcholine and phosphatidylethanolamine. Pathway analysis revealed an association of phosphatidylcholine and sphingomyelin with inflammation and myo-inositol with cellular proliferation.

Journal article

O'Hagan C, Li JV, Marchesi JR, Plummer S, Garaiova I, Good MAet al., 2017, Long-term multi-species Lactobacillus and Bifidobacterium dietary supplement enhances memory and changes regional brain metabolites in middle-aged rats, Neurobiology of Learning and Memory, Vol: 144, Pages: 36-47, ISSN: 1095-9564

Ageing is associated with changes in the gut microbiome that may contribute to age-related changes in cognition. Previous work has shown that dietary supplements with multi-species live microorganisms can influence brain function, including induction of hippocampal synaptic plasticity and production of brain derived neurotrophic factor, in both young and aged rodents. However, the effect of such dietary supplements on memory processes has been less well documented, particularly in the context of aging. The main aim of the present study was to examine the impact of a long-term dietary supplement with a multi-species live Lactobacillus and Bifidobacteria mixture (Lactobacillus acidophilus CUL60, L. acidophilus CUL21, Bifidobacterium bifidum CUL20 and B. lactis CUL34) on tests of memory and behavioural flexibility in 15–17-month-old male rats. Following behavioural testing, the hippocampus and prefrontal cortex was extracted and analysed ex vivo using 1H nuclear magnetic resonance (1H NMR) spectroscopy to examine brain metabolites. The results showed a small beneficial effect of the dietary supplement on watermaze spatial navigation and robust improvements in long-term object recognition memory and short-term memory for object-in-place associations. Short–term object novelty and object temporal order memory was not influenced by the dietary supplement in aging rats. 1H NMR analysis revealed diet-related regional-specific changes in brain metabolites; which indicated changes in several pathways contributing to modulation of neural signaling. These data suggest that chronic dietary supplement with multi-species live microorganisms can alter brain metabolites in aging rats and have beneficial effects on memory.

Journal article

Li JV, Swann J, Marchesi JR, 2017, Biology of the Microbiome 2: Metabolic Role, Gastroenterology Clinics of North America, Vol: 46, Pages: 37-47, ISSN: 0889-8553

The human microbiome is a new frontier in biology and one that is helping to define what it is to be human. Recently, we have begun to understand that the “communication” between the host and its microbiome is via a metabolic superhighway. By interrogating and understanding the molecules involved we may start to know who the main players are, and how we can modulate them and the mechanisms of health and disease.

Journal article

Anwar MA, Vorkas PA, Li J, Adesina-Georgiadis KN, Reslan OM, Raffetto JD, Want EJ, Khalil RA, Holmes E, Davies AHet al., 2016, Prolonged Mechanical Circumferential Stretch Induces Metabolic Changes in Rat Inferior Vena Cava, EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY, Vol: 52, Pages: 544-552, ISSN: 1078-5884

Journal article

Hodgson DM, Smith A, Dahale S, Stratford JP, Li JV, Grüning A, Bushell ME, Marchesi JR, Avignone Rossa Cet al., 2016, Segregation of the Anodic Microbial Communities in a Microbial Fuel Cell Cascade., Frontiers in Microbiology, Vol: 7, Pages: 699-699, ISSN: 1664-302X

Metabolic interactions within microbial communities are essential for the efficient degradation of complex organic compounds, and underpin natural phenomena driven by microorganisms, such as the recycling of carbon-, nitrogen-, and sulfur-containing molecules. These metabolic interactions ultimately determine the function, activity and stability of the community, and therefore their understanding would be essential to steer processes where microbial communities are involved. This is exploited in the design of microbial fuel cells (MFCs), bioelectrochemical devices that convert the chemical energy present in substrates into electrical energy through the metabolic activity of microorganisms, either single species or communities. In this work, we analyzed the evolution of the microbial community structure in a cascade of MFCs inoculated with an anaerobic microbial community and continuously fed with a complex medium. The analysis of the composition of the anodic communities revealed the establishment of different communities in the anodes of the hydraulically connected MFCs, with a decrease in the abundance of fermentative taxa and a concurrent increase in respiratory taxa along the cascade. The analysis of the metabolites in the anodic suspension showed a metabolic shift between the first and last MFC, confirming the segregation of the anodic communities. Those results suggest a metabolic interaction mechanism between the predominant fermentative bacteria at the first stages of the cascade and the anaerobic respiratory electrogenic population in the latter stages, which is reflected in the observed increase in power output. We show that our experimental system represents an ideal platform for optimization of processes where the degradation of complex substrates is involved, as well as a potential tool for the study of metabolic interactions in complex microbial communities.

Journal article

Phetcharaburanin J, Lees H, Marchesi JR, Nicholson JK, Holmes E, Seyfried F, Li JVet al., 2016, Systemic Characterization of an Obese Phenotype in the Zucker Rat Model Defining Metabolic Axes of Energy Metab-olism and Host-Microbial Interactions, Journal of Proteome Research, Vol: 15, Pages: 1897-1906, ISSN: 1535-3907

The Zucker (fa/fa) rat is a valuable and extensively utilized model for obesity research. However, the metabolicnetworks underlying the systemic response in the obese Zucker rats remain to be elucidated. This information is importantto further our understanding of the circulation of the microbial or host-microbial metabolites and their impact on hostmetabolism. 1H Nuclear Magnetic Resonance spectroscopy-based metabolic profiling was used to probe global metabolicdifferences in portal vein and peripheral blood plasma, urine and fecal water between obese (fa/fa, n=12) and lean (fa/+,n=12) Zucker rats. Urinary concentrations of host-microbial co-metabolites were found to be significantly higher in leanZucker rats. Higher concentrations of fecal lactate, short chain fatty acids (SCFAs), 3-hydroxyphenyl propionic acid andglycerol, and lower levels of valine and glycine were observed in obese rats compared with lean animals. Regardless ofphenotype, concentrations of SCFAs, tricarboxylic acid cycle intermediates, and choline metabolites were higher in portalvein blood compared to peripheral blood. However, higher levels of succinate, phenylalanine and tyrosine were observedin portal vein blood compared with peripheral blood from lean rats but not in obese rats. Our findings indicate that theabsorption of propionate and acetate, choline and TMA are independent of the Zucker rat phenotypes. However, urinaryhost-microbial co-metabolites were highly associated with phenotypes, suggesting distinct gut microbial metabolic activitiesin lean and obese Zucker rats. This work advances our understanding of metabolic processes associated with obesity,particularly the metabolic functionality of the gut microbiota in the context of obesity.

Journal article

Gratton J, Phetcharaburanin J, Mullish BH, Williams HRT, Thursz M, Nicholson JK, Holmes E, Marchesi JR, Li Jet al., 2016, An optimized sample handling strategy for metabolic profiling of human feces, Analytical Chemistry, Vol: 88, Pages: 4661-4668, ISSN: 0003-2700

Fecal metabolites are being increasingly studied to unravel the host-gut microbial metabolic interactions. However, there are currently no guidelines for fecal sample collection and storage based on a systematic evaluation of the effect of time, storage temperature, storage duration and sampling strategy. Here we derive an optimized protocol for fecal sample handling with the aim of maximizing metabolic stability and minimizing sample degradation. Samples obtained from five healthy individuals were analyzed to assess topographical homogeneity of feces, and to evaluate storage duration-, temperature- and freeze-thaw cycle-induced metabolic changes in crude stool and fecal water using a 1H NMR spectroscopy-based metabolic profiling approach. Inter-individual variation was much greater than that attributable to storage conditions. Individual stool samples were found to be heterogeneous and spot sampling resulted in a high degree of metabolic variation. Crude fecal samples were remarkably unstable over time and exhibited distinct metabolic profiles at different storage temperatures. Microbial fermentation was the dominant driver in time-related changes observed in fecal samples stored at room temperature and this fermentative process was reduced when stored at 4°C. Crude fecal samples frozen at -20°C manifested elevated amino acids and nicotinate and depleted short chain fatty acids compared to crude fecal control samples. The relative concentrations of branched-chain and aromatic amino acids significantly increased in the freeze-thawed crude fecal samples, suggesting a release of microbial intracellular contents. The metabolic profiles of fecal water samples were more stable compared to crude samples. Our recommendation is that intact fecal samples should be collected, kept at 4°C or on ice during transportation, and extracted ideally within 1 h of collection, or a maximum of 24 h. Fecal water samples should be extracted from a representative amount (~15 g)

Journal article

Holmes E, Nicholson JK, Li J, Darzi AWet al., 2016, Phenotyping the patient journey, Metabolic Phenotyping in Personalized and Public Healthcare, Pages: 49-74, ISBN: 9780128003442

© 2016 Elsevier Inc. All rights reserved. This chapter describes the concept of the patient journey, that is, the various interactions between a patient and a medical team as the patient first encounters the system, is diagnosed, treated, and followed up after whatever course of action was deemed appropriate. The various bottlenecks in the process are explained. As a new paradigm, the role of metabolic phenotyping (metabotyping) in monitoring the patient journey is discussed and examples are provided. The potential of such metabolic phenotyping in the clinic has implications in terms of stratified or personalized medicine, including adding information to aid diagnosis or to allow better prognosis, and these implications are listed. Finally, one example of the process, a dedicated phenome center, is illustrated.

Book chapter

Li JV, nicholson J, holmes E, darzi Aet al., 2016, Chapter 3 - Phenotyping the Patient Journey, Metabolic Phenotyping in Personalized and Public Healthcare, Publisher: Academic Press, ISBN: 9780128004142

HEALTHCARE. EDTED BY Elaine Holmes, Head of Computational and Systems Medicine Professor of Chemical ... Metabolic Phenotyping in Personalized and Public Healthcare authoritatively evaluates metabolic profiling and its uses&nbsp;...

Book chapter

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