{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:12:14Z","timestamp":1789708334343,"version":"4.0.1"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T00:00:00Z","timestamp":1700092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture","doi-asserted-by":"publisher","award":["CA-V-PHR-4122-H"],"award-info":[{"award-number":["CA-V-PHR-4122-H"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>The objective of this study was to identify alterations in the vaginal discharge (VD) metabolome and potential biomarkers to predict metritis development and a cure in dairy cows. This prospective cohort study was conducted on two dairies located in CA and TX. Vaginal discharge was evaluated and collected using the Metricheck\u00ae device. Cows were examined for metritis at 4, 7, and 9 days in milk (DIM). Cows with a fetid, watery, and reddish-brown uterine discharge were classified as having metritis and randomized to receive ceftiofur (n = 10) or remain untreated (n = 7). A cure was defined as the absence of a fetid, watery, reddish-brown uterine discharge at 14 d after enrollment. Vaginal discharge samples were collected from 86 cows within 6 h after parturition, at 4 and 7 DIM, at metritis diagnosis, and at 4 and 7 days after metritis diagnosis. Cows with metritis (MET; n = 17) were paired with counterparts without metritis (HTH) of a similar DIM and parity (n = 34). The uterine metabolome was evaluated using untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Metabolomic data were analyzed using the MetaboAnalyst 5.0. Data were log-transformed and auto-scaled for normalization. Univariate analyses, including the fold-change, were performed to identify the metabolites linked to metritis development and its cure and principal component analysis and partial least squares discriminant analysis were performed to explain metabolite variance between animals developing or not developing metritis and being cured or not being cured of metritis. Comparing HTH with MET cows at calving, 12 metabolites were upregulated, and one was downregulated. At four and seven DIM, 51 and 74 metabolites, respectively, were altered between MET and HTH cows. After metritis development, three and five metabolites were upregulated in cows that were cured and in cows that received treatment and were cured, respectively. In all scenarios, the metabolites lignoceric, malic, and maleic acids, ornithine, and hypotaurine, which are associated with arginine\/aminoacyl-tRNA biosynthesis and taurine\/purine metabolism, were upregulated in HTH cows. Metritis was associated with changes in the uterine metabolome. Cows not being cured of metritis had changes in the uterus metabolome independent of receiving ceftiofur or remaining untreated. Metabolome analysis may be an important tool to understand the vaginal discharge changes during postpartum and the dynamics of metritis development and cures and help to identify biomarkers to predict metritis being cured.<\/jats:p>","DOI":"10.3390\/metabo13111156","type":"journal-article","created":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T08:19:43Z","timestamp":1700122783000},"page":"1156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Changes in Uterine Metabolome Associated with Metritis Development and Cure in Lactating Holstein Cows"],"prefix":"10.3390","volume":"13","author":[{"given":"Eduardo B.","family":"de Oliveira","sequence":"first","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95106, USA"},{"name":"Veterinary Medicine Teaching and Research Center, Tulare, CA 93274, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo F.","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M. V.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Veterinary Medicine Teaching and Research Center, Tulare, CA 93274, USA"},{"name":"Department of Animal Science, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7534-732X","authenticated-orcid":false,"given":"Deniece R.","family":"Williams","sequence":"additional","affiliation":[{"name":"Veterinary Medicine Teaching and Research Center, Tulare, CA 93274, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-8761","authenticated-orcid":false,"given":"Richard V.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelia","family":"Silva Del Rio","sequence":"additional","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95106, USA"},{"name":"Veterinary Medicine Teaching and Research Center, Tulare, CA 93274, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1281-3693","authenticated-orcid":false,"given":"Paulo R.","family":"Menta","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinicius S.","family":"Machado","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8377-6469","authenticated-orcid":false,"given":"Fabio S.","family":"Lima","sequence":"additional","affiliation":[{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.3168\/jds.2014-9296","article-title":"Assessment of visceral pain associated with metritis in dairy cows","volume":"98","author":"Stojkov","year":"2015","journal-title":"J. Dairy Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.3168\/jds.2013-7569","article-title":"Efficacy of ampicillin trihydrate or ceftiofur hydrochloride for treatment of metritis and subsequent fertility in dairy cows","volume":"97","author":"Lima","year":"2014","journal-title":"J. Dairy Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10560","DOI":"10.3168\/jds.2019-17951","article-title":"Early-lactation diseases and fertility in 2 seasons of calving across US dairy herds","volume":"103","author":"Pinedo","year":"2020","journal-title":"J. Dairy Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7377","DOI":"10.3168\/jds.2019-18028","article-title":"Using chitosan microparticles to treat metritis in lactating dairy cows","volume":"103","author":"Cunha","year":"2020","journal-title":"J. Dairy Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7345","DOI":"10.3168\/jds.2018-15383","article-title":"Economic comparison of systemic antimicrobial therapies for metritis in dairy cows","volume":"102","author":"Lima","year":"2019","journal-title":"J. Dairy Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.3168\/jds.2020-19125","article-title":"The economic cost of metritis in dairy herds","volume":"104","author":"Silva","year":"2021","journal-title":"J. Dairy Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.3168\/jds.2006-482","article-title":"Rectal temperature, calving-related factors, and the incidence of puerperal metritis in postpartum dairy cows","volume":"90","author":"Benzaquen","year":"2007","journal-title":"J. Dairy Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.vetmic.2017.12.022","article-title":"Shift of uterine microbiota associated with antibiotic treatment and cure of metritis in dairy cows","volume":"214","author":"Jeon","year":"2018","journal-title":"Vet. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11786","DOI":"10.3168\/jds.2019-17106","article-title":"Symposium review: The uterine microbiome associated with the development of uterine disease in dairy cows","volume":"102","author":"Galvao","year":"2019","journal-title":"J. Dairy Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6324","DOI":"10.1128\/AEM.01753-15","article-title":"Uterine Microbiota Progression from Calving until Establishment of Metritis in Dairy Cows","volume":"81","author":"Jeon","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9054","DOI":"10.3168\/jds.2021-21327","article-title":"Characterization of metabolic profile, health, milk production, and reproductive outcomes of dairy cows diagnosed with concurrent hyperketonemia and hypoglycemia","volume":"105","author":"Hubner","year":"2022","journal-title":"J. Dairy Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7158","DOI":"10.3168\/jds.2012-5812","article-title":"Evaluation of peripartal calcium status, energetic profile, and neutrophil function in dairy cows at low or high risk of developing uterine disease","volume":"95","author":"Martinez","year":"2012","journal-title":"J. Dairy Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.rvsc.2015.11.004","article-title":"Alterations in innate immunity reactants and carbohydrate and lipid metabolism precede occurrence of metritis in transition dairy cows","volume":"104","author":"Dervishi","year":"2016","journal-title":"Res. Vet. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cimid.2011.01.004","article-title":"Lipid mobilization and inflammatory responses during the transition period of dairy cows","volume":"34","author":"Contreras","year":"2011","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jeon, S.J., Cunha, F., Vieira-Neto, A., Bicalho, R.C., Lima, S., Bicalho, M.L., and Galvao, K.N. (2017). Blood as a route of transmission of uterine pathogens from the gut to the uterus in cows. Microbiome, 5.","DOI":"10.1186\/s40168-017-0328-9"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3525","DOI":"10.3168\/jds.2022-22552","article-title":"Differences in uterine and serum metabolome associated with metritis in dairy cows","volume":"106","author":"Figueiredo","year":"2023","journal-title":"J. Dairy Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.3168\/jds.2010-4075","article-title":"The association of serum metabolites with clinical disease during the transition period","volume":"94","author":"Chapinal","year":"2011","journal-title":"J. Dairy Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9261","DOI":"10.3168\/jds.2020-18643","article-title":"The association of cow related factors assessed at metritis diagnosis with metritis cure risk, fertility, milk yield, and culling for untreated and ceftiofur-treated dairy cows","volume":"103","author":"Machado","year":"2020","journal-title":"J. Dairy Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105431","DOI":"10.1016\/j.prevetmed.2021.105431","article-title":"Predictive models to identify Holstein cows at risk of metritis and clinical cure and reproductive\/productive failure following antimicrobial treatment","volume":"194","author":"Merenda","year":"2021","journal-title":"Prev. Vet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12887","DOI":"10.3168\/jds.2021-20262","article-title":"Integration of statistical inferences and machine learning algorithms for prediction of metritis cure in dairy cows","volume":"104","author":"Ferreira","year":"2021","journal-title":"J. Dairy Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.rvsc.2021.07.006","article-title":"Metabolomic analysis of untargeted bovine uterine secretions in dairy cows with endometritis using ultra-performance liquid chromatography\/quadrupole time-of-flight mass spectrometry","volume":"139","author":"Wang","year":"2021","journal-title":"Res. Vet. Sci."},{"key":"ref_22","unstructured":"Djukovic, D., Gowda, G.A.N., and Raftery, D. (2013). Proteomic and Metabolomic Approaches to Biomarker Discovery, Academic Press."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"184","DOI":"10.2174\/2213235X03666141216201446","article-title":"Metabolomics Approach Reveals Altered Plasma Amino Acid and Sphingolipid Profiles Associated with Patholological State in Transition Dairy Cows","volume":"2","author":"Hailemariam","year":"2014","journal-title":"Curr. Metabol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1021\/acs.jproteome.6b00538","article-title":"GC-MS Metabolomics Identifies Metabolite Alterations That Precede Subclinical Mastitis in the Blood of Transition Dairy Cows","volume":"16","author":"Dervishi","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11306-018-1379-z","article-title":"Urine metabolic fingerprinting can be used to predict the risk of metritis and highlight the pathobiology of the disease in dairy cows","volume":"14","author":"Dervishi","year":"2018","journal-title":"Metabolomics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.2460\/javma.2004.224.1634","article-title":"Efficacy of ceftiofur hydrochloride sterile suspension administered parenterally for the treatment of acute postpartum metritis in dairy cows","volume":"224","author":"Chenault","year":"2004","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.theriogenology.2005.08.021","article-title":"Defining postpartum uterine disease in cattle","volume":"65","author":"Sheldon","year":"2006","journal-title":"Theriogenology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ospina, P., Nydam, D., Stokol, T., and Overton, T. (2010, January 10\u201311). Comparison between Individual and Pooled Samples of Non-esterified Fatty Acids (NEFA) and B-hydroxybutyrate (BHBA) in Transition Dairy Cows to Determine Herd Alarm Level Status. Proceedings of the Forty-Third Annual Conference of the American Association of Bovine Practitioners, Knoxville, TN, USA.","DOI":"10.21423\/aabppro20104110"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.3168\/jds.S0022-0302(03)73704-7","article-title":"Splanchnic metabolism of dairy cows during the transition from late gestation through early lactation","volume":"86","author":"Reynolds","year":"2003","journal-title":"J. Dairy Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.3168\/jds.2018-15601","article-title":"Plasma metabolite changes in dairy cows during parturition identified using untargeted metabolomics","volume":"102","author":"Luo","year":"2019","journal-title":"J. Dairy Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev-animal-020518-115227","article-title":"Tolerance and Innate Immunity Shape the Development of Postpartum Uterine Disease and the Impact of Endometritis in Dairy Cattle","volume":"7","author":"Sheldon","year":"2019","journal-title":"Annu. Rev. Anim. Biosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.2527\/jas.2014-8496","article-title":"Physiology and endocrinology symposium: Uterine infection: Linking infection and innate immunity with infertility in the high-producing dairy cow","volume":"93","author":"Bromfield","year":"2015","journal-title":"J. Anim. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.3168\/jds.2017-13135","article-title":"Symposium review: Mechanisms linking metabolic stress with innate immunity in the endometrium","volume":"101","author":"Sheldon","year":"2018","journal-title":"J. Dairy Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-020-00311-7","article-title":"NAD(+) metabolism: Pathophysiologic mechanisms and therapeutic potential","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1042\/BST20190033","article-title":"Nicotinamide adenine dinucleotide (NAD+): Essential redox metabolite, co-substrate and an anti-cancer and anti-ageing therapeutic target","volume":"48","author":"Griffiths","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1007\/s00726-011-0962-7","article-title":"Mechanism underlying the antioxidant activity of taurine: Prevention of mitochondrial oxidant production","volume":"42","author":"Jong","year":"2012","journal-title":"Amino Acids"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/978-1-4614-6130-2_23","article-title":"Influence of taurine haloamines (TauCl and TauBr) on the development of Pseudomonas aeruginosa biofilm: A preliminary study","volume":"775","author":"Marcinkiewicz","year":"2013","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.5808\/GI.2018.16.4.e21","article-title":"An Advanced Understanding of Uterine Microbial Ecology Associated with Metritis in Dairy Cows","volume":"16","author":"Jeon","year":"2018","journal-title":"Genom. Inform."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/j.1365-2958.1995.tb02432.x","article-title":"Aminoacyl-tRNA synthetase gene regulation in Bacillus subtilis: Induction, repression and growth-rate regulation","volume":"16","author":"Putzer","year":"1995","journal-title":"Mol. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1007\/s00726-016-2219-y","article-title":"Effects of taurine on gut microbiota and metabolism in mice","volume":"48","author":"Yu","year":"2016","journal-title":"Amino Acids"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Greene, J.M., Feugang, J.M., Pfeiffer, K.E., Stokes, J.V., Bowers, S.D., and Ryan, P.L. (2013). L-Arginine enhances cell proliferation and reduces apoptosis in human endometrial RL95-2 cells. Reprod. Biol. Endocrinol., 11.","DOI":"10.1186\/1477-7827-11-15"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yang, Z., Luo, F., Liu, G., Luo, Z., Ma, S., Gao, H., He, H., and Tao, J. (2022). Plasma Metabolomic Analysis Reveals the Relationship between Immune Function and Metabolic Changes in Holstein Peripartum Dairy Cows. Metabolites, 12.","DOI":"10.3390\/metabo12100953"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1093\/biolreprod\/54.6.1261","article-title":"Unusual abundance of arginine and ornithine in porcine allantoic fluid","volume":"54","author":"Wu","year":"1996","journal-title":"Biol. Reprod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7437","DOI":"10.3168\/jds.2013-7679","article-title":"Biomarkers of inflammation, metabolism, and oxidative stress in blood, liver, and milk reveal a better immunometabolic status in peripartal cows supplemented with Smartamine M or MetaSmart","volume":"97","author":"Osorio","year":"2014","journal-title":"J. Dairy Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1093\/jas\/sky250","article-title":"Jugular infusion of arginine has a positive effect on antioxidant mechanisms in lactating dairy cows challenged intravenously with lipopolysaccharide1","volume":"96","author":"Zhao","year":"2018","journal-title":"J. Anim. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.anireprosci.2006.03.017","article-title":"Association between endometritis diagnosis using a novel intravaginal device and reproductive performance in dairy cattle","volume":"99","author":"McDougall","year":"2007","journal-title":"Anim. Reprod. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5429","DOI":"10.3168\/jds.2009-2117","article-title":"Evaluation of the Metricheck device and the gloved hand for the diagnosis of clinical endometritis in dairy cows","volume":"92","author":"Pleticha","year":"2009","journal-title":"J. Dairy Sci."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/11\/1156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:24:11Z","timestamp":1760131451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/11\/1156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,16]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["metabo13111156"],"URL":"https:\/\/doi.org\/10.3390\/metabo13111156","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,16]]}}}