{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:14:46Z","timestamp":1792685686454,"version":"4.5.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T00:00:00Z","timestamp":1740268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>This study investigated differences in uterine and serum metabolome associated with clinical cure failure of metritis in dairy cows. Metritis was diagnosed in lactating Holstein cows from two Florida dairies and defined by the presence of fetid, watery, reddish-brown vaginal discharge from 4 to 12\u00a0days postpartum (dpp). Cows with metritis (n\u2009=\u200924) were paired with cows without metritis of similar parity and dpp (n\u2009=\u200924). On the day of metritis diagnosis (day 0), all cows with metritis received antimicrobial therapy. The continued presence of the fetid, watery, reddish-brown discharge on day 5 (n\u2009=\u200916) was defined as clinical cure failure, whereas clinical cure was defined by its absence (n\u2009=\u20098). Metabolome analyses of uterine lavage (days 0 and 5) and serum samples (day 0) were conducted using untargeted gas chromatography time-of-flight mass spectrometry. Normalized data were analyzed using partial least squares\u2013discriminant analysis and ANOVA, adjusting P-values for multiple comparisons. Differences in the uterine metabolome on day 0 associated with clinical cure failure were linked to carbohydrate, amino acid, and lipid metabolism. Greater concentrations of arachidonic acid, ribose, and glutaric acid were associated with clinical cure failure, suggesting a greater degree of tissue lesion and inflammation. No differences in the serum metabolome were associated with cure failure. No differences in uterine metabolome were associated with clinical cure failure on day 5. The findings suggest that clinical cure failure is associated with a greater uterine inflammatory process that did not persist until cure assessment day.<\/jats:p>","DOI":"10.1093\/biolre\/ioaf038","type":"journal-article","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T16:38:06Z","timestamp":1740328686000},"page":"858-866","source":"Crossref","is-referenced-by-count":9,"title":["Differences in uterine and serum metabolome associated with clinical cure failure of metritis in dairy cows"],"prefix":"10.1093","volume":"112","author":[{"given":"Frederico Narciso de Souza","family":"Pereira","sequence":"first","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Washington State University , Pullman, WA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline Martelo","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Washington State University , Pullman, WA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klibs Neblan","family":"Galv\u00e3o","sequence":"additional","affiliation":[{"name":"Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida , Gainesville, FL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Sisconeto","family":"Bisinotto","sequence":"additional","affiliation":[{"name":"Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida , Gainesville, FL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caio Cesar","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Washington State University , Pullman, WA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,23]]},"reference":[{"key":"2025052711562688700_ref1","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":"2025052711562688700_ref2","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":"2025052711562688700_ref3","doi-asserted-by":"crossref","first-page":"8248","DOI":"10.3168\/jds.2018-14510","article-title":"Assessment of daily activity patterns and biomarkers of pain, inflammation, and stress in lactating dairy cows diagnosed with clinical metritis","volume":"101","author":"Barragan","year":"2018","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref4","first-page":"385","article-title":"Applying nutrition and physiology to improve reproduction in dairy cattle","volume":"7","author":"Santos","year":"2010","journal-title":"Society for Reproduction and Fertility"},{"key":"2025052711562688700_ref5","doi-asserted-by":"crossref","first-page":"8234","DOI":"10.3168\/jds.2023-24562","article-title":"Graduate student literature review: implications of transition cow health for reproductive function and targeted reproductive management","volume":"107","author":"Bruinj\u00e9","year":"2024","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref6","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":"Oliveira","year":"2020","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref7","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.3168\/jds.2020-19076","article-title":"Effects of metritis treatment strategies on health, behavior, reproductive, and productive responses of Holstein cows","volume":"104","author":"Merenda","year":"2021","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref8","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.3168\/jds.2010-3697","article-title":"Short communication: metritis affects milk production and cull rate of Holstein multiparous and primiparous dairy cows differently","volume":"94","author":"Wittrock","year":"2011","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref9","doi-asserted-by":"crossref","first-page":"7056","DOI":"10.3168\/jds.2020-19661","article-title":"Failure of clinical cure in dairy cows treated for metritis is associated with reduced productive and reproductive performance","volume":"104","author":"Figueiredo","year":"2021","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref10","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":"2025052711562688700_ref11","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":"P\u00e9rez-B\u00e1ez","year":"2021","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref12","doi-asserted-by":"crossref","first-page":"8918","DOI":"10.3168\/jds.2020-19430","article-title":"Economic comparison between ceftiofur-treated and nontreated dairy cows with metritis","volume":"104","author":"Silva","year":"2021","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref13","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":"Javma"},{"key":"2025052711562688700_ref14","doi-asserted-by":"crossref","first-page":"4363","DOI":"10.3168\/jds.2011-5111","article-title":"Evaluation of two doses of ceftiofur crystalline free acid sterile suspension for treatment of metritis in lactating dairy cows","volume":"95","author":"McLaughlin","year":"2012","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref15","doi-asserted-by":"crossref","first-page":"7092","DOI":"10.3168\/jds.2023-24406","article-title":"A randomized controlled trial evaluating the efficacy of systemic ceftiofur administration for metritis therapy in dairy cows and the effect of metritis cure on economically important outcomes","volume":"107","author":"Menta","year":"2024","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref16","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, reproductive performance, milk yield, and culling for untreated and ceftiofur-treated dairy cows","volume":"103","author":"Machado","year":"2020","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref17","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.3168\/jds.2023-24452","article-title":"Predictive models for metritis cure using farm-collected data, metabolic and inflammation biomarkers, and hemogram variables measured at diagnosis","volume":"107","author":"Menta","year":"2024","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref18","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":"Oliveira","year":"2021","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref19","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":"2025052711562688700_ref20","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.3168\/jds.2023-23611","article-title":"Application of behavior data to predictive exploratory models of metritis self-cure and treatment failure in dairy cows","volume":"107","author":"Prim","year":"2024","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref21","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":"2025052711562688700_ref22","doi-asserted-by":"crossref","first-page":"11864","DOI":"10.1038\/s41598-024-61704-0","article-title":"Shifts in uterine microbiome associated with pregnancy outcomes at first insemination and clinical cure in dairy cows with metritis","volume":"14","author":"Figueiredo","year":"2024","journal-title":"Sci Rep"},{"key":"2025052711562688700_ref23","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.3390\/metabo13111156","article-title":"Changes in uterine metabolome associated with metritis development and cure in lactating Holstein cows","volume":"13","author":"Oliveira","year":"2023","journal-title":"Metabolites"},{"key":"2025052711562688700_ref24","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s42523-024-00314-7","article-title":"Integrating uterine microbiome and metabolome to advance the understanding of the uterine environment in dairy cows with metritis","volume":"6","author":"Casaro","year":"2024","journal-title":"Animal Microbiome"},{"key":"2025052711562688700_ref25","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":"2025052711562688700_ref26","doi-asserted-by":"crossref","first-page":"6079","DOI":"10.3168\/jds.2023-23905","article-title":"Evaluating differences in milk production, reproductive performance, and survival associated with vaginal discharge characteristics and fever in postpartum dairy cows","volume":"107","author":"Figueiredo","year":"2024","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref27","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":"2025052711562688700_ref28","article-title":"Differences in reproductive and productive performance, and culling associated with time to clinical cure in dairy cows treated for metritis","volume-title":"J Dairy Sci","author":"Pereira"},{"key":"2025052711562688700_ref29","doi-asserted-by":"crossref","first-page":"e01066","DOI":"10.1128\/AEM.01066-20","article-title":"Effect of chitosan microparticles on the uterine microbiome of dairy cows with metritis","volume":"86","author":"Galv\u00e3o","year":"2020","journal-title":"Appl Environ Microbiol"},{"key":"2025052711562688700_ref30","doi-asserted-by":"crossref","first-page":"W398","DOI":"10.1093\/nar\/gkae253","article-title":"MetaboAnalyst 6.0: towards a unified platform for metabolomics data processing, analysis and interpretation","volume":"52","author":"Pang","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"2025052711562688700_ref31","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc B Methodol"},{"key":"2025052711562688700_ref32","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1139\/cjas-2017-0069","article-title":"Identification of serum metabolites associated with the risk of metritis in transition dairy cows","volume":"98","author":"Hailemariam","year":"2018","journal-title":"Can J Anim Sci"},{"key":"2025052711562688700_ref33","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.rvsc.2020.10.012","article-title":"Common and specific mineral and metabolic features in dairy cows with clinical metritis, hypocalcaemia or ketosis","volume":"135","author":"Dervishi","year":"2021","journal-title":"Res Vet Sci"},{"key":"2025052711562688700_ref34","doi-asserted-by":"crossref","first-page":"8098","DOI":"10.3168\/jds.2023-23433","article-title":"Blood metabolomics and impacted cellular mechanisms during transition into lactation in dairy cows that develop metritis","volume":"106","author":"Casaro","year":"2023","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref35","doi-asserted-by":"crossref","first-page":"e363","DOI":"10.1002\/mco2.363","article-title":"Arachidonic acid metabolism in health and disease","volume":"4","author":"Zhang","year":"2023","journal-title":"MedComm"},{"key":"2025052711562688700_ref36","first-page":"1","article-title":"Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets","volume":"6","author":"Wang","year":"2021","journal-title":"Sig Transduct Target Ther"},{"key":"2025052711562688700_ref37","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.3390\/biom10081133","article-title":"Arachidonic acid as an early indicator of inflammation during non-alcoholic fatty liver disease development","volume":"10","author":"Sztolsztener","year":"2020","journal-title":"Biomolecules"},{"key":"2025052711562688700_ref38","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.theriogenology.2004.03.017","article-title":"Clinical evaluation of postpartum vaginal mucus reflects uterine bacterial infection and the immune response in cattle","volume":"63","author":"Williams","year":"2005","journal-title":"Theriogenology"},{"key":"2025052711562688700_ref39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.113.115972","article-title":"Differential endometrial cell sensitivity to a cholesterol-dependent Cytolysin links Trueperella pyogenes to uterine disease in Cattle1","volume":"90","author":"Amos","year":"2014","journal-title":"Biol Reprod"},{"key":"2025052711562688700_ref40","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.theriogenology.2015.07.004","article-title":"Effects of intrauterine infusion of Trueperella pyogenes on endometrial mRNA expression of proinflammatory cytokines and luteolytic cascade genes and their association with luteal life span in dairy cows","volume":"84","author":"Lima","year":"2015","journal-title":"Theriogenology"},{"key":"2025052711562688700_ref41","doi-asserted-by":"crossref","DOI":"10.3389\/fcimb.2017.00373","article-title":"Neutrophils to the ROScue: mechanisms of NADPH oxidase activation and bacterial resistance","volume":"7","author":"Nguyen","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"key":"2025052711562688700_ref42","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.immuni.2021.06.006","article-title":"The neutrophil","volume":"54","author":"Burn","year":"2021","journal-title":"Immunity"},{"key":"2025052711562688700_ref43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13620-020-00161-3","article-title":"Evaluation of oxidant\/antioxidant status, metabolic profile and milk production in cows with metritis","volume":"73","author":"Mikulkov\u00e1","year":"2020","journal-title":"Irish Veterinary Journal"},{"key":"2025052711562688700_ref44","first-page":"1","volume-title":"Handbook of Neurotoxicity","author":"Amaral","year":"2021"},{"key":"2025052711562688700_ref45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7575\/aiac.abcmed.v.6n.1p.1","article-title":"Understanding D-ribose and mitochondrial function","volume":"6","author":"Mahoney","year":"2018","journal-title":"Advances in Bioscience and Clinical Medicine"},{"key":"2025052711562688700_ref46","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":"Galv\u00e3o","year":"2019","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s42523-021-00077-5","article-title":"Ceftiofur reduced Fusobacterium leading to uterine microbiota alteration in dairy cows with metritis","volume":"3","author":"Jeon","year":"2021","journal-title":"Animal Microbiome"},{"key":"2025052711562688700_ref48","doi-asserted-by":"crossref","first-page":"8366","DOI":"10.3168\/jds.2023-24585","article-title":"Randomized clinical trial of ketoprofen or ceftiofur for treatment of metritis in dairy cows","volume":"107","author":"Paiano","year":"2024","journal-title":"J Dairy Sci"},{"key":"2025052711562688700_ref49","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.theriogenology.2020.01.017","article-title":"Preventing postpartum uterine disease in dairy cattle depends on avoiding, tolerating and resisting pathogenic bacteria","volume":"150","author":"Sheldon","year":"2020","journal-title":"Theriogenology"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioaf038\/62055156\/ioaf038.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/112\/5\/858\/62055156\/ioaf038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/112\/5\/858\/62055156\/ioaf038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T15:56:41Z","timestamp":1748361401000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/112\/5\/858\/8030601"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,23]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,2,23]]},"published-print":{"date-parts":[[2025,5,13]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioaf038","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,5]]},"published":{"date-parts":[[2025,2,23]]}}}