Pathogenesis of uterine diseases in dairy cattle and implications for fertility
Uterine diseases in cattle occur at all stages of the reproduction cycle but the majority of cases is found in the postpartum period. The inflammation of the uterus is generally defined as metritis or endometritis, with several graduations, e.g. puerperal metritis, clinical metritis, clinical or subclinical endometritis. Whether uterine diseases have a negligible, moderate or detrimental effect on fertility is still under discussion and depends on definitions and classification. In the past, it was assumed that the pregnant uterus is free of pathogens, but recent studies found several species including pathogens in the uterus and endometrium of pregnant cows. After parturition, a broad diversity of bacteria with >200 different species has been found in the early postpartum period. Not all of these bacteria, however, are considered as pathogens. Furthermore, bacteriological findings provide only evidence for infection but not for inflammation. For some bacteria, particularly Escherichia coli and Trueperella pyogenes pathogenic mechanism resulting in metritis and endometritis have been elucidated in detail. The role of bacteria that can be regarded as opportunistic or potential pathogens, e.g. Bacillus pumilus, is still under investigation. The understanding of the uterine microbiota and its interactions is increasing with the use of modern high-resolution techniques such as Fourier-transform infrared spectroscopy. Endometrial cytology provides additional information about alterations in the endometrium. Knowledge of innate uterine defense mechanism in cattle has increased a lot in the recent past. It can be speculated that improving or modulating uterine defense mechanism will be part of future prevention and treatment approaches beyond the use of antimicrobials. In this context, cellular and molecular defense mechanisms have been in the focus of interest, e.g. the role of interleukins or mucins. This review gives a short overview on some aspects of recent research on uterine diseases in cattle.
Amos MR, Healey GD, Goldstone RJ, Mahan SM, Duvel A, Schuberth HJ, Sandra O, Zieger P, Dieuzy-Labaye I, Smith DG, Sheldon IM. 2014. Differential endometrial cell sensitivity to a cholesterol-dependent cytolysin links Trueperella pyogenes to uterine disease in cattle. Biol Reprod, 90:1-13.
Arosh JA, Parent J, Chapdelaine P, Sirois J, Fortier MA. 2002. Expression of cyclooxygenases 1 and 2 and prostaglandin E synthase in bovine endometrial tissue during the estrous cycle. Biol Reprod, 67:161-169.
Baranski W, Lukasik K, Skarzynski D, Sztachanska M, Zdunczyk S, Janowski T. 2013. Secretion of prostaglandins and leukotrienes by endometrial cells in cows with subclinical and clinical endometritis. Theriogenology, 80:766-772.
Bicalho ML, Machado VS, Oikonomou G, Gilbert RO, Bicalho RC. 2012. Association between virulence factors of Escherichia coli, Fusobacterium necrophorum, and Arcanobacterium pyogenes and uterine diseases of dairy cows. Vet Microbiol, 157:125-231.
Braga VMM, Gendler SJ. 1993. Modulation of Muc-1 mucin expression in the mouse uterus during the estrus cycle, early pregnancy and placentation. J Cell Sci, 105:397-405.
Chapinal N, Carson M, Duffield TF, Capel M, Godden S, Overton M, Santos JEP, LeBlanc SJ. 2011. The association of serum metabolites with clinical disease during the transition period. J Dairy Sci, 94:4897-4903.
Chapwanya A, Meade KG, Foley C, Narciandi F, Evans ACO, Doherty ML, Callanan JJ, O'Farrelly C. 2012. The postpartum endometrial inflammatory response: a normal physiological event with potential implications for bovine fertility. Reprod Fertil Dev, 24:1028-1039.
Chastant-Maillard S. 2015. Impact of bovine herpesvirus 4 (BoHV-4) on reproduction. Transbound Emerg Dis, 62:245-251.
De Boer MW, LeBlanc SJ, Dubuc J, Meier S, Heuwieser W, Arlt S, Gilbert RO, McDougall S. 2014. Invited review: systematic review of diagnostic tests for reproductive-tract infection and inflammation in dairy cows. J Dairy Sci, 97:3983-3999.
Dohmen MJW, Lohuis JACM, Huszenicza G, Nagy P, Gacs M. 1995. The relationship between bacteriological and clinical findings in cows with subacute/chronic endometritis. Theriogenology, 43:1379-1388.
Dohmen MJW, Joop K, Sturk A, Bols PEJ, Lohuis JACM. 2000. Relationship between intra-uterine bacterial contamination, endotoxin levels and the development of endometritis in postpartum cows with dystocia or retained placenta. Theriogenology, 54:1019-1032.
Drillich M, Tesfaye D, Rings F, Schellander K, Heuwieser W, Hoelker M. 2012. Effects of polymorphonuclear neutrophile infiltration into the endometrial environment on embryonic development in superovulated cows. Theriogenology, 77:570-578.
Dubuc J, Duffield TF, Leslie KE, Walton JS, LeBlanc SJ. 2010. Definitions and diagnosis of postpartum endometritis in dairy cows. J Dairy Sci, 93:5225-5233.
Fenwick MA, Llewellyn S, Fitzpatrick R, Kenny DA, Murphy JJ, Patton J, Wathes DC. 2008. Negative energy balance in dairy cows in associated with specific changes in IGF-binding protein expression in the oviduct. Reproduction, 135:63-75.
Fischer C, Drillich M, Odau S, Heuwieser W, Einspanier R, Gabler C. 2010. Selected pro-inflammatory factor transcripts in bovine endometrial epithelial cells are regulated during the oestrous cycle and elevated in case of subclinical or clinical endometritis. Reprod Fertil Dev, 22:818-829.
Földi J, Kulcsar M, Pecsi A, Huyghe B, de Sa C, Lohuis JA, Cox P, Huszenicza G. 2006. Bacterial complications of postpartum uterine involution in cattle. Anim Reprod Sci, 96:265-281.
Gabler C, Drillich M, Fischer C, Holder C, Heuwieser W, Einspanier R. 2009. Endometrial expression of selected transcripts involved in prostaglandin synthesis in cows with endometritis. Theriogenology, 71:993-1004.
Gabler C, Fischer C, Drillich M, Einspanier R, Heuwieser W. 2010. Time-dependent mRNA expression of selected pro-inflammatory factors in the endometrium of primiparous cows postpartum. Reprod Biol Endocrinol, 8:152. doi: 10.1186/1477-7827-8-152.
Galvão KN, Santos NR, Galvão JS, Gilbert RO. 2011. Association between endometritis and endometrial cytokine expression in postpartum Holstein cows. Theriogenology, 76:290-299.
Gärtner MA, Peter S, Jung M, Drillich M, Einspanier R, Gabler C. 2016. Increased mRNA expression of selected pro-inflammatory factors in inflamed bovine endometrium in vivo as well as in endometrial epithelial cells exposed to Bacillus pumilus in vitro. Reprod Fertil Dev, 28:982-294.
Giuliodori MJ, Magnasco RP, Becu-Villalobos D, Lacau-Mengido IM, Risco CA, de la Sota RL. 2013. Clinical endometritis in an Argentinean herd of dairy cows: risk factors and reproductive efficiency. J Dairy Sci, 96:210-218.
Goldstone RJ, Talbot R, Schuberth HJ, Sandra O, Sheldon IM, Smith DG. 2014. Draft genome sequence of Escherichia coli MS499, isolated from the infected uterus of a postpartum cow with metritis. Genome Announc, 2:e00217-214. doi: 10.1128/genomeA.00217-14.
Hailemariam D, Ibrahim S, Hoelker M, Drillich M, Heuwieser W, Looft C, Cinar MU, Tholen E, Schellander K, Tesfaye D. 2014. MicroRNA-regulated molecular mechanism underlying bovine subclinical endometritis. Reprod Fertil Dev, 26:898-913.
Herath S, Lilly ST, Fischer DP, Williams EJ, Dobson H, Bryant CE, Sheldon IM. 2009. Bacterial lipopolysaccharide induces an endocrine switch from prostaglandin F2alpha to prostaglandin E2 in bovine endometrium. Endocrinology, 150:1912-1920.
Hill J, Gilbert R. 2008. Reduced quality of bovine embryos cultured in media conditioned by exposure to an inflamed endometrium. Aust Vet J, 86:312-316.
Hoelker M, Salilew-Wondim D, Drillich M, Christine GB, Ghanem N, Goetze L, Tesfaye D, Schellander K, Heuwieser W. 2012. Transcriptional response of the bovine endometrium and embryo to endometrial polymorphonuclear neutrophil infiltration as an indicator of subclinical inflammation of the uterine environment. Reprod Fertil Dev, 24:778-793.
Ibrahim M, Peter S, Gärtner MA, Michel G, Jung M, Einspanier R, Gabler C. 2016. Increased mRNA expression of selected antimicrobial peptides around ovulation and during inflammatory processes in the bovine endometrium postpartum. Theriogenology, 86:2040-2053.
Jeon SJ, Cunha F, Ma X, Martinez N, Vieira-Neto A, Daetz R, Bicalho RC, Lima S, Santos JE, Jeong KC, Galvão KN. 2016. Uterine microbiota and immune parameters associated with fever in dairy cows with metritis. PLoS One, 11:e0165740. doi: 10.1371/journal.pone.0165740.
Jeon SJ, Cunha F, Vieira-Neto A, Bicalho RC, Lima S, Bicalho ML, Galvão KN. 2017. Blood as a route of transmission of uterine pathogens from the gut to the uterus in cows. Microbiome, 5:109. doi. org/10.1186/s40168-017-0328-9.
Jeon SJ, Lima FS, Vieira-Neto A, Machado VS, Lima SF, Bicalho RC, Santos JEP, Galvão KN. 2018. Shift of uterine microbiota associated with antibiotic treatment and cure of metritis in dairy cows. Vet Microbiol, 214:132-139.
Johnson GA, Bazer FW, Jaeger LA, Ka H, Garlow JE, Pfarrer C, Spencer TE, Burghardt RC. 2001. Muc-1, integrin, and osteopontin expression during the implantation cascade in sheep. Biol Reprod, 65:820-828.
Kasimanickam R, Duffield TF, Foster RA, Gartley CJ, Leslie KE, Walton JS, Johnson WH. 2004. Endometrial cytology and ultrasonography for the detection of subclinical endometritis in postpartum dairy cows. Theriogenology, 62:9-23.
Kasimanickam R, Kasimanickam V, Kastelic JP. 2014. Mucin 1 and cytokines mRNA in endometrium of dairy cows with postpartum uterine disease or repeat breeding. Theriogenology, 81:952-958.
Karstrup CC, Klitgaard K, Jensen TK, Agerholm JS, Pedersen HG. 2017. Presence of bacteria in the endometrium and placentomes of pregnant cows. Theriogenology, 99:41-47.
LeBlanc SJ, Duffield TF, Leslie KE, Bateman KG, Keefe GP, Walton JS, Johnson WH. 2002. Defining and diagnosing postpartum clinical endometritis and its impact on reproductive performance in dairy cows. J Dairy Sci, 85:2223-2236.
LeBlanc SJ. 2010. Monitoring metabolic health of dairy cattle in the transition period. J Reprod Dev, 56:S29-S35.
LeBlanc SJ, Osawa T, Dubuc J. 2011. Reproductive tract defense and disease in postpartum dairy cows. Theriogenology, 76:1610-1618.
LeBlanc SJ. 2012. Interactions of metabolism, inflammation, and reproductive tract health in the postpartum period in dairy cattle. Reprod Domest Anim, 47:18-30.
Leroy JLMR, Van Soom A, Opsomer G, Bols PEJ. 2008. The consequences of metabolic changes in high-yielding dairy cows on oocyte and embryo quality. Animal, 2:1120-1127.
Madoz LV, Giuliodori MJ, Jaureguiberry M, Plöntzke J, Drillich M, de la Sota RL. 2013. The relationship between endometrial cytology during estrous cycle and cutoff points for the diagnosis of subclinical endometritis in grazing dairy cows. J Dairy Sci, 96:4333-4339.
Madoz LV, Giuliodori MJ, Migliorisi AL, Jaureguiberry M, de la Sota RL. 2014. Endometrial cytology, biopsy, and bacteriology for the diagnosis of subclinical endometritis in grazing dairy cows. J Dairy Sci, 97:195-201.
Moore SG, Ericsson AC, Poock SE, Melendez P, Lucy MC. 2017. Hot topic: 16S rRNA gene sequencing reveals the microbiome of the virgin and pregnant bovine uterus. J Dairy Sci, 100:4953-4960.
Peter S, Michel G, Hahn A, Ibrahim M, Lubke-Becker A, Jung M, Einspanier R, Gabler C. 2015. Puerperal influence of bovine uterine health status on the mRNA expression of pro-inflammatory factors. J Physiol Pharmacol, 66:449-462.
Potter TJ, Guitian J, Fishwick J, Gordon PJ, Sheldon IM. 2010. Risk factors for clinical endometritis in postpartum dairy cattle. Theriogenology, 74:127-134.
Prunner I, Pothmann H, Wagener K, Giuliodori M, Huber J, Ehling-Schulz M, Drillich M. 2014. Dynamics of bacteriologic and cytologic changes in the uterus of postpartum dairy cows. Theriogenology, 82:1316-1322.
Saito S, Tsuda H, Michimata T. 2002. Prostaglandin D2 and reproduction. Am J Reprod Immunol, 47:295-302.
Santos TMA, Gilbert R, Bicalho RC. 2011. Metagenomic analysis of the uterine bacterial microbiota in healthy and metritic postpartum dairy cows. J Dairy Sci, 94:291-302.
Santos TMA, Bicalho RC. 2012. Diversity and succession of bacterial communities in the uterine fluid of postpartum metritic, endometritic and healthy dairy cows. PLoS One, 7:e53048. doi: 10.1371/journal.pone.0053048.
Sheldon IM, Noakes DE, Rycroft AN, Pfeiffer DU, Dobson H. 2002. Influence of uterine bacterial contamination after parturition on ovarian dominant follicle selection and follicle growth and function in cattle. Reproduction, 123:837-845.
Sheldon IM, Lewis GS, LeBlanc S, Gilbert RO. 2006. Defining postpartum uterine disease in cattle. Theriogenology, 65:1516-1530.
Sheldon IM, Cronin J, Goetze L, Donofrio G, Schuberth H-J. 2009. Defining postpartum uterine disease and the mechanisms of infection and immunity in the female reproductive tract in cattle. Biol Reprod, 81:1025-1032.
Sheldon IM, Rycroft AN, Dogan B, Craven M, Bromfield JJ, Chandler A, Roberts MH, Price SB, Gilbert RO, Simpson KW. 2010. Specific strains of Escherichia coli are pathogenic for the endometrium of cattle and cause pelvic inflammatory disease in cattle and mice. PLoS One, 5: e9192. doi: 10.1371/journal.pone.0009192.
Sheldon IM, Cronin JG, Healey GD, Gabler C, Heuwieser W, Streyl D, Bromfield JJ, Miyamoto A, Fergani C, Dobson H. 2014. Innate immunity and inflammation of the bovine female reproductive tract in health and disease. Reproduction, 148:R41-R51.
Sheldon IM. 2015. Genes and environmental factors that influence disease resistance to microbes in the female reproductive tract of dairy cattle. Reprod Fertil Dev, 27:72-81.
Valour D, Hue I, Degrelle SA, Déjean S, Marot G, Dubois O, Germain G, Humblot P, Ponter A, Charpigny G, Grimard B. 2013. Pre- and post-partum mild underfeeding influences gene expression in the reproductive tract of cyclic dairy cows. Reprod Domest Anim, 48:484-499.
Wagener K, Drillich M, Baumgardt S, Kämpfer P, Busse HJ, Ehling-Schulz M. 2014a. Falsiporphyromonas endometrii gen. nov., sp. nov., isolated from the post-partum bovine uterus, and emended description of the genus Porphyromonas Shah and Collins 1988. Int J Syst Evol Microbiol, 64(Pt 2):642-649.
Wagener K, Grunert T, Prunner I, Ehling-Schulz M, Drillich M. 2014b. Dynamics of uterine infections with Escherichia coli, Streptococcus uberis and Trueperella pyogenes in post-partum dairy cows and their association with clinical endometritis. Vet J, 202:527-532.
Wagener K, Prunner I, Pothmann H, Drillich M, Ehling-Schulz M. 2015. Diversity and health status specific fluctuations of intrauterine microbial communities in postpartum dairy cows. Vet Microbiol, 175:286-293.
Wagener K, Gabler C, Drillich M. 2017a. A review of the ongoing discussion about definition, diagnosis and pathomechanism of subclinical endometritis in dairy cows. Theriogenology, 94:21-30.
Wagener K, Pothmann H, Prunner I, Peter S, Erber R, Aurich C, Drillich M, Gabler C. 2017b. Endometrial mRNA expression of selected pro-inflammatory factors and mucins in repeat breeder cows with and without subclinical endometritis. Theriogenology, 90:237-244.
Werner A, Suthar V, Plöntzke J, Heuwieser W. 2012. Relationship between bacteriological findings in the second and fourth weeks postpartum and uterine infection in dairy cows considering bacteriological results. J Dairy Sci, 95:7105-7114.
Westermann S, Drillich M, Kaufmann TB, Madoz LV, Heuwieser W. 2010. A clinical approach to determine false positive findings of clinical endometritis by vaginoscopy by the use of uterine bacteriology and cytology in dairy cows. Theriogenology, 74:1248-1255.
Williams EJ, Herath S, England GCW, Dobson H, Bryant CE, Sheldon IM. 2008. Effect of Escherichia coli infection of the bovine uterus from the whole animal to the cell. Animal, 2:1153-1157.
Zerbe H, Schuberth HJ, Engelke F, Frank J, Klug E, Leibold W. 2003. Development and comparison of in vivo and in vitro models for endometritis in cows and mares. Theriogenology, 60:209-223.