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Urine metabolic fingerprinting can be used to predict the risk of metritis and highlight the pathobiology of the disease in dairy cows

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Abstract

Introduction

Metritis is an uterine pathology that causes economic losses for the dairy industry. It is associated with lower reproductive efficiency, increased culling rates, decreased milk production and increased veterinary costs.

Objectives

To gain a more detailed view of the urine metabolome and to detect metabolite signature in cows with metritis. In addition, we aimed to identify early metabolites which can help to detect cows at risk to develop metritis in the future.

Methods

We used nuclear magnetic resonance spectroscopy starting at 8 and 4 weeks prior to the expected day of parturition, during the week of diagnosis of metritis, and at 4 and 8 weeks after diagnosis of metritis in Holstein dairy cows.

Results

At 8 weeks before parturition, pre-metritic cows had a total of 30 altered metabolites. Interestingly, 28 of them increased in urine when compared with control cows (P < 0.05). At 4 weeks before parturition, 34 metabolites were altered. At the week of diagnosis of metritis a total of 20 metabolites were altered (P < 0.05). The alteration continued at 4 and 8 weeks after diagnosis.

Conclusions

The metabolic fingerprints in the urine of pre-metritic and metritic cows point toward excretion of multiple amino acids, tricarboxylic acid cycle metabolites and monosaccharides. Combination of galactose, leucine, lysine and panthotenate at 8 weeks before parturition might serve as predictive biomarkers for metritis.

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References

  • Aubron, C., Huet, O., Ricome, S., Borderie, D., Pussard, E., Leblanc, P. E., et al. (2012). Changes in urine composition after trauma facilitate bacterial growth. BMC Infectious Disease, 12, 330–340.

    Article  Google Scholar 

  • Badenhorst, C. P. S., Erasmus, E., van der Sluis, R., Nortje, C., & van Dijk, A. A. (2014). A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids. Drug Metabolism Reviews, 46, 343–361.

    Article  PubMed  CAS  Google Scholar 

  • Begriche, K., Igoudjil, A., Pessayre, D., & Fromenty, B. (2006). Mitochondrial dysfunction in NASH: Causes, consequences and possible means to prevent it. Mitochondrion, 6, 1–28.

    Article  PubMed  CAS  Google Scholar 

  • Blum, J. W., Reding, T., Jans, F., Wanner, M., Zemp, M., & Bachmann, K. (1985). Variations of 3-methylhistidine in blood of dairy cows. Journal of Dairy Science, 68, 2580–2587.

    Article  PubMed  CAS  Google Scholar 

  • Bouatra, S., Aziat, F., Mandal, R., Guo, A. C., Wilson, M. R., Knox, C., et al. (2013). The human urine metabolome. PLoS ONE, 8, e73076.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Broom, K. A., Anthony, D. C., Lowe, J. P., Griffin, J. L., Scott, H., Blamire, A. M., et al. (2007). MRI and MRS alterations in the preclinical phase of murine prion disease: Association with neuropathological and behavioural changes. Neurobiology of Disease, 26, 707–717.

    Article  PubMed  CAS  Google Scholar 

  • Burri, R., Steffen, C., & Herschkowitz, N. (1991). N-acetyl-L-aspartate is a major source of acetyl groups for lipid synthesis during rat brain development. Developmental Neuroscience, 13, 403–411.

    Article  PubMed  CAS  Google Scholar 

  • Canadian Council on Animal Care (CCAC). (1993). Guide to the care and use of experimental animals, 2nd ed. CCAC: Ottawa.

    Google Scholar 

  • Chan, J. P. W., Chang, C., Hsu, W. L., Liu, W. B., & Chen, T. H. (2010). Association of increase serum acute-phase protein concentration with reproductive performances in dairy cows with postpartum metritis. Veterinary Clinical Pathology, 39, 72–78.

    Article  PubMed  Google Scholar 

  • Chapwanya, A., Meade, K. G., Doherty, M. L., Callana, J. J., Mee, J. F., & O’Farrelly, C. (2009). Histopathological and molecular evaluation of Holstein-Fresian cows postpartum: Toward an improved understanding of uterine innate immunity. Theriogenology, 71, 1396–1407.

    Article  PubMed  CAS  Google Scholar 

  • Clark, J. B. (1998). N-acetyl aspartate: A marker for neuronal loss or mitochondrial dysfunction. Developmental Neuroscience, 20, 271–276.

    Article  PubMed  CAS  Google Scholar 

  • Costamagna, D., Costelli, P., Sampaolesi, M., & Penna, F. (2015). Role of inflammation in muscle homeostasis and myogenesis. Mediators of Inflammation. https://doi.org/10.1155/2015/805172.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dervishi, E., Zhang, G., Dunn, S. M., Mandal, R., Wishart, D. S., & Ametaj, B. N. (2017). GC–MS metabolomics identifies metabolite alterations that precede subclinical mastitis in the blood of transition dairy cows. Journal of Proteome Research, 16, 433–446.

    Article  PubMed  CAS  Google Scholar 

  • Dervishi, E., Zhang, G., Hailemariam, D., Goldansaz, S. A., Deng, Q., Dunn, S. M., et al. (2016). Alterations in innate immunity reactants and carbohydrate and lipid metabolism precede occurrence of metritis in transition dairy cows. Research in Veterinary Science, 104, 30–39.

    Article  PubMed  CAS  Google Scholar 

  • Dubuc, J., Duffield, T. F., LeBlanc, S. J., & Veira, D. M. (2010). Risk factor for postpartum uterine diseases in dairy cows. Journal of Dairy Science, 93, 5764–5771.

    Article  PubMed  CAS  Google Scholar 

  • Griffith, O. W. (1986). Beta-amino acids: Mammalian metabolism and utility as alpha-amino acid analogues. Annual Review of Biochemistry, 55, 855–878.

    Article  PubMed  CAS  Google Scholar 

  • Guidarelli, A., Cerioni, L., & Cantoni, O. (2007). Inhibition of complex III promotes loss of Ca2 + dependence for mitochondrial superoxide formation and permeability transition evoked by peroxynitrite. Journal of Cell Science, 120, 1908–1914.

    Article  PubMed  CAS  Google Scholar 

  • Hailemariam, D., Mandal, R., Saleem, F., Dunn, S. M., Wishart, D. S., & Ametaj, B. N. (2014a). Identification of predictive biomarkers of disease state in transition dairy cows. Journal of Dairy Science, 97, 2680–2693.

    Article  PubMed  CAS  Google Scholar 

  • Hailemariam, D., Mandal, R., Saleem, F., Dunn, S. M., Wishart, D. S., & Ametaj, B. N. (2014b). Metabolomics approach reveals altered amino acid and sphingolipid profiles associated with pathological state in transition dairy cows. Current Metabolomics, 2, 184–195.

    Article  CAS  Google Scholar 

  • Hammon, D. S., Evjen, I. M., Dhiman, T. R., Goff, J. P., & Walters, J. L. (2006). Neutrophil function and energy status in Holstein cows with uterine health disorders. Veterinary Immunology Immunopathology, 113, 21–26.

    Article  PubMed  CAS  Google Scholar 

  • Hao, L., Lu, X., Sun, M., Li, K., Shen, L., & Wu, T. (2015). Protective effects of L-arabinose in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. Food and Nutrion Research, 59, 28886.

    Article  CAS  Google Scholar 

  • Huzzey, J. M., Duffield, T. F., LeBlanc, S. J., Veira, D. M., Weary, D. M., & von Keyserlingk, M. A. G. (2009). Short communication: Haptaglobin as an early indicator of metritis. Journal of Dairy Science, 92, 621–625.

    Article  PubMed  CAS  Google Scholar 

  • Karnovsky, A., Weymouth, T., Hull, T., Tarcea, V. G., Scardoni, G., Laudanna, C., et al. (2012). Metscape 2 bioinformatics tool for the analysis and visualization of metabolomics and gene expression data. Bioinformatics, 28, 373–380.

    Article  PubMed  CAS  Google Scholar 

  • Mehta, V., & Namboodiri, M. A. (1995). N-acetylaspartate as an acetyl source in the nervous system. Molecular Brain Research, 31, 151–157.

    Article  PubMed  CAS  Google Scholar 

  • Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F., & Kroemer, G. (2015). Acetyl coenzyme A: A central metabolite and second messenger. Cell Metabolism, 21, 805–821.

    Article  PubMed  CAS  Google Scholar 

  • R Development Core Team. (2008). R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. http://www.R-project.org.

  • Roberts, L. D., Boström, P., O’Sullivan, J. F., Schinzel, R. T., Lewis, G. D., Dejam, A., et al. (2014). β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metabolism, 19, 96–108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Saude, E. J., Slupsky, C. M., & Sykes, B. D. (2006). Optimization of NMR analysis of biological fluids for quantitative accuracy. Metabolomics, 2, 113–123.

    Article  CAS  Google Scholar 

  • Shannon, P., van der Heide, S., Carter, E. L., Jalloh, I., Menon, D. K., Hutchinson, P. J., et al. (2003). Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Research, 13, 2498–2504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sheldon, I. M., Lewis, G. S., LeBlanc, S., & Gilbert, R. O. (2006). Defining postpartum uterine disease in cattle. Theriogenology, 65, 1516–1530.

    Article  PubMed  Google Scholar 

  • Sheldon, I. M., Lewis, G. S., LeBlanc, S., Gilbert, R. O., et al. (2009). Defining postpartum uterine disease and the mechanisms of infection and immunity in the female reproductive tract in cattle. Biology of Reproduction, 81, 1025–1032.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shen, Z., Ajmo, J. M., Rogers, C. Q., Liang, X., Le, L., Murr, M. M., et al. (2009). Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-production in cultured macrophage cell lines. American Journal of Physiology, Gastrointestinal and Liver Physiology, 296, G1047–G1053.

    Article  CAS  Google Scholar 

  • Shi, C. X., Zhao, M. X., Shu, X. D., Xiong, X. Q., Wang, J. J., Chen, Q., et al. (2016). β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes. Scientific Reports, 24, 21924.

    Article  CAS  Google Scholar 

  • Sun, L. W., Zhang, H. Y., Wu, L., Shu, S., Xia, C., Xu, C., et al. (2014). 1H-Nuclear magnetic resonance-based plasma metabolic profiling of dairy cows with clinical and subclinical ketosis. Journal of Dairy Science, 97, 1552–1562.

    Article  PubMed  CAS  Google Scholar 

  • Tahiliani, A. G., & Beinlich, C. J. (1991). Pantothenic acid in health and disease. Vitamines and Hormons, 46, 165–228.

    Article  CAS  Google Scholar 

  • The National Academy of Science, NRC. (2001). Nutrient requirements of dairy Cattle. 7th Revised ed., Washington, DC: NRC

    Google Scholar 

  • Weljie, A. M., Newton, J., Mercier, ,P., Carlson, E., & Slupsky, C. M. (2006). Targeted profiling: Quantitative analysis of 1H NMR metabolomics data. Analytical Chemistry, 78, 4430–4442.

    Article  PubMed  CAS  Google Scholar 

  • Wishart, D. S. (2008). Quantitative metabolomics using NMR. Trends in Analytical Chemistry, 27, 228–237.

    Article  CAS  Google Scholar 

  • Xia, J., Broadhurst, D. I., Wilson, M., & Wishart, D. S. (2013). Translational biomarker discovery in clinical metabolomics: An introductory tutorial. Metabolomics, 9, 280 – 299.

    Article  PubMed  CAS  Google Scholar 

  • Yeung, J. E., & Hoberg, C. S. (2004). Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. European Molecular Biology Organization Journal, 23, 2369–2380.

    Article  CAS  Google Scholar 

  • Yuan, K., Farney, J. K., Mamedova, L. K., Sordillo, L. M., & Bradford, B. J. (2013). TNFα altered inflammatory responses, impaired health and productivity, but did not affect glucose or lipid metabolism in early-lactation dairy cows. PLoS ONE, 19, e80316.

    Article  CAS  Google Scholar 

  • Zell, R., Geck, P., Werdan, K., & Boekstegers, P. (1997). TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: Evidence for primary impairment of mitochondrial function. Molecular and Cellular Biochemestry, 177, 61–67.

    Article  CAS  Google Scholar 

  • Zhang, G., Dervishi, E., Dunn, S. M., Mandal, R., Liu, P., Han, B., et al. (2017). Metabotyping reveals distinct metabolic alterations in ketotic cows and identifies early predictive serum biomarkers for the risk of disease. Metabolomics, 13, 43.

    Article  CAS  Google Scholar 

  • Zhang, H., Wu, L., Xu, C., Xia, C., Sun, L., & Shu, S. (2013). Plasma metabolomic profiling of dairy cows affected with ketosis using gas chromatography/mass spectrometry. BMC Veterinary Research, 9, 186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou, Z., Vailati-Riboni, M., Luchini, D., & Loor, J. (2017). Methionine and choline supply during the periparturient period alter plasma amino acid and one-carbon metabolism profiles to various extents: Potential role in hepatic metabolism and antioxidant status. Nutrients, 9, 10.

    Article  CAS  Google Scholar 

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Acknowledgements

This research work was funded by Alberta Livestock and Meat Agency Ltd. (ALMA, Edmonton, AB, Canada), Genome Alberta (Calgary, AB, Canada), and Natural Sciences and Engineering Research Council of Canada (Ottawa, ON, Canada) with Dr. Burim N. Ametaj and Dr. David S. Wishart as Principal Investigators. We are grateful to the technical staff at Dairy Research and Technology Center, University of Alberta, for their help and care with the cows. We acknowledge full or partial help of S. A. Goldansaz, Q. Deng, and J. F. Odhiambo in collection of samples from the cows. Elda Dervishi and Guanshi Zhang contributed equally in this work.

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Authors and Affiliations

  1. Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada

    E. Dervishi, G. Zhang, D. Hailemariam & B. N. Ametaj

  2. Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, AB T6G 2E9, Canada

    G. Zhang, R. Mandal & D. S. Wishart

Authors
  1. E. Dervishi
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  2. G. Zhang
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  3. D. Hailemariam
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  4. R. Mandal
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  5. D. S. Wishart
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  6. B. N. Ametaj
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Contributions

ED and GZH contributed equally to this work. The manuscript was written through contributions of all authors. ED wrote the manuscript, collected samples, did clinical monitoring and evaluation of the cows, data analysis and maintained the database of the project. GZ contributed in collection of samples, lab analysis, and data statistical analysis and writing the manuscript. DH wrote part of the manuscript, collected samples, did clinical monitoring and evaluation of the cows. RM and DSW contributed in sample analysis. BNA contributed in conceiving the idea and designing of the experiments and supervised the experiment, lab analyses, statistical processing as well as writing of the manuscript.

Corresponding author

Correspondence to E. Dervishi.

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The authors declare no conflict of interest.

Research involving animal and human rights

All experimental procedures were approved by the University of Alberta Animal Policy and Welfare Committee for Livestock, and animals were cared for in accordance with the guidelines of the Canadian Council on Animal Care (1993).

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Dervishi, E., Zhang, G., Hailemariam, D. et al. Urine metabolic fingerprinting can be used to predict the risk of metritis and highlight the pathobiology of the disease in dairy cows. Metabolomics 14, 83 (2018). https://doi.org/10.1007/s11306-018-1379-z

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  • DOI: https://doi.org/10.1007/s11306-018-1379-z

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