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1. High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy of Paired Clinical Liver Tissue Samples from Hepatocellular Cancer and Surrounding Region.

Author

Fernandes, Wendy M., Harris, Nicola, Zamalloa, Ane, Adofina, Lissette, Srinivasan, Parthi, Menon, Krishna, Heaton, Nigel, Miquel, Rosa, Zen, Yoh, Kelly, Geoff, Jarvis, James A., Oregioni, Alain, Chokshi, Shilpa, Riva, Antonio, and Cox, I. Jane

Subjects
MAGIC angle spinning, NUCLEAR magnetic resonance, BACTERIAL metabolites, HEPATOCELLULAR carcinoma, LIVER cancer
Abstract

The global burden of liver cancer is increasing. Timely diagnosis is important for optimising the limited available treatment options. Understanding the metabolic consequences of hepatocellular carcinoma (HCC) may lead to more effective treatment options. We aimed to document metabolite differences between HCC and matched surrounding tissues of varying aetiology, obtained at the time of liver resection, and to interpret metabolite changes with clinical findings. High-resolution magic angle spinning nuclear magnetic resonance (HRMAS-NMR) spectroscopy analyses of N = 10 paired HCC and surrounding non-tumour liver tissue samples were undertaken. There were marked HRMAS-NMR differences in lipid levels in HCC tissue compared to matched surrounding tissue and more subtle changes in low-molecular-weight metabolites, particularly when adjusting for patient-specific variability. Differences in lipid-CH3, lipid-CH2, formate, and acetate levels were of particular interest. The obvious differences in lipid content highlight the intricate interplay between metabolic adaptations and cancer cell survival in the complex microenvironment of liver cancer. Differences in formate and acetate might relate to bacterial metabolites. Therefore, documentation of metabolites in HCC tissue according to histology findings in patients is of interest for personalised medicine approaches and for tailoring targeted treatment strategies. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Rat liver extracellular matrix and perfusion bioreactor culture promote human amnion epithelial cell differentiation towards hepatocyte-like cells

Author

Campinoti, Sara, Almeida, Bruna, Goudarzi, Negin, Bencina, Stefan, Grundland Freile, Fabio, McQuitty, Claire, Natarajan, Dipa, Cox, I. Jane, Le Guennec, Adrien, Khati, Vamakshi, Gaudenzi, Giulia, Gramignoli, Roberto, Urbani, Luca, Campinoti, Sara, Almeida, Bruna, Goudarzi, Negin, Bencina, Stefan, Grundland Freile, Fabio, McQuitty, Claire, Natarajan, Dipa, Cox, I. Jane, Le Guennec, Adrien, Khati, Vamakshi, Gaudenzi, Giulia, Gramignoli, Roberto, and Urbani, Luca

Abstract

Congenital and chronic liver diseases have a substantial health burden worldwide. The most effective treatment available for these patients is whole organ transplantation; however, due to the severely limited supply of donor livers and the side effects associated with the immunosuppressive regimen required to accept allograft, the mortality rate in patients with end-stage liver disease is annually rising. Stem cell-based therapy aims to provide alternative treatments by either cell transplantation or bioengineered construct transplantation. Human amnion epithelial cells (AEC) are a widely available, ethically neutral source of cells with the plasticity and potential of multipotent stem cells and immunomodulatory properties of perinatal cells. AEC have been proven to be able to achieve functional improvement towards hepatocyte-like cells, capable of rescuing animals with metabolic disorders; however, they showed limited metabolic activities in vitro. Decellularised extracellular matrix (ECM) scaffolds have gained recognition as adjunct biological support. Decellularised scaffolds maintain native ECM components and the 3D architecture instrumental of the organ, necessary to support cells’ maturation and function. We combined ECM-scaffold technology with primary human AEC, which we demonstrated being equipped with essential ECM-adhesion proteins, and evaluated the effects on AEC differentiation into functional hepatocyte-like cells (HLC). This novel approach included the use of a custom 4D bioreactor to provide constant oxygenation and media perfusion to cells in 3D cultures over time. We successfully generated HLC positive for hepatic markers such as ALB, CYP3A4 and CK18. AEC-derived HLC displayed early signs of hepatocyte phenotype, secreted albumin and urea, and expressed Phase-1 and -2 enzymes. The combination of liver-specific ECM and bioreactor provides a system able to aid differentiation into HLC, indicating that the innovative perfusion ECM-scaffold technology, QC 20240115

Published
2023
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4. Rat liver extracellular matrix and perfusion bioreactor culture promote human amnion epithelial cell differentiation towards hepatocyte-like cells

Author

Campinoti, Sara, primary, Almeida, Bruna, additional, Goudarzi, Negin, additional, Bencina, Stefan, additional, Grundland Freile, Fabio, additional, McQuitty, Claire, additional, Natarajan, Dipa, additional, Cox, I Jane, additional, Le Guennec, Adrien, additional, Khati, Vamakshi, additional, Gaudenzi, Giulia, additional, Gramignoli, Roberto, additional, and Urbani, Luca, additional

Published
2023
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6. Mapping of population disparities in the cholangiocarcinoma urinary metabolome

Author

Alsaleh, Munirah, primary, Leftley, Zoe, additional, O’Connor, Thomas, additional, Hughes, Thomas, additional, Barbera, Thomas A., additional, Koomson, Larry K., additional, Zabron, Abigail, additional, Reeves, Helen, additional, Cramp, Matthew, additional, Ryder, Stephen D., additional, Greer, Shaun, additional, Prince, Martin, additional, Sithithaworn, Paiboon, additional, Khuntikeo, Narong, additional, Loilome, Watcharin, additional, Yongvanit, Puangrat, additional, Cox, I. Jane, additional, Williams, Roger, additional, Wadsworth, Christopher A., additional, Holmes, Elaine, additional, Nash, Kathryn, additional, Andrews, Ross, additional, and Taylor-Robinson, Simon D., additional

Published
2021
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7. Chronically elevated branched chain amino acid levels are pro-arrhythmic

Author

Portero, Vincent, Nicol, Thomas, Podliesna, Svitlana, Marchal, Gerard A., Baartscheer, Antonius, Casini, Simona, Tadros, Rafik, Treur, Jorien L., Tanck, Michael W.T., Cox, I. Jane, Probert, Fay, Hough, Tertius A., Falcone, Sara, Beekman, Leander, Müller-Nurasyid, Martina, Kastenmüller, Gabi, Gieger, Christian, Peters, Annette, Kääb, Stefan, Sinner, Moritz F., Blease, Andrew, Verkerk, Arie O., Bezzina, Connie R., Potter, Paul K., Remme, Carol Ann, Portero, Vincent, Nicol, Thomas, Podliesna, Svitlana, Marchal, Gerard A., Baartscheer, Antonius, Casini, Simona, Tadros, Rafik, Treur, Jorien L., Tanck, Michael W.T., Cox, I. Jane, Probert, Fay, Hough, Tertius A., Falcone, Sara, Beekman, Leander, Müller-Nurasyid, Martina, Kastenmüller, Gabi, Gieger, Christian, Peters, Annette, Kääb, Stefan, Sinner, Moritz F., Blease, Andrew, Verkerk, Arie O., Bezzina, Connie R., Potter, Paul K., and Remme, Carol Ann

Abstract

Aims. Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and results. We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions. Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulatio

Published
2021

8. Chronically elevated branched chain amino acid levels are pro-arrhythmic

Author

Portero, Vincent, primary, Nicol, Thomas, additional, Podliesna, Svitlana, additional, Marchal, Gerard A, additional, Baartscheer, Antonius, additional, Casini, Simona, additional, Tadros, Rafik, additional, Treur, Jorien L, additional, Tanck, Michael W T, additional, Cox, I Jane, additional, Probert, Fay, additional, Hough, Tertius A, additional, Falcone, Sara, additional, Beekman, Leander, additional, Müller-Nurasyid, Martina, additional, Kastenmüller, Gabi, additional, Gieger, Christian, additional, Peters, Annette, additional, Kääb, Stefan, additional, Sinner, Moritz F, additional, Blease, Andrew, additional, Verkerk, Arie O, additional, Bezzina, Connie R, additional, Potter, Paul K, additional, and Remme, Carol Ann, additional

Published
2021
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9. Chronically elevated branched chain amino acid levels are pro-arrhythmic.

Author

Portero, Vincent, Nicol, Thomas, Podliesna, Svitlana, Marchal, Gerard A, Baartscheer, Antonius, Casini, Simona, Tadros, Rafik, Treur, Jorien L, Tanck, Michael W T, Cox, I Jane, Probert, Fay, Hough, Tertius A, Falcone, Sara, Beekman, Leander, Müller-Nurasyid, Martina, Kastenmüller, Gabi, Gieger, Christian, Peters, Annette, Kääb, Stefan, and Sinner, Moritz F

Subjects
BRANCHED chain amino acids, AMINOTRANSFERASES, CARDIAC arrest, HEART failure, SUDDEN death, ARRHYTHMIA, NONSENSE mutation
Abstract

Aims Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and results We employed a phenotype-driven N -ethyl- N -nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2 p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2 p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2 p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure. [ABSTRACT FROM AUTHOR]

Published
2022
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10. A Double-Blind, Randomized Placebo-Controlled Trial of Probiotic Lactobacillus casei Shirota in Stable Cirrhotic Patients

Author

Macnaughtan, Jane, primary, Figorilli, Francesco, additional, García-López, Elisabet, additional, Lu, Haw, additional, Jones, Helen, additional, Sawhney, Rohit, additional, Suzuki, Kaori, additional, Fairclough, Sarah, additional, Marsden, Joanne, additional, Moratalla, Alba, additional, Cox, I. Jane, additional, Thomas, Linda, additional, Davies, Nathan, additional, Williams, Roger, additional, Mookerjee, Raj, additional, Wright, Gavin, additional, and Jalan, Rajiv, additional

Published
2020
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11. Characterisation of the Serum Metabolic Signature of Cholangiocarcinoma in a United Kingdom Cohort

Author

Alsaleh, Munirah, primary, Leftley, Zoe, additional, Barbera, Thomas A., additional, Koomson, Larry K., additional, Zabron, Abigail, additional, Crossey, Mary M.E., additional, Reeves, Helen L., additional, Cramp, Matthew, additional, Ryder, Stephen, additional, Greer, Shaun, additional, Prince, Martin, additional, Sithithaworn, Paiboon, additional, Shariff, Mohamed, additional, Khuntikeo, Narong, additional, Loilome, Watcharin, additional, Yongvanit, Puangrat, additional, Shen, Yi-Liang, additional, Cox, I. Jane, additional, Williams, Roger, additional, Wadsworth, Christopher A., additional, Holmes, Elaine, additional, Nash, Kathryn, additional, and Taylor-Robinson, Simon D., additional

Published
2020
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13. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Kassam, Zain, Gurry, Thomas Jerome, Alm, Eric J, Bajaj, Jasmohan S., Fagan, Andrew, Gavis, Edith A., Liu, Eric, Cox, I. Jane, Kheradman, Raffi, Heuman, Douglas, Wang, Jessica, Williams, Roger, Sikaroodi, Masoumeh, Fuchs, Michael, John, Binu, Thacker, Leroy R., Riva, Antonio, Smith, Mark, Taylor-Robinson, Simon D., Gillevet, Patrick M, Massachusetts Institute of Technology. Department of Biological Engineering, Kassam, Zain, Gurry, Thomas Jerome, Alm, Eric J, Bajaj, Jasmohan S., Fagan, Andrew, Gavis, Edith A., Liu, Eric, Cox, I. Jane, Kheradman, Raffi, Heuman, Douglas, Wang, Jessica, Williams, Roger, Sikaroodi, Masoumeh, Fuchs, Michael, John, Binu, Thacker, Leroy R., Riva, Antonio, Smith, Mark, Taylor-Robinson, Simon D., and Gillevet, Patrick M

Abstract

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusion: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. Keywords: Cirrhosis; Dysbiosis; Hospitalizations; Metabolomics; Stroop App

Published
2019

14. Cholangiocarcinoma: a guide for the nonspecialist

Author

Alsaleh,Munirah, Leftley,Zoe, Barbera,Thomas A., Sithithaworn,Paiboon, Khuntikeo,Narong, Loilome,Watcharin, Yongvanit,Puangrat, Cox,I Jane, Chamodol,Nittaya, Syms,Richard R.A., Andrews,Ross H., and Taylor-Robinson,Simon D.

Subjects
International Journal of General Medicine
Abstract

Munirah Alsaleh,1 Zoe Leftley,1 Thomas A Barbera,1 Paiboon Sithithaworn,2 Narong Khuntikeo,2 Watcharin Loilome,2 Puangrat Yongvanit,2 I Jane Cox,3 Nittaya Chamodol,2 Richard RA Syms,4 Ross H Andrews,1,2 Simon D Taylor-Robinson1 1Division of Surgery and Cancer, Imperial College London, London W2 INY, UK; 2Cholangiocarcinoma Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; 3Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NT, UK; 4Department of Electrical and Electronic Engineering, Imperial College London, London SW7 2AZ, UK Abstract: Cholangiocarcinoma (CCA) is a tumor with increasing prevalence around the world. The prevalence of CCA is highest in East Asia and most significantly in the countries through which the Mekong River flows, owing to the presence of liver flukes, which are consumed in raw fish dishes. Outside Asia, the causes of bile duct cancers for the most part are unknown. In this review, we assess the current state of knowledge in both fluke-associated and sporadic CCA, from etiological, diagnostic, and treatment perspectives. Keywords: cholangiocarcinoma, etiology, diagnosis, treatment, bile ducts

Published
2018

15. Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis

Author

Bajaj, Jasmohan S., primary, Salzman, Nita, additional, Acharya, Chathur, additional, Takei, Hajime, additional, Kakiyama, Genta, additional, Fagan, Andrew, additional, White, Melanie B., additional, Gavis, Edith A., additional, Holtz, Mary L., additional, Hayward, Michael, additional, Nittono, Hiroshi, additional, Hylemon, Phillip B., additional, Cox, I. Jane, additional, Williams, Roger, additional, Taylor-Robinson, Simon D., additional, Sterling, Richard K., additional, Matherly, Scott C., additional, Fuchs, Michael, additional, Lee, Hannah, additional, Puri, Puneet, additional, Stravitz, R. Todd, additional, Sanyal, Arun J., additional, Ajayi, Lola, additional, Le Guennec, Adrien, additional, Atkinson, R. Andrew, additional, Siddiqui, Mohammad S., additional, Luketic, Velimir, additional, Pandak, William M., additional, Sikaroodi, Masoumeh, additional, and Gillevet, Patrick M., additional

Published
2019
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16. Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn's disease

Author

Taylor-Robinson Simon D, Cobbold Jeremy FL, Walker David G, Cox I Jane, Williams Horace RT, Marshall Sara E, and Orchard Timothy R

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background Certain urinary metabolites are the product of gut microbial or mammalian metabolism; others, such as hippurate, are mammalian-microbial 'co-metabolites'. It has previously been observed that Crohn's disease (CD) patients excrete significantly less hippurate than controls. There are two stages in the biosynthesis of this metabolite: 1) gut microbial metabolism of dietary aromatic compounds to benzoate, and 2) subsequent hepatorenal conjugation of benzoate with glycine, forming hippurate. Differences in such urinary co-metabolites may therefore reflect systemic consequences of altered gut microbial metabolism, though altered host metabolic pathways may also be involved. Methods It was hypothesised that reduced hippurate excretion in CD patients was due to alterations in the gut microbiota, and not differences in dietary benzoate, nor defective host enzymatic conjugation of benzoate. 5 mg/kg sodium benzoate were administered orally to 16 CD patients and 16 healthy controls on a low-benzoate diet. Baseline and peak urinary hippurate excretion were measured. Results Baseline hippurate levels were significantly lower in the CD patients (p = 0.0009). After benzoate ingestion, peak urinary levels of hippurate did not differ significantly between the cohorts. Consequently the relative increase in excretion was significantly greater in CD (p = 0.0007). Conclusions Lower urinary hippurate levels in CD are not due to differences in dietary benzoate. A defect in the enzymatic conjugation of benzoate in CD has been excluded, strongly implicating altered gut microbial metabolism as the cause of decreased hippurate levels in CD.

Published
2010
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18. The Plasma and Serum Metabotyping of Hepatocellular Carcinoma in a Nigerian and Egyptian Cohort using Proton Nuclear Magnetic Resonance Spectroscopy

Author

Shariff, Mohamed I.F., primary, Kim, Jin Un, additional, Ladep, Nimzing G., additional, Gomaa, Asmaa I., additional, Crossey, Mary M.E., additional, Okeke, Edith, additional, Banwat, Edmund, additional, Waked, Imam, additional, Cox, I. Jane, additional, Williams, Roger, additional, Holmes, Elaine, additional, and Taylor-Robinson, Simon D., additional

Published
2017
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19. The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity

Author

Possamai, Lucia A, McPhail, Mark JW, Khamri, Wafa, Wu, Bishan, Concas, Danilo, Harrison, Mark, Williams, Roger, Cox, Roger D, Cox, I Jane, Anstee, Quentin M, and Thursz, Mark R

Subjects
Male, Proton Magnetic Resonance Spectroscopy, METABOLISM, KERATIN-18, MICROFLORA, Article, STERILE INFLAMMATION, microbiota, Animals, PARACETAMOL, metabonomics, acetaminophen, Mice, Inbred C3H, RECEPTOR 4, Science & Technology, Gastroenterology & Hepatology, NECROSIS, Alanine Transaminase, Cytochrome P-450 CYP2E1, acute liver failure, Glutathione, Intestines, Disease Models, Animal, MICE, Liver, germ-free, Cytokines, MOUSE-LIVER, ACUTE LIVER-FAILURE, Chemical and Drug Induced Liver Injury, Life Sciences & Biomedicine
Abstract

Background & Aim Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. Methods Conventionally housed C3H/HeH (CH) and C3H/HeH germ free (GF) mice were administered a 200mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 hours was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using 1H-NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ (LPS-r) mice were assessed to determine the contribution of LPS/TLR4 signalling. Results Baseline glutathione levels were significantly reduced (p=0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Inter-individual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH (p=0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 hours(cross-validated ANOVA p=1x10-22). Interruption of TLR4 signalling in LPS-r mice had additional protective effects. Conclusion Variations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/LPS signalling.

Published
2014

20. Urinary Metabotyping of Hepatocellular Carcinoma in a UK Cohort Using Proton Nuclear Magnetic Resonance Spectroscopy

Author

Shariff, Mohamed I.F., primary, Kim, Jin U., additional, Ladep, Nimzing G., additional, Crossey, Mary M.E., additional, Koomson, Larry K., additional, Zabron, Abigail, additional, Reeves, Helen, additional, Cramp, Matthew, additional, Ryder, Stephen, additional, Greer, Shaun, additional, Cox, I. Jane, additional, Williams, Roger, additional, Holmes, Elaine, additional, Nash, Kathryn, additional, and Taylor-Robinson, Simon D., additional

Published
2016
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27. Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function

Author

Bajaj, Jasmohan S., primary, Cox, I. Jane, additional, Betrapally, Naga S., additional, Heuman, Douglas M., additional, Schubert, Mitchell L., additional, Ratneswaran, Maiyuran, additional, Hylemon, Phillip B., additional, White, Melanie B., additional, Daita, Kalyani, additional, Noble, Nicole A., additional, Sikaroodi, Masoumeh, additional, Williams, Roger, additional, Crossey, Mary M. E., additional, Taylor-Robinson, Simon D., additional, and Gillevet, Patrick M., additional

Published
2014
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31. S1180 Crohn's Disease Is Associated with a Specific Urinary Metabolic Profile

Author

Williams, Horace R., primary, Cox, I Jane, additional, North, Bernard V., additional, Patel, Venisha M., additional, Marshall, Sara E., additional, Jewell, Derek P., additional, Ghosh, Subrata, additional, Thomas, Huw J., additional, Teare, Julian P., additional, Jakobovits, Simon, additional, Zeki, Sebastian S., additional, Welsh, Kenneth I., additional, Taylor-Robinson, Simon D., additional, and Orchard, Timothy, additional

Published
2008
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40. Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function.

Author

Bajaj JS, Cox IJ, Betrapally NS, Heuman DM, Schubert ML, Ratneswaran M, Hylemon PB, White MB, Daita K, Noble NA, Sikaroodi M, Williams R, Crossey MM, Taylor-Robinson SD, and Gillevet PM

Subjects
Arginine analogs & derivatives, Arginine urine, Biomarkers blood, Biomarkers urine, Case-Control Studies, Feces microbiology, Female, Gastrins blood, Hippurates urine, Humans, Intestines microbiology, Lactic Acid urine, Liver Cirrhosis blood, Liver Cirrhosis complications, Liver Cirrhosis diagnosis, Liver Cirrhosis urine, Magnetic Resonance Spectroscopy, Male, Metabolomics, Middle Aged, Risk Factors, Time Factors, Treatment Outcome, Intestines drug effects, Liver Cirrhosis microbiology, Microbiota drug effects, Omeprazole adverse effects, Proton Pump Inhibitors adverse effects, Systems Biology methods
Abstract

Proton pump inhibitors (PPI) have been associated with infectious complications in cirrhosis, but their impact on distal gut microbiota composition and function is unclear. We aimed to evaluate changes in stool microbiota composition and function in patients with cirrhosis and healthy controls after omeprazole therapy. Both 15 compensated cirrhotic patients and 15 age-matched controls underwent serum gastrin measurement, stool microbiota profiling with multitagged pyrosequencing, and urinary metabolic profiling with NMR spectroscopy to assess microbial cometabolites before/after a 14-day course of 40 mg/day omeprazole under constant diet conditions. Results before (pre) and after PPI were compared in both groups, compared with baseline by systems biology techniques. Adherence was >95% without changes in diet or MELD (model for end-stage liver disease) score during the study. Serum gastrin concentrations significantly increased after PPI in cirrhosis (pre 38.3 ± 35.8 vs. 115.6 ± 79.3 pg/ml P < 0.0001) and controls (pre 29.9 ± 14.5 vs. 116.0 ± 74.0 pg/ml, P = 0.001). A significant microbiota change was seen in both controls and cirrhosis after omeprazole (QIIME P < 0.0001). Relative Streptococcaceae abundance, normally abundant in saliva, significantly increased postomeprazole in controls (1 vs. 5%) and cirrhosis (0 vs. 9%) and was correlated with serum gastrin levels (r = 0.4, P = 0.005). We found significantly reduced hippurate in cirrhosis vs. controls both pre- and postomeprazole and increased lactate in both groups post vs. preomeprazole, whereas dimethylamine (DMA) decreased in cirrhosis only. On correlation network analysis, significant changes in linkages of bacteria with metabolites (hippurate/DMA/lactate) were found postomeprazole, compared with pre-PPI in cirrhosis patients. In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth., (Copyright © 2014 the American Physiological Society.)

Published
2014
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41. Polychlorinated biphenyls in bile of patients with biliary tract cancer.

Author

Adenugba A, Khan SA, Taylor-Robinson SD, Cox IJ, Toledano MB, Thillainayagam AV, Bansi DS, Thomas HC, Gibson RW, and Beck AJ

Subjects
Adult, Aged, Aged, 80 and over, Environmental Pollutants chemistry, Environmental Pollutants isolation & purification, Female, Humans, Isotope Labeling, Male, Middle Aged, Polychlorinated Biphenyls chemistry, Polychlorinated Biphenyls isolation & purification, Xenobiotics analysis, Xenobiotics chemistry, Xenobiotics isolation & purification, Bile chemistry, Biliary Tract Neoplasms chemistry, Environmental Pollutants analysis, Polychlorinated Biphenyls analysis
Abstract

Background: Polychlorinated biphenyls (PCBs) are anthropogenic, organic compounds. Although banned in the 1970s, PCBs are poorly biodegradable and hence ubiquitous in the environment. They accumulate in adipose tissue and are implicated various malignancies, including breast and pancreatic cancer. The hepatobiliary system is the main excretory route for such xenobiotic toxins. Incidence rates of intrahepatic biliary tract cancer are increasing worldwide. Measurement and comparison of PCB levels in bile from human patients with benign and malignant bile duct disease has not previously been done., Objectives: To compare PCB concentrations in bile from patients with malignant (n=8) and non-malignant (n=7) biliary disease., Methods and Results: Fifteen human bile samples, collected endoscopically, were analysed using gas chromatography mass spectrometry for seven target PCB congeners (28, 52, 101, 118, 153, 138, and 180), known to occur in the environment and food. Amongst males, total PCB concentrations in bile ranged from 6 ng mL(-1) (aged 73 years) to 49 ng mL(-1) (aged 90 years); and in females between 8 ng mL(-1) (aged 33 years) to 43 ng mL(-1) (aged 67 years) bile. Although there was no overall difference in mean PCB levels between non-cancer and cancer patients, levels of congener 28 were significantly higher in patients with biliary tract cancer (p<0.05)., Conclusions: Despite the banning of PCBs over 30 years ago, these xenobiotics are present in the bile of patients with biliary disease. PCB levels tend to increase with age, suggesting chronic bioaccumulation. Further research is necessary to investigate the relevance of increased levels of congener 28 in bile in biliary tract cancer.

Published
2009
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