Biofluid metabonomics using 1H NMR spectroscopy: the road to biomarker discovery in gastroenterology and hepatology

Metabolic profiling or ‘metabonomics’ is an investigatory method that allows metabolic changes associated with the presence of an underlying pathological process to be investigated. Various biofluids can be utilized in the process but urine, serum and fecal extract are most pertinent to the investigation of gastrointestinal and hepatological disease. Nuclear magnetic resonance spectroscopy-based metabonomic research has the potential to generate novel noninvasive diagnostic tests, based on biomarkers of disease, which are simple and cost effective yet retain high sensitivity and specificity characteristics. The process involves a number of key steps, including sample collection, data acquisition, chemometric techniques and, finally, validation. This technique-driven review aims to demystify the metabonomics pathway, while also illustrating the potential of this technique with recent examples of its application in hepato–gastroenterological disease.

[1]  Huanwen Chen,et al.  Combining desorption electrospray ionization mass spectrometry and nuclear magnetic resonance for differential metabolomics without sample preparation. , 2006, Rapid communications in mass spectrometry : RCM.

[2]  J. Lindon,et al.  Systems biology: Metabonomics , 2008, Nature.

[3]  John L Markley,et al.  Method for determining molar concentrations of metabolites in complex solutions from two-dimensional 1H-13C NMR spectra. , 2007, Analytical chemistry.

[4]  Douglas B. Kell,et al.  Proposed minimum reporting standards for data analysis in metabolomics , 2007, Metabolomics.

[5]  Malfertheiner,et al.  World Gastroenterology Organization Practice Guidelines for the diagnosis and management of IBD in 2010. , 2010, Inflammatory bowel diseases.

[6]  M M G Godoy,et al.  Hepatitis C virus infection diagnosis using metabonomics , 2010, Journal of viral hepatitis.

[7]  J. Doré,et al.  Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon , 2003, Gut.

[8]  M. Barker,et al.  Partial least squares for discrimination , 2003 .

[9]  A. Okada,et al.  Increased aspartate and glutamate levels in both gastric and colon cancer tissues. , 1993, The Tokushima journal of experimental medicine.

[10]  T. Murdoch,et al.  Urinary metabolic profiles of inflammatory bowel disease in interleukin-10 gene-deficient mice. , 2008, Analytical chemistry.

[11]  Jianghua Feng,et al.  1H NMR analysis for metabolites in serum and urine from rats administrated chronically with La(NO3)3. , 2002, Analytical biochemistry.

[12]  L. Maron,et al.  Utility of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in patients with end-stage liver disease awaiting liver transplant. , 2007, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[13]  R Somorjai,et al.  Detecting colorectal cancer by 1H magnetic resonance spectroscopy of fecal extracts , 2009, NMR in biomedicine.

[14]  Reino Laatikainen,et al.  High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism. , 2009, The Analyst.

[15]  V. Felipo,et al.  Serum metabolic signature of minimal hepatic encephalopathy by (1)H-nuclear magnetic resonance. , 2010, Journal of proteome research.

[16]  Philippe Marteau,et al.  Specificities of the fecal microbiota in inflammatory bowel disease , 2006, Inflammatory bowel diseases.

[17]  S. Riordan,et al.  Synbiotic modulation of gut flora: Effect on minimal hepatic encephalopathy in patients with cirrhosis , 2004, Hepatology.

[18]  M. Walsh,et al.  Effect of acute dietary standardization on the urinary, plasma, and salivary metabolomic profiles of healthy humans. , 2006, The American journal of clinical nutrition.

[19]  Nigel W. Hardy,et al.  The Metabolomics Standards Initiative , 2007, Nature Biotechnology.

[20]  Anthony F. P. Nash,et al.  A 1H NMR-based metabonomic study of urine and plasma samples obtained from healthy human subjects. , 2003, Journal of pharmaceutical and biomedical analysis.

[21]  Jeremy K Nicholson,et al.  NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats. , 2003, Chemical research in toxicology.

[22]  A. Astrup,et al.  Standardization of factors that influence human urine metabolomics , 2011, Metabolomics.

[23]  Daniel Monleón,et al.  Metabolite profiling of fecal water extracts from human colorectal cancer , 2009, NMR in biomedicine.

[24]  G. Hwang,et al.  Toxicometabolomics of Urinary Biomarkers for Human Gastric Cancer in a Mouse Model , 2010, Journal of toxicology and environmental health. Part A.

[25]  J. Lindon,et al.  So what's the deal with metabonomics? , 2003, Analytical chemistry.

[26]  W. Deen,et al.  Metabolism and excretion of methylamines in rats. , 1994, Toxicology and applied pharmacology.

[27]  B. Seibel,et al.  Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage. , 2002, The Journal of experimental biology.

[28]  Ian C. P. Smith,et al.  MR metabolomics of fecal extracts: applications in the study of bowel diseases , 2009, Magnetic resonance in chemistry : MRC.

[29]  S. Burzynski.  Aging: gene silencing or gene activation? , 2005, Medical hypotheses.

[30]  C Boesch,et al.  Molecular aspects of magnetic resonance imaging and spectroscopy. , 1999, Molecular aspects of medicine.

[31]  L. Tenori,et al.  Are patients with potential celiac disease really potential? The answer of metabonomics. , 2011, Journal of proteome research.

[32]  Tianlu Chen,et al.  Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS. , 2009, Journal of proteome research.

[33]  Ivano Bertini,et al.  Standard operating procedures for pre-analytical handling of blood and urine for metabolomic studies and biobanks , 2011, Journal of biomolecular NMR.

[34]  I. Wilson,et al.  Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. , 2007, Journal of proteome research.

[35]  M. Zheng,et al.  Urinary metabolic profiling of colorectal carcinoma based on online affinity solid phase extraction-high performance liquid chromatography and ultra performance liquid chromatography-mass spectrometry. , 2010, Molecular bioSystems.

[36]  L. Tanoue.  Cancer Statistics, 2009 , 2010 .

[37]  Jian Zhang,et al.  Metabolomics study of esophageal adenocarcinoma. , 2011, The Journal of thoracic and cardiovascular surgery.

[38]  K. Shirai,et al.  Clinical usefulness of CYFRA 21‐1 for esophageal squamous cell carcinoma in radiation therapy , 2006, Journal of gastroenterology and hepatology.

[39]  Stephen M. Rao,et al.  Inhibitory Control Test Is a Simple Method to Diagnose Minimal Hepatic Encephalopathy and Predict Development of Overt Hepatic Encephalopathy , 2007, The American Journal of Gastroenterology.

[40]  John C. Lindon,et al.  Metabonomics: metabolic processes studied by NMR spectroscopy of biofluids , 2000 .

[41]  D. Lavanchy,et al.  The global burden of hepatitis C , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[42]  J. Griffin,et al.  Cryogenic probe 13C NMR spectroscopy of urine for metabonomic studies. , 2002, Analytical chemistry.

[43]  David S. Wishart,et al.  MetaboMiner – semi-automated identification of metabolites from 2D NMR spectra of complex biofluids , 2008, BMC Bioinformatics.

[44]  J. Nicholson,et al.  Metabonomics in ulcerative colitis: diagnostics, biomarker identification, and insight into the pathophysiology. , 2010, Journal of proteome research.

[45]  Davy Sinnaeve,et al.  Evaluation of standard and advanced preprocessing methods for the univariate analysis of blood serum 1H-NMR spectra , 2010, Analytical and bioanalytical chemistry.

[46]  K Weissenborn,et al.  Neuropsychological characterization of hepatic encephalopathy. , 2001, Journal of hepatology.

[47]  J. Hampe,et al.  Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease , 2004, Gut.

[48]  D. Jewell,et al.  Characterization of Inflammatory Bowel Disease With Urinary Metabolic Profiling , 2009, The American Journal of Gastroenterology.

[49]  Ian D Wilson,et al.  Analytical strategies in metabonomics. , 2007, Journal of proteome research.

[50]  M. Spraul,et al.  750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. , 1995, Analytical chemistry.

[51]  T. Hirose,et al.  Quantification of molecules in (1)H-NMR metabolomics with formate as a concentration standard. , 2010, The Journal of toxicological sciences.

[52]  Z. Bentwich,et al.  Carcinoembryonic Antigen , 1978 .

[53]  J. K. Nicholson,et al.  Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice , 2007, Diabetologia.

[54]  O. Nielsen,et al.  Technology Insight: metabonomics in gastroenterology—basic principles and potential clinical applications , 2008, Nature Clinical Practice Gastroenterology &Hepatology.

[55]  R. Hoffmann,et al.  Probiotic Yogurt for the Treatment of Minimal Hepatic Encephalopathy , 2008, The American Journal of Gastroenterology.

[56]  S. Truelove,et al.  Luminal ions and short chain fatty acids as markers of functional activity of the mucosa in ulcerative colitis. , 1982, Journal of clinical pathology.

[57]  J. Lindon,et al.  'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[58]  Tianlu Chen,et al.  Urinary metabonomic study on colorectal cancer. , 2010, Journal of proteome research.

[59]  Rachel Cavill,et al.  Metabolic profiling of human colorectal cancer using high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy and gas chromatography mass spectrometry (GC/MS). , 2009, Journal of proteome research.

[60]  Nigel W. Hardy,et al.  Proposed minimum reporting standards for chemical analysis , 2007, Metabolomics.

[61]  M. Sherman.  Optimum imaging for small suspected hepatocellular carcinoma , 2010, Gut.

[62]  W. Scheppach,et al.  The butyrate story: old wine in new bottles? , 2004, Current opinion in clinical nutrition and metabolic care.

[63]  Mark R Viant,et al.  Two-dimensional J-resolved NMR spectroscopy: review of a key methodology in the metabolomics toolbox. , 2010, Phytochemical analysis : PCA.

[64]  Ying Zhang,et al.  HMDB: the Human Metabolome Database , 2007, Nucleic Acids Res..

[65]  J. Jansson,et al.  Metabolomics Reveals Metabolic Biomarkers of Crohn's Disease , 2009, PloS one.

[66]  Muireann Coen,et al.  Proton nuclear magnetic resonance-based metabonomics for rapid diagnosis of meningitis and ventriculitis. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[67]  P. Mannon,et al.  The fundamental basis of inflammatory bowel disease. , 2007, The Journal of clinical investigation.

[68]  Huiru Tang,et al.  An optimised sample preparation method for NMR-based faecal metabonomic analysis. , 2010, The Analyst.

[69]  C. Manichanh,et al.  Review article: the role of bacteria in onset and perpetuation of inflammatory bowel disease , 2006, Alimentary pharmacology & therapeutics.

[70]  Khean Lee Goh,et al.  Screening for gastric cancer in Asia: current evidence and practice. , 2008, The Lancet. Oncology.

[71]  J. Lupton,et al.  Modulation of colonic epithelial cell proliferation, histone acetylation, and luminal short chain fatty acids by variation of dietary fiber (wheat bran) in rats. , 1992, Cancer research.

[72]  R Balfour Sartor,et al.  Microbial influences in inflammatory bowel diseases. , 2008, Gastroenterology.

[73]  S. Winawer.  The multidisciplinary management of gastrointestinal cancer. Colorectal cancer screening. , 2007, Best practice & research. Clinical gastroenterology.

[74]  Gary Peltz,et al.  2D NMR metabonomic analysis: a novel method for automated peak alignment , 2007, Bioinform..

[75]  M. McCarthy,et al.  Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice , 2006, Proceedings of the National Academy of Sciences.

[76]  G. Rechkemmer,et al.  Potential of short chain fatty acids to modulate the induction of DNA damage and changes in the intracellular calcium concentration by oxidative stress in isolated rat distal colon cells. , 1999, Carcinogenesis.

[77]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[78]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[79]  H. Thomas,et al.  Urinary metabolic biomarkers of hepatocellular carcinoma in an Egyptian population: a validation study. , 2011, Journal of proteome research.

[80]  E. Vaughan,et al.  1H NMR metabolite profiling of feces as a tool to assess the impact of nutrition on the human microbiome , 2008, NMR in biomedicine.

[81]  R. Chalmers,et al.  High-resolution 1H-NMR spectroscopy of blood plasma for metabolic studies. , 1995, Clinical chemistry.

[82]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[83]  R. Lewensohn,et al.  Metabolomics: Moving to the Clinic , 2010, Journal of Neuroimmune Pharmacology.

[84]  Haifeng Lu,et al.  Symbiotic gut microbes modulate human metabolic phenotypes , 2008, Proceedings of the National Academy of Sciences.

[85]  David I. Ellis,et al.  Metabolomics: Current analytical platforms and methodologies , 2005 .

[86]  C. Paraskeva,et al.  The short-chain fatty acid butyrate induces apoptosis in colorectal tumour cell lines. , 1995, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[87]  Ivano Bertini,et al.  Evidence of different metabolic phenotypes in humans , 2008, Proceedings of the National Academy of Sciences.

[88]  H. Ogata,et al.  Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. , 2008, International journal of medical microbiology : IJMM.

[89]  P. James,et al.  Protein identification in the post-genome era: the rapid rise of proteomics , 1997, Quarterly Reviews of Biophysics.

[90]  Age K. Smilde,et al.  UvA-DARE ( Digital Academic Repository ) Assessment of PLSDA cross validation , 2008 .

[91]  D. Strachan,et al.  Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility , 2008, Nature Genetics.

[92]  Paul B Watkins,et al.  Effects of a prolonged standardized diet on normalizing the human metabolome. , 2009, The American journal of clinical nutrition.

[93]  Nigel W. Hardy,et al.  The metabolomics standards initiative (MSI) , 2007, Metabolomics.

[94]  T. Ebbels,et al.  Analytical reproducibility in (1)H NMR-based metabonomic urinalysis. , 2002, Chemical research in toxicology.

[95]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[96]  B. Flehinger,et al.  Colorectal cancer screening. , 1991, Journal of the National Cancer Institute.

[97]  Johan Trygg,et al.  Chemometrics in metabolomics--a review in human disease diagnosis. , 2010, Analytica chimica acta.

[98]  Robert S Plumb,et al.  Statistical heterospectroscopy, an approach to the integrated analysis of NMR and UPLC-MS data sets: application in metabonomic toxicology studies. , 2006, Analytical chemistry.

[99]  T. Ebbels,et al.  Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts , 2007, Nature Protocols.

[100]  Jouni Uitto,et al.  Comparison of 1D and 2D NMR spectroscopy for metabolic profiling. , 2008, Journal of proteome research.

[101]  L. Tenori,et al.  The metabonomic signature of celiac disease. , 2009, Journal of proteome research.

[102]  H. Thomas,et al.  Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy in a Nigerian population. , 2010, Journal of proteome research.

[103]  Hui Cong,et al.  Application of 1H NMR‐based metabonomics in the study of metabolic profiling of human hepatocellular carcinoma and liver cirrhosis , 2009, Cancer science.

[104]  E. K. Kemsley,et al.  Metabolomics of fecal extracts detects altered metabolic activity of gut microbiota in ulcerative colitis and irritable bowel syndrome. , 2011, Journal of proteome research.

[105]  G. Siuzdak,et al.  From exogenous to endogenous: the inevitable imprint of mass spectrometry in metabolomics. , 2007, Journal of proteome research.

[106]  Oliver F Bathe,et al.  Feasibility of Identifying Pancreatic Cancer Based on Serum Metabolomics , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[107]  A. Heinecke,et al.  CYFRA 21-1 serum analysis in patients with esophageal cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[108]  C Zuppi,et al.  1H NMR spectra of normal urines: reference ranges of the major metabolites. , 1997, Clinica chimica acta; international journal of clinical chemistry.