Postpartum uterine infection and endometritis in dairy cattle
Iain Martin Sheldon, Sian E Owens
Abstract
After parturition, uterine involution, regeneration of the endometrium, return of ovarian cyclic activity, and the control of pathogenic bacteria in the uterus is required before cows are likely to conceive again. However, pathogenic bacteria often cause uterine disease in modern dairy cattle, leading to decreased productivity and reduced fertility. This review aims to provide an overview of postpartum uterine infection and disease in dairy cattle. Metritis and endometritis are the main postpartum clinical conditions; although, subclinical endometritis is an emerging issue. Postpartum uterine disease is associated with the isolation of Escherichia coli, Trueperella pyogenes, and anaerobic pathogenic bacteria. Sensing of bacteria or their pathogen-associated molecules, such as lipopolysaccharide, by the innate immune system generates inflammatory responses. Endometrial inflammation includes increased expression of complement, calgranulins, interleukins and acute phase proteins, as well as the chemotaxis of neutrophils and macrophages to the site of infection. Uterine disease is also characterised by tissue damage, including endometrial cytolysis caused by the cholesteroldependent cytolysin, pyolysin. The responses to pathogens are energetically expensive, and depletion of the key cellular nutrients, glucose or glutamine, impairs inflammatory responses by endometrial tissues. For sustainable intensification of the dairy industry over the next 50 years, it is vital to understand why high-milkyield cows are so susceptible to uterine pathology and develop new ways to prevent uterine disease.
Keywords
References
Amos MR, Healey GD, Goldstone RJ, Mahan S, Duvel A, Schuberth HJ, Sandra O, Zieger P, DieuzyLabaye I, Smith DGE, Sheldon IM. 2014. Differential endometrial cell sensitivity to a cholesterol-dependent cytolysin links Trueperella pyogenes to uterine disease in cattle. Biol Reprod, 90:54,1-13.
Ayliffe TR, Noakes DE. 1982. Effects of exogenous oestrogen and experimentally induced endometritis on absorption of sodium benzylpenicillin from the cow's uterus. Vet Rec, 110:96-98.
Beam SW, Butler WR. 1997. Energy balance and ovarian follicle development prior to the first ovulation postpartum in dairy cows receiving three levels of dietary fat. Biol Reprod, 56:133-142.
Beam SW, Butler WR. 1999. Effects of energy balance on follicular development and first ovulation in postpartum dairy cows. J Reprod Fertil Suppl, 54:411- 424.
Blander JM, Sander LE. 2012. Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol, 12:215-225.
Bonnett BN, Martin SW, Gannon VP, Miller RB, Etherington WG. 1991. Endometrial biopsy in Holstein-Friesian dairy cows. III. Bacteriological analysis and correlations with histological findings. Can J Vet Res, 55:168-173.
Borsberry S, Dobson H. 1989. Periparturient diseases and their effect on reproductive performance in five dairy herds. Vet Rec, 124:217-219.
Bromfield JJ, Sheldon IM. 2011. Lipopolysaccharide initiates inflammation in bovine granulosa cells via the TLR4 pathway and perturbs oocyte meiotic progression in vitro. Endocrinology, 152:5029-5040.
Bromfield JJ, Santos JE, Block J, Williams RS, Sheldon IM. 2015. Physiology and Endocrinology Symposium: Uterine infection: linking infection and innate immunity with infertility in the high-producing dairy cow. J Anim Sci, 93:2021-2033.
Chagas LM, Bass JJ, Blache D, Burke CR, Kay JK, Lindsay DR, Lucy MC, Martin GB, Meier S, Rhodes FM, Roche JR, Thatcher WW, Webb R. 2007. Invited review: New perspectives on the roles of nutrition and metabolic priorities in the subfertility of high-producing dairy cows. J Dairy Sci, 90:4022-4032.
Chapwanya A, Meade KG, Doherty ML, Callanan JJ, O'Farrelly C. 2013. Endometrial epithelial cells are potent producers of tracheal antimicrobial peptide and serum amyloid A3 gene expression in response to E. coli stimulation. Vet Immunol Immunopathol, 151:157- 162.
Cheong SH, Sa Filho OG, Absalon-Medina VA, Pelton SH, Butler WR, Gilbert RO. 2016. Metabolic and endocrine differences between dairy cows that do or do not ovulate first postpartum dominant follicles. Biol Reprod, 94:18, 1-11.
Cronin JG, Turner ML, Goetze L, Bryant CE, Sheldon IM. 2012. Toll-Like receptor 4 and MyD88- dependent signaling mechanisms of the innate immune system are essential for the response to lipopolysaccharide by epithelial and stromal cells of the bovine endometrium. Biol Reprod, 86:51, 1-9.
Cronin JG, Kanamarlapudi V, Thornton CA, Sheldon IM. 2016. Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells. Mucosal Immunol, 9:1125-1136.
Crowe MA, Padmanabhan V, Mihm M, Beitins IZ, Roche JF. 1998. Resumption of follicular waves in beef cows is not associated with periparturient changes in follicle-stimulating hormone heterogeneity despite major changes in steroid and luteinizing hormone concentrations. Biol Reprod, 58:1445-1450.
Davies D, Meade KG, Herath S, Eckersall PD, Gonzalez D, White JO, Conlan RS, O'Farrelly C, Sheldon IM. 2008. Toll-like receptor and antimicrobial peptide expression in the bovine endometrium. Reprod Biol Endocrinol, 6:53.
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, 97:3983-399.
Dhaliwal GS, Murray RD, Woldehiwet Z. 2001. Some aspects of immunology of the bovine uterus related to treatments for endometritis. Anim Reprod Sci, 67:135-152.
Dohmen MJ, Joop K, Sturk A, Bols PE, Lohuis JA. 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.
Dubuc J, Duffield TF, Leslie KE, Walton JS, LeBlanc SJ. 2010. Risk factors for postpartum uterine diseases in dairy cows. J Dairy Sci, 93:5764-5771.
Duffy P, Crowe MA, Boland MP, Roche JF. 2000. Effect of exogenous LH pulses on the fate of the first dominant follicle in postpartum beef cows nursing calves. J Reprod Fertil, 118:9-17.
Elliott L, McMahon KJ, Gier HT, Marion GB. 1968. Uterus of the cow after parturition: bacterial content. Am J Vet Res, 29:77-81. Esposito G, Irons PC, Webb EC, Chapwanya A. 2014. Interactions between negative energy balance, metabolic diseases, uterine health and immune response in transition dairy cows. Anim Reprod Sci, 144:60-71.
Fonseca FA, Britt JH, McDaniel BT, Wilk JC, Rakes AH. 1983. Reproductive traits of Holsteins and Jerseys. Effects of age, milk yield, and clinical abnormalities on involution of cervix and uterus, ovulation, estrous cycles, detection of estrus, conception rate and days open. J Dairy Sci, 66:1128-1147.
Fourichon C, Seegers H, Malher X. 2000. Effect of disease on reproduction in the dairy cow: a metaanalysis. Theriogenology, 53:1729-1759.
Gier HT, Marion GB. 1968. Uterus of the cow after parturition: involutional changes. Am J Vet Res, 29:83- 96.
Gilbert RO, Shin ST, Guard CL, Erb HN, Frajblat M. 2005. Prevalence of endometritis and its effects on reproductive performance of dairy cows. Theriogenology, 64:1879-1888.
Griffin JFT, Hartigan PJ, Nunn WR. 1974. Nonspecific uterine infection and bovine fertility. I. Infection patterns and endometritis during the first seven weeks post-partum. Theriogenology, 1:91-106.
Healy LL, Cronin JG, Sheldon IM. 2014. Endometrial cells sense and react to tissue damage during infection of the bovine endometrium via interleukin 1. Sci Rep, 4:7060, 1-9. doi:10.1038/srep07060.
Healy LL, Cronin JG, Sheldon IM. 2015. Polarized epithelial cells secrete interleukin 6 apically in the bovine endometrium. Biol Reprod, 92:151, 1-12.
Herath S, Fischer DP, Werling D, Williams EJ, Lilly ST, Dobson H, Bryant CE, Sheldon IM. 2006. Expression and function of Toll-like receptor 4 in the endometrial cells of the uterus. Endocrinology, 147:562- 570.
Hussain AM, Daniel RCW, O'Boyle D. 1990. Postpartum uterine flora following normal and abnormal puerperium in cows. Theriogenology, 34:291-302.
Huszenicza G, Fodor M, Gacs M, Kulcsar M, Dohmen MJW, Vamos M, Porkolab L, Legl T, Bartyik J, Lohuis JACM, Janosi S, Szita G. 1991. Uterine bacteriology, resumption of cyclic ovarian activity and fertility in postpartum cows kept in largescale dairy herds. Reprod Domest Anim, 34:237-245.
Karsch FJ, Battaglia DF, Breen KM, Debus N, Harris TG. 2002. Mechanisms for ovarian cycle disruption by immune/inflammatory stress. Stress, 5:101-112.
Karstrup CC, Klitgaard K, Jensen TK, Agerholm JS, Pedersen HG. 2017. Presence of bacteria in the endometrium and placentomes of pregnant cows. Theriogenolgy, 99:43-47.
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 e2.
Kerestes M, Faigl V, Kulcsar M, Balogh O, Foldi J, Febel H, Chilliard Y, Huszenicza G. 2009. jPeriparturient insulin secretion and whole-body insulin responsiveness in dairy cows showing various forms of ketone pattern with or without puerperal metritis. Domest Anim Endocrinol, 37:250-261.
Knudsen LR, Karstrup CC, Pedersen HG, Agerholm JS, Jensen TK, Klitgaard K. 2015. Revisiting bovine pyometra--new insights into the disease using a cultureindependent deep sequencing approach. Vet Microbiol, 175:319-324.
Kono H, Rock KL. 2008. How dying cells alert the immune system to danger. Nat Rev Immunol, 8:279-89. Kotas ME, Medzhitov R. 2015. Homeostasis, inflammation, and disease susceptibility. Cell, 160:816- 827.
Kvidera SK, Horst EA, Abuajamieh M, Mayorga EJ, Fernandez MV, Baumgard LH. 2017. Glucose requirements of an activated immune system in lactating Holstein cows. J Dairy Sci, 100:2360-2374.
Lamkanfi M, Dixit VM. 2014. Mechanisms and functions of inflammasomes. Cell, 157:1013-1022. 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.
Machado VS, Bicalho ML, Meira Junior EB, Rossi R, Ribeiro BL, Lima S, Santos T, Kussler A, Foditsch C, Ganda EK, Oikonomou G, Cheong SH, Gilbert RO, Bicalho RC. 2014. Subcutaneous immunization with inactivated bacterial components and purified protein of Escherichia coli, Fusobacterium necrophorum and Trueperella pyogenes prevents puerperal metritis in Holstein dairy cows. PLOS One, 9:e91734.
Machado VS, Oikonomou G, Bicalho ML, Knauer WA, Gilbert R, Bicalho RC. 2012. Investigation of postpartum dairy cows' uterine microbial diversity using metagenomic pyrosequencing of the 16S rRNA gene. Vet Microbiol, 159:460-469.
Marey MA, Yousef MS, Kowsar R, Hambruch N, Shimizu T, Pfarrer C, Miyamoto A. 2016. Local immune system in oviduct physiology and pathophysiology: attack or tolerance? Domest Anim Endocrinol, 56(suppl):S204-211.
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.
Moresco EM, LaVine D, Beutler B. 2011. Toll-like receptors. Curr Biol, 21:R488-93.
Noakes DE, Wallace LM, Smith GR. 1990. Pyometra in a Friesian heifer: bacteriological and endometrial changes. Vet Rec, 126:509.
Noakes DE, Wallace L, Smith GR. 1991. Bacterial flora of the uterus of cows after calving on two hygienically contrasting farms. Vet Rec, 128:440-442.
Noleto PG, Saut JP, Sheldon IM. 2017. Short communication: Glutamine modulates inflammatory responses to lipopolysaccharide in ex vivo bovine endometrium. J Dairy Sci, 100:2207-2212.
Nolte O, Morscher J, Weiss HE, Sonntag H. 2001. Autovaccination of dairy cows to treat post partum metritis caused by Actinomyces pyogenes. Vaccine, 19:3146-3153.
Okano A, Tomizuka T. 1987. Ultrasonic observation of postpartum uterine involution in the cow. Theriogenology, 27:369-376.
Olson JD, Ball L, Mortimer RG, Farin PW, Adney WS, Huffman EM. 1984. Aspects of bacteriology and endocrinology of cows with pyometra and retained fetal membranes. Am J Vet Res, 45:2251-2255.
Peeler EJ, Otte MJ, Esslemont RJ. 1994. Interrelationships of periparturient diseases in dairy cows. Vet Rec, 134:129-132.
Peng Y, Wang Y, Hang S, Zhu W. 2013. Microbial diversity in uterus of healthy and metritic postpartum Holstein dairy cows. Folia Microbiol (Praha), 58:593- 600.
Potter T, Guitian J, Fishwick J, Gordon PJ, Sheldon IM. 2010. Risk factors for clinical endometritis in postpartum dairy cattle. Theriogenology, 74:127-134. Preta G, Lotti V, Cronin JG, Sheldon IM. 2015.
Protective role of the dynamin inhibitor Dynasore against the cholesterol-dependent cytolysin of Trueperella pyogenes. FASEB J, 29:1516-1528.
Risco CA, Drost M, Thatcher WW, Savio J, Thatcher MJ. 1994. Effects of calving-related disorders on prostaglandin, calcium, ovarian activity and uterine involution in postpartum dairy cows. Theriogenology, 42:183-203.
Ruder CA, Sasser RG, Williams RJ, Ely JK, Bull RC, Butler JE. 1981. Uterine infections in the postpartum cow: II Possible synergistic effect of Fusobacterium necrophorum and Corynebacterium pyogenes. Theriogenology, 15:573-580.
Sannmann I, Heuwieser W. 2015. Technical note: Intraobserver, interobserver, and test-retest reliabilities of an assessment of vaginal discharge from cows with and without acute puerperal metritis. J Dairy Sci, 98:5460-5466.
Santos TM, 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.
Savio JD, Boland MP, Hynes N, Roche JF. 1990. Resumption of follicular activity in the early postpartum period of dairy cows. J Reprod Fertil, 88:569-579.
Sheldon IM, Noakes DE, Dobson H. 2000. The influence of ovarian activity and uterine involution determined by ultrasonography on subsequent reproductive performance. Theriogenology, 54:409-419. Sheldon IM, Noakes DE, Rycroft AN, Dobson H. 2002a. Effect of postpartum manual examination of the vagina on uterine bacterial contamination in cows. Vet Rec, 151:531-534.
Sheldon IM, Noakes DE, Rycroft AN, Pfeiffer DU, Dobson H. 2002b. 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, Noakes DE, Rycroft AN, Dobson H. 2003. The effect of intrauterine administration of estradiol on postpartum uterine involution in cattle. Theriogenology, 59:1357-1371.
Sheldon IM. 2004. The postpartum uterus. Vet Clin North Am Food Anim Pract, 20:569-591.
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 HJ. 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.
Sheldon IM. 2014. Genes and environmental factors that influence disease resistance to microbes in the female reproductive tract of dairy cattle. Reprod Fertil Dev, 27:72-81.
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. Stagg K, Diskin MG, Sreenan JM, Roche JF. 1995. Follicular development in long-term anoestrous suckler beef cows fed two levels of energy postpartum. Anim Reprod Sci, 38:49-61.
Tian W, Noakes DE. 1991a. A radiographic method for measuring the effect of exogenous hormone therapy on uterine involution in ewes. Vet Rec, 129:463-466.
Tian W, Noakes DE. 1991b. Plasma 3 methyl-histidine concentrations and uterine involution in the post partum cow. Vet Rec, 128:109-110.
Turner ML, Cronin JC, Healey GD, Sheldon IM. 2014. Epithelial and stromal cells of bovine endometrium have roles in innate immunity and initiate inflammatory responses to bacterial lipopeptides in vitro via Toll-like receptors TLR2, TLR1 and TLR6. Endocrinology, 155:1453-1465. Turner ML, Cronin JG, Noleto PG, Sheldon IM. 2016. Glucose availability and AMP-activated protein kinase link energy metabolism and innate immunity in the bovine endometrium. PLOS One, 11:e0151416.
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.
Wagner WC, Hansel W. 1969. Reproductive physiology of the post partum cow. l. Clinical histological findings. J Reprod Fertil, 18:493-500.
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, Fischer DP, England GCW, Dobson H, Pfeiffer DU, Sheldon IM. 2005. Clinical evaluation of postpartum vaginal mucus reflects uterine bacterial infection and the inflammatory response to endometritis in cattle. Theriogenology, 63:102-117.
Zwald NR, Weigel KA, Chang YM, Welper RD, Clay JS. 2004. Genetic selection for health traits using producer-recorded data. I. Incidence rates, heritability estimates, and sire breeding values. J Dairy Sci, 87:4287-4294.