Next Article in Journal
Determining Hearing Thresholds in Dogs Using the Staircase Method
Previous Article in Journal
Freezing Stallion Semen—What Do We Need to Focus on for the Future?
Previous Article in Special Issue
Postpartum Body Condition Score (BCS) and Lactation Stage (30 and 60 Days) Affecting Essential Fatty Acids (EFA) and Milk Quality of Najdi Sheep
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Uterine Disease in Dairy Cows: A Comprehensive Review Highlighting New Research Areas

by
Zsóka Várhidi
1,
György Csikó
2,
Árpád Csaba Bajcsy
3 and
Viktor Jurkovich
4,*
1
Department of Animal Hygiene, Herd Health and Mobile Clinic, University of Veterinary Medicine, 1078 Budapest, Hungary
2
Department of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, Hungary
3
Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
4
Centre for Animal Welfare, University of Veterinary Medicine, 1078 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Submission received: 18 December 2023 / Revised: 28 January 2024 / Accepted: 30 January 2024 / Published: 2 February 2024
(This article belongs to the Special Issue Physiology and Pathology of the Peripartal Period in Dairy Animals)

Abstract

:

Simple Summary

This literature review summarizes recent knowledge on uterine diseases in dairy cows. Metritis and endometritis are major problems in intensive dairy farming at present and cause significant long-term economic losses. Therefore, the efficient treatment and prevention of uterine diseases in the peri- and postpuerperal periods are essential. The use of antibiotics in these disease conditions is limited, either due to their limited effectiveness or due to recent legislation intended to reduce the use of antimicrobials. Therefore, finding efficient alternatives to antibiotics is necessary. This literature review provides an overview of the current and future possibilities for the non-antibiotic-based control of metritis and endometritis in dairy cows.

Abstract

Uterine disease is an intensely studied part of dairy cattle health management as it heavily affects many commercial dairy farms and has serious economic consequences. Forms of the disease, pathophysiology, pathogens involved and the effects of uterine disease on the health and performance of cows have already been well described by various authors. Lately, researchers’ attention has shifted towards the healthy microbiome of the uterus and the vagina to put emphasis on prevention rather than treatment. This aligns with the growing demand to reduce the use of antibiotics or—whenever possible—replace them with alternative treatment options in farm animal medicine. This review provides a comprehensive summary of the last 20 years of uterine disease research and highlights promising new areas for future studies.

1. Introduction

Uterine disease is still undoubtedly a major concern on most high-producing dairy cattle farms, as it affects about half of all dairy cows and has serious consequences regarding reproductive performance and milk production [1]. Problems with reproductive performance are the main reasons for culling on large-scale dairy cattle farms [2,3,4]. The average proportion of reproductive culling is around 30% of all premature disposals [5]. The economic costs of uterine disease consist of a lower milk yield, decreased pregnancy rate, higher chances of premature culling and increased replacement costs [6,7]. Although the disease itself, the economic consequences and the treatment options have been continuously studied in the past couple of years, there has not been a comprehensive summary of recent findings since the early 2000s [8]. The aim of this review is to provide researchers and veterinarians with an up-to-date review of research published during the last 20 years and show the most promising areas of related research in the upcoming years, paying special attention to intravaginal probiotics.

2. Uterine Disease of Dairy Cows

2.1. Forms of Uterine Disease of Dairy Cows

2.1.1. Metritis: First 21 Days after Calving

Metritis is defined as the inflammation of the uterine wall, including the endometrium, the muscular layers and the serosa, which occurs until the first 21 days after calving—primarily within 7–10 days—and can affect up to 40% of dairy cows. Clinical signs include a watery, red-brown uterine discharge, usually with a fetid odour. The uterus of a metritic cow is enlarged and flaccid and does not have the longitudinal folds that typically characterize involution. Metritis is classified into three grades based on the accompanying systemic symptoms. In Grade 1 metritis, there is no sign of systemic signs of illness or fever. In Grade 2, or acute puerperal metritis, clinical signs include fever (>39.5 °C), reduced appetite, decreased milk production and prolonged resting periods (lethargy). In Grade 3, or toxic metritis, the cow is recumbent and shows toxaemic signs [9,10,11].

2.1.2. Endometritis: From 21 Days after Calving

Endometritis is defined as inflammation of the endometrium only that does not extend beyond the stratum spongiosum. Endometritis occurs from 21 days after calving onwards and is classified as clinical or subclinical [12]. The disease can affect about 20% of dairy cows [13,14,15].
Clinical endometritis is characterized by visible mucopurulent (50% mucus; 50% pus) or purulent discharge at the vulva or in the vagina. The severity of clinical endometritis is usually graded by evaluating the vaginal discharge. In Grade 0, or normal (without endometritis), the discharge is clear or translucent. In Grade 1, the mucoid discharge contains flecks of white or off-white pus. In Grade 2, the discharge contains less than 50% white or off-white mucopurulent material. In Grade 3, it is purulent, usually with a white or yellow colour, but sometimes it can contain blood too [9,16]. In subclinical endometritis, the infection and inflammation of the endometrium do not result in discharge.

2.1.3. Pyometra: Between 42 and 60 Days after Calving

Pyometra is sometimes also considered a type of endometritis; however, usually, it is discussed separately [8,10]. It is characterized by the accumulation of pus in the distended uterus with a closed cervix and a persistent corpus luteum in an ovary. Some pus my leak into the vagina too. Bacterial infection of the oviducts and salpingitis can occur and influence fertility as well. Pyometra occurs between 42 and 60 days after calving, with a relatively low prevalence rate of less than 2% [8,9,17,18,19].

2.2. Risk Factors of Uterine Disease in Dairy Cows

Cattle are more susceptible to uterine disease than other mammals (e.g., other ruminants) because bacterial contamination of the uterus in cattle dynamically alternates with clearance [8]. Most cows experience bacterial contamination of their uterus in the first two weeks after calving. Problems arise when this bacterial load becomes persistent. During and after parturition, the physical barriers of the female genital tract are compromised, thus creating the possibility of an ascending infection. Bacteria can get into the uterine lumen from the environment, as well as the skin and faeces of the animal, especially if hygienic conditions are not up to standard in the calving stable. Combined with the endometrial tissue damage and the immunosuppressed status of the fresh-calved cow (which can be worsened if the stress levels increase due to poor handling of the animal), this can easily lead to inflammation of various organs of the genital tract, especially of the uterus, and cause delayed involution [8].
Risk factors (Figure 1) for uterine disease include uterine damage caused or worsened by the following: stillbirth, twin calving, retained placenta, caesarean section; metabolic conditions like milk fever and ketosis; damage associated with displaced abomasum; a dysbalance between the immune system and the invading pathogens due to a disrupted leukocyte function; the type of uterine bacterial flora present [8,20]. Cows with a history of postpartum uterine disease and/or abnormal parturition have higher odds of developing subclinical uterine disease than cows without postpartum uterine infections and those with normal parturition previously. Therefore, multiparous cows have higher odds of being diagnosed with uterine disease than primiparous ones, but it is their parturition history, not the actual number of parturitions, that increases the risk [21,22]. There is a difference between the efficacy of the defence mechanisms of primiparous versus multiparous cows. Older cows have lower uterine elasticity and slower involution than younger ones. On the other hand, young animals’ limited exposure to bacterial contamination delays proper immune response, while older cows may eliminate pathogenic bacteria faster [18].
The most significant risk factor for developing metritis is a history of retained placenta. Consequently, all factors that increase the probability of retained placenta simultaneously increase the risk of developing metritis. A negative energy balance in the peripartal period and certain changes in body condition score also affect the odds of developing a uterine disease. A decrease in prepartum body condition score of at least 1 until days 28–35 postpartum significantly increases the risk. Once metritis occurs, the odds of ovarian inactivity on days 28–35 increase and 100-day milk production decreases [23,24]. Further significant risk factors for metritis in dairy herds are first pregnancy, calving in winter, having a male calf and a shorter gestation length [25].
Although endometritis in dairy cattle tends to be cured without intervention, a study found that approximately 25% of cows with endometritis had persistent or recurrent inflammation even after the voluntary waiting period [26]. Risk factors for endometritis, in addition to the above-mentioned, included summer calving, male offspring, calving assistance, induced calving, metritis, lameness, clinical mastitis and clinically relevant urovagina [26,27]. On the contrary, another study found that calving between November and April increased the risk of uterine infection in the first month postpartum [28]. These results can be explained by the different climatic conditions between studies. Dystocia increases the risk of endometritis both directly and indirectly (increasing the probability of metritis). There is a positive correlation between the degree of metritis and the odds of developing endometritis [18]. One research group found that the cleanliness of the animal or the environment was not a significant risk factor [27]. On the contrary, a different study concluded that the odds of developing uterine disease were not influenced by the gender and viability of the calf or calving assistance [23].
A herd-level risk factor for subclinical endometritis is housing freshly calved cows in bedded pack barns. Cow-level risk factors for subclinical endometritis include ketosis, acute metritis and higher milk production in primiparous cows. In contrast, multiparous cows with higher milk production showed lower odds of having subclinical endometritis in a study [29].
Risk factors for pyometra include hormonal dysfunction (early ovulation after calving combined with a retained corpus luteum) due to or combined with persistent infection of the uterus during and after parturition (previously explained in detail as risk factors for uterine disease in general) [8,11].

2.3. Diagnostic Methods

There are several diagnostic methods to detect the different forms of uterine disease. Szenci et al. [17] listed rectal palpation, transrectal ultrasonography, cytological examination, histopathological examination of endometrial biopsy samples, vaginal palpation, vaginoscopy and Metricheck™ (Simcro Tech Ltd., Hamilton, New Zealand). The metritis score system is an easy cow-side method, especially for puerperal metritis, that guides veterinarians on whether an animal requires treatment. Rectal temperature, decreased milk yield, dehydration, rumination and vaginal discharge are scored from 0 to 3 (0 being normal and 3 being the most severe symptom) [9,16]. Vaginoscopy, cytological and even ultrasonographic examinations have limited use in large dairy herds on a daily basis due to their time and equipment requirements. Endometrial biopsy sample histology has been considered the reference test for diagnosing endometritis. Similar results can be obtained with both the cytobrush technique and the low-volume uterine lavage [30]. McDougall et al. [31] concluded that the Metricheck™ device, which allows for the easy and precise sampling of vaginal discharge, had a higher sensitivity and lower specificity in diagnosing endometritis than vaginoscopy. They speculated that the diagnostic method that was first used might have stimulated uterine contractions and the second method increased the chances of detecting purulent discharge in the same cow. Pleticha et al. [32] used vaginoscopy as a reference method, in comparison to vaginal palpation and the Metricheck™ device, in three different groups of cows to avoid bias by vaginal stimulation. Significantly more cows were diagnosed with endometritis using the Metricheck™ device than using vaginoscopy or manual examination, but this did not result in a higher reproductive performance in the Metricheck group. Dubuc et al. [30] suggested that, in many cases, cytological and clinical endometritis may represent different manifestations of inflammation because only 36–38% of cows with clinical endometritis showed evidence of cytological endometritis. In a later study, Denis-Robichaud and Dubuc [33] reported this proportion as being 55% of the total. They suggested the introduction of a new term, purulent vaginal discharge (PVD), as it could indicate not only endometritis but cervicitis and vaginitis as well. Another study [34] described endometrial cytology, performed using the cytobrush technique or low-volume uterine flushing, as a minimally invasive method, which had no adverse effects on subsequent reproductive performance. They also suggested that the terms PVD and cytological endometritis should be used instead of the classical terminology [34]. Kelly et al. [35] also used PVD evaluation with the Metricheck™ device and ultrasonographic endometritis scoring and found both methods practical and reliable, while, in some instances, they could also detect different manifestations of reproductive tract diseases.
A Chinese study by Sun et al. [36] compared a multiplex PCR diagnostic method with clinical examination, a sulphur-containing amino acid test and conventional culture and biochemical tests from vaginal discharge samples. They tested the method with three major agents of endometritis in dairy cows: Staphylococcus aureus, Escherichia coli and Bacillus cereus. These three tested field isolates showed positive amplification, whereas other strains (Pasteurella spp., E. faecalis, Streptococcus spp.) showed no amplification. The study concluded that the multiplex PCR method had equal specificity and higher sensitivity than the conventional PCR method. Furthermore, it was cheaper and time-saving, as various pathogens could be detected simultaneously [36]. Another experiment [37] evaluated urinary test strips on uterine lavage samples. Leukocyte esterase, protein and pH were measured; however, the reagent strip, as an alternative cow-side method, had a relatively poor performance compared to endometrial cytology [37]. Lima [38] suggested potential new technologies to improve the diagnosis of uterine diseases. Activity monitors, biomarkers, immune cell profiling and machine learning algorithms are listed as promising additional diagnostic tools that can help to detect high-risk animals and predict the success rate of antimicrobial therapy.
Subclinical endometritis can be diagnosed by histological examinations of the uterus as a gold standard method in the absence of discharge. Cells can be collected by uterine lavage, cytobrush or cytotape techniques [39,40,41]. Cytobrush and uterine lavage are viable and comparable sampling methods [42,43]. Van Schyndel et al. [43] also tested leukocyte esterase strips, which proved to be an easy cow-side diagnostic method, either alone or in combination with other techniques, when the cut-point was set at leukocyte esterase (LE) ≥ 2. On the contrary, brix refractometry had a very poor performance in diagnosing subclinical endometritis [43]. Baranski et al. [44] collected endometrial surface scrapings by cytobrush and performed bacteriologic and cytologic examinations. They concluded that subclinical endometritis may be more associated with the recovery of the endometrium after calving than a bacterial infection [44]. McDougall et al. [45] had similar findings: they stated that the more important determinant of subsequent reproductive performance was inflammation, rather than the presence of pathogens.
Pyometra can be diagnosed by transrectal palpation of the uterus and/or transrectal ultrasonography by scanning uterine content and a persisting corpus luteum on one of the ovaries [42,46].

3. Bacterial Flora of the Reproductive Tract

Vaginal microbiota (microbiota in general include bacteria, viruses, fungi, protozoa and small parasites) is an essential element of reproductive health in dairy cattle, which changes over time due to internal (e.g., oestrus cycle; immune system) and external (e.g., infection; injury) factors. Most studies focused on the bacterial communities of the vagina and uterus [47]. Otero et al. [48] studied a group of heifers over the period of 18 months before their first insemination. The predominant bacteria of the vagina were Enterococci and Staphylococci, followed by a lower abundance of Enterobacteriaceae and Lactobacilli. The relative abundance of Lactobacilli seemed to increase with the age of the animal [48]. Quereda et al. [49] also suggested that—contrary to humans—the vaginal microbiota of healthy dairy heifers was not dominated by Lactobacillus spp. The most abundant genera or families, according to them, were Ureaplasma, Histophilus, Corynebacteriaceae, Porphyromonas, Mycoplasma and Ruminococcaceae [49].
Ault et al. [50] studied healthy multiparous beef cattle before insemination, and they detected 34 phyla and 792 genera. They found that the abundance of Corynebacteria and Staphylococci is significantly higher two days before insemination in cows that did not conceive [50]. They also described some changes in microbiota before insemination, indicating that the number of bacterial species in the reproductive tract significantly decreased over time, but this was not linked to pregnancy status [51].
Westermann et al. [52] sampled the uterus of 230 cows with vaginal discharge by a cytobrush technique, and in 19.6% of these samples, they did not find any bacteria. This result suggests that evaluating vaginal discharge alone comes with a fair share of false-positive diagnoses that lead to unnecessary or inadequate treatment. From the positive samples, they isolated T. pyogenes, E. coli, coagulase-negative Staphylococci, α-haemolytic Streptococci, C. bovis and Bacillus spp. [52]. Udhayavel et al. [53] found 16.66% of the samples collected from cows with clinical endometritis to be sterile. E. coli, Klebsiella spp., Proteus spp., Pseudomonas aeruginosa and Clostridium spp. were identified from endometritic samples. Based on in vitro antibiotic sensitivity testing, they found ceftriaxone to be effective in 64% of bacterial uterine infection cases, followed by gentamicin, enrofloxacin and chlortetracycline, in 32% of cases [53].
Knudsen et al. [54] suggested that examining uterine flush samples alone might not provide a complete picture, as the microbiota of the endometrium were absent. They compared uterine flush samples with endometrial biopsies and found a correlation in the microbiota, but they also stated that endometrial biopsy samples were more diverse. They concluded that Porphyromonadaceae, Fusobacteriaceae, Leptotrichiaceae and Mycoplasmataceae may be associated with uterine disease—all of them, however, could also be isolated from healthy cows, while they observed Ruminococcaceae in high abundance in both healthy and endometritic cows [54].
A Brazilian research group [55] obtained 205 bacterial and 120 yeast isolates from the vagina of 20 beef cows. The most frequent bacteria from their isolates were Staphylococcus spp. and E. coli. Yeast colonies were identified as Candida tropicalis, C. albicans and C. krusei. Their Staphylococcus spp. bacterial isolates were tested for the antimicrobial sensitivity of 16 drugs. The lowest sensitivity was presented to tetracycline and erythromycin (46.9%), followed by amoxicillin (65.6%) and rifampicin (71.8%)—all other drugs were 100% effective in the study [55]. Another Brazilian group [56] also collected vaginal samples from 20 healthy beef cattle, and they found that Firmicutes, Bacteroides and Proteobacteria were the three most abundant phyla. They also reported many unclassified bacteria, which indicates that further research is necessary to fully understand bovine reproductive tract microbiota. Eight out of nine genera that they identified could also be found in the bovine gastrointestinal tract or faeces, and only Aeribacillus (Firmicutes) (the most abundant) has not yet been isolated from the gastrointestinal tract. They could not find any association between specific vaginal microbiota and pregnancy status or parity. Regarding the detection of fungi, authors isolated the phyla Ascomycota and Basidiomycota, with the Ascomycota population decreasing after conception [56]. These results are consistent with the findings of Chen et al. [57], who also described Firmicutes, Proteobacteria and Bacteroidetes as the most abundant phyla. This research group tried to find differences between open and inseminated cows, but they could not detect any statistical difference [57]. Swartz et al. [58] had similar findings, describing Bacteroidetes, Fusobacteria and Proteobacteria as the predominant bacterial phyla.
The vaginal and uterine microbiome of a cow changes dynamically after parturition. Healthy cows develop differentiated uterine flora early on, while cows later diagnosed with uterine diseases tend to show a loss of bacterial diversity and dominance by a few bacterial taxa [59]. Jeon et al. [60] suggested that on day 2 postpartum, Bacteroidetes spp. and Fusobacterium spp. are already more abundant in pre-metritic cows and between days 4 and 8, this tendency becomes even more apparent. On the other hand, Tasara et al. [61] only found statistically significant changes in the species richness and alpha diversity of uterine microbial communities between healthy and metritic cows between days 7 and 10 postpartum. The synergistic effect was also supported by Wang et al. [62] and Bicalho et al. [63], who found an increased abundance of Fusobacterium spp. [62,63] and the unique presence of Trueperella spp. [62,63] and Peptoniphilus spp. [62] on day 30 and between days 25 and 35 postpartum in cows with clinical endometritis, respectively. However, in subclinical endometritis 30 days postpartum, almost none of the known intrauterine pathogens were detected, and uterine flush samples were characterized by the enrichment of Lactobacillus spp. and Acinetobacter spp. [62]. Similar results were obtained on day 35 postpartum by Pascottini et al. [64], who reported that cows with clinical endometritis showed a decreased bacterial diversity, with Bacteroidetes spp. and Fusobacterium spp. being more dominant, whereas cows with subclinical endometritis had similar microbiota to healthy cows.
An interesting contrast to the uterine characteristics described above appears in the study of Wang et al. [65] regarding vaginal flora: healthy cows had a significantly lower vaginal bacterial diversity compared to cows with endometritis, and diseased cows lacked dominant bacterial species [65]. However, other studies suggest E. coli [66], Histophilus spp. [67,68], Mogibacterium spp. [68], Bacteroides spp. [67,69], Fusobacterium spp. [69] and Proteobacterium spp. [69] are more abundant in the vaginal microbiome of diseased cows. Parity seems to affect the composition of vaginal microbiota in such a way that multiparous cows have a significantly greater diversity [70], as well as having greater diversity in their uterine microbiota [71].

4. Disease Prevention

Placing the emphasis on disease prevention rather than treatment is beneficial to the cow’s health and the farm’s economy. A housing design that allows cows to separate from the herd during calving, a spacious calving pen and a clean environment help to avoid infection during and after parturition and reduce stress. An optimal diet throughout pregnancy and early lactation prevents metabolic disorders, deficiencies and suboptimal body conditions. Educating staff on calving assistance and identifying high-risk animals in advance can reduce risk factors that arise during calving. Using female sexed semen and having smaller female calves compared to bigger males can prevent problems around calving too. Close monitoring in the early days of lactation and a quick response to any sign of disease prevent the escalation of health issues Figure 1, [72,73].

5. Treatment Options

Defeating endometritis (both clinical and subclinical) is not a medical emergency, but it is very important for the reproductive performance of the cow. It is important to note that spontaneous healing of endometritis may occur if oestrus successfully clears up the uterus. Metritis, on the other hand, may require systemic treatment to restore the general good condition of the cow [74]. Metritis treatment usually includes a combination of antibiotics, NSAIDs and hormones, including uterotonics. Generally speaking, the most commonly used antibiotics have been tetracycline, amoxicillin, ampicillin and sulfonamides, often with trimethoprim, cephapirin, ceftiofur and benzylpenicillin procaine. When deciding which antibiotic agent could be included in the treatment plan, one must consider legal restrictions, effectiveness against Gram negatives and anaerobes, the form and severity of disease, and non-antibiotic options [75]. The most frequently used NSAIDs are flunixin meglumine, ketoprofen, meloxicam and carprofen. Hormones and uterotonic drugs include oxytocin, which can be used in the first few hours (max. 72 h) after calving, and, after this timeframe, prostaglandin F2α can be used from day 3 postpartum [24,76]. The benefit of PGF2α is believed to be oestrus induction in the presence of a PGF2α responsive corpus luteum once the ovarian activity is restored during involution. Oestrus promotes the clearance of bacteria and inflammatory products [77]. Although Galvao et al. [77] found that treatment with PGF2α did not decrease the prevalence of subclinical endometritis at the time points they studied (days 35 and 49 postpartum), it did improve conception rate and the odds of pregnancy in cows with a low body condition score. However, other researchers disagree on whether PGF2α administration affects certain cases, e.g., before week 4 postpartum or in cows without a palpable corpus luteum [42]. Supportive therapy for metritis includes fluid therapy, calcium and energy supplementation [42]. The prognosis depends on the severity of symptoms [17].
There is an ongoing dispute about intrauterine versus systemic (antibiotic) treatments. There have been some promising results regarding intrauterine treatment with cephapirin [78], chlortetracycline [13] and dextrose [79]. A research group in India compared five different intrauterine treatment (antibiotic and/or non-antibiotic) methods to a control group and concluded that Lugol’s iodine, followed by E. coli LPS 24 h later, was the most effective in increasing first service pregnancy rate, although cervicovaginal mucus was found not clear in 40% of the cows in this treatment group [80]. However, some suggest that intrauterine treatments irritate the mucous membrane of the uterus, and active agents barely reach the deeper histological layers of the uterus and the rest of the reproductive organs; therefore, they provide no advantage compared to no-treatment control groups [17,24,81].
Haimerl et al. [82] concluded that a significant decline in metritis prevalence occurred following treatment with the most used antibiotic, ceftiofur. Ceftiofur has been approved for the treatment of puerperal metritis on five consecutive days in Europe and the USA (although legal regulations may differ among countries; therefore, it is impossible to make a statement on treatment practices that is valid globally), and it does not require milk withdrawal. With the emerging antimicrobial resistance of zoonotic organisms, there is a high demand for prudent antibiotic use in food animals worldwide. For each disease, including reproductive tract diseases, it is critically important to select the most appropriate drug at its optimal dosage and duration. This way, side effects and the pressure to select resistant strains can be minimized. Ceftiofur, the most frequently used drug to treat metritis, for example, is a third-generation cephalosporin, and as such, it is valued for treating severe to life-threatening human infections. Ceftiofur has been associated with developing resistance to ceftriaxone, which is only available for humans [83,84]. Haimerl and Heuwieser [83] even reported that ceftiofur treatment does not improve reproductive performance, although clinical improvement is evident. Uterine pathogens such as E. coli may contain different antibiotic resistance genes and might even be multi-drug-resistant, including ceftiofur [85].
There is a general need for comparative studies of different antibiotic and non-antibiotic treatment options. One rare example of that is the study of Jeon et al. [84], who compared ceftiofur to ampicillin and a no-treatment control group. They found that regardless of treatment, uterine microbiota became more homogenous over time after parturition but ceftiofur contributed to more dynamic changes from days 1 to 6. The relative abundance of Bacteroidetes increased significantly after ceftiofur administration, whereas it did not change after ampicillin treatment or in the absence of treatment. This indicates that Bacteroidetes seem more resistant to ceftiofur; therefore, new therapeutic methods with more effectivity against this phylum should improve the cure rates of metritis [84]. Another comparison of ceftiofur to ampicillin was carried out by Merenda et al. [86], who concluded that ceftiofur reduced rectal temperature but, in primiparous cows, reduced the pregnancy rate and increased the median days to pregnancy compared to ampicillin. Ampicillin treatment, on the other hand, resulted in a greater prevalence of purulent vaginal discharge and cytological endometritis compared to ceftiofur [86].
Lima et al. [87] compared the economic aspects of ceftiofur and ampicillin treatment options for cows without metritis. The analysis considered the cost of therapy, reproductive management, discarded milk and the income from saleable milk and culled cows. They concluded that the choice of antibiotic did not significantly alter survival rates, reproductive performance or the costs of the disease [87].

6. Treatment Alternatives with Regard to Probiotics

In recent years, promising experiments have begun to evaluate the therapeutic value of 50% dextrose solution and proteolytic enzyme (trypsin, chymotrypsin, papain) solutions as substitutes for antibiotics. Further examinations are required to confirm the positive effects of these agents, as results have been somewhat inconsistent so far [17,38,79,88]. Vaccination against the predominant bacteria has also been described as a promising alternative to antibiotics. Subcutaneous vaccinations containing inactivated bacterial components and/or protein subunits were found to significantly reduce the incidence of puerperal metritis in heifers, leading to improved reproductive performance [89]. Other areas of investigation include but are not limited to probiotics, bacteriophages, acetylsalicylic acid, botanical essential oils, chitosan microparticles and even acupuncture therapy, with varying success—further research is needed in this field [38,90,91,92].
The use of probiotics is a new and promising research area for the prevention or treatment of uterine disease. The definition of probiotics, coming from the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) states that probiotics are “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” [93]. This definition was reinforced by an expert panel with minor grammatical changes and was supplemented with additional recommendations [94]. It applies to humans and animals and accepts positive health effects outside the gastrointestinal tract but requires an adequate number of live microorganisms at the time of administration [93].
There are several mechanisms of probiotic actions (Figure 2), which include enhancing epithelial cell barrier functions by increasing the expression of genes involved in tight junction signalling, establishing biofilms on mucosal layers, immune modulation, competition for adhesion and preventing the adhesion of pathogen bacteria, competition for nutrients, the production of antimicrobial compounds (bacteriocins, organic acids, antimicrobial proteins, enzymes, H2O2 and CO2) and maintaining optimal vaginal pH [95].
So far, the group of bacteria that are most often studied as potential intravaginal probiotics is the group of lactic acid bacteria (LAB; Table 1). This is a diverse group of Gram-positive bacteria from different taxa that produce lactic acid as the primary endproduct of carbohydrate fermentation. Otero et al. [96] isolated 76 strains of Lactobacillus spp. and 7 strains of Streptococcus spp. from the vagina of healthy heifers and adult cows. After that, they performed in vitro experiments to evaluate the probiotic potential of these strains and found that the majority of them have the potential to inhibit E. coli, whereas only a few strains showed the potential to inhibit T. pyogenes. Two years later, they were able to isolate 82 Lactobacillus spp. strains from the bovine vagina and performed screening assays of antagonistic substance production and surface characteristics. Three strains showed the highest potential to be included in future studies. These are Lactobacillus gasseri CRL1412 and CRL1421 and Lactobacillus delbrueckii subsp. delbrueckii CRL1461 [97].
Genís et al. [98,99] tested four LAB species in vitro and concluded that, among them, the following three strains have the potential to inhibit E. coli infection: Pediococcus acidilactici (reduced E. coli infection by 89.7%), Lactobacillus sakei (decrease in infection by 87%) and Lactobacillus reuteri (decrease in infection by 73.5%). However, when infection was combined with inflammation, only P. acidilactici and L. reuteri showed the potential to reduce E. coli infection (up to 83%). After a separate strain experiment, LAB combinations were tested and a combination of L. rhamnosus ratio 25, P. acidilactici ratio 25 and L. reuteri ratio 2 proved to be the most effective in modulating E. coli infection (E. coli count was reduced by 95.1%) and endometrial inflammation (E. coli infection was reduced by 89.78%) in vitro [98,99]. Liu et al. [100] also tested L. rhamnosus against E. coli infection in vitro and concluded that L. rhamnosus pretreatment has the potential to limit the inflammatory response to E. coli and the subsequent damage to bovine endometrial epithelial cells.
P. acidilactici was the focus of the research of Wang et al. [101]. They could isolate Enterococcus, Lactobacillus and Pediococcus from both healthy and metritic cows and reported that the bacterial load of the vaginal mucus increased after calving. E. coli was the predominant species in the vaginal microbiota of cows with metritis, and they used different strains as indicators for an inhibition assay. Two isolates of P. acidilactici (FUA3138 and FUA3140) produced a bacteriocin, namely, the pediocin AcH/PA-1. P. acidilactici FUA3072 was used as a reference strain as it had been previously characterized [101].
Rodríguez et al. [102] characterized the lactobacilli microflora of dairy and beef cows and identified the facultative heterofermentative group as the most dominant. L. plantarum was the most abundant species. L. acidophilus was the most dominant species of the obligate homofermentative group. The third group, the one of the obligate heterofermentatives, was only presented by L. brevis [102]. Niu et al. [103] examined Lactobacillus strain SQ0048 and described the genes and pathways involved in the adhesion to host cells and the inhibition of pathogens, including the Interleukin-17 (IL-17) signalling pathway and the antigen processing and presentation pathways.
Following the in vitro experiments, a few in vivo tests were performed (Table 2). One research group [104] used a combination of three bacterial strains—Lactobacillus sakei FUA 3089, P. acidilactici FUA 3140 and FUA 3138—intravaginally in dairy cows once a week from 2 weeks before calving until 4 weeks following calving [104]. The LAB mixture reduced the occurrence of purulent vaginal discharge at 3 weeks after calving and the plasma haptoglobin concentrations at 2 and 3 weeks after calving. The treated multiparous cows also had a higher milk yield than the control group, but no difference could be measured in primiparous cows [104]. The same LAB combination was used in another piece of research at weeks -2 and -1 pre-calving in one treatment group and at weeks -2 and -1 pre-calving, plus week 1 after calving, in a second treatment group. The results suggest that intravaginal LAB treatment can reduce the incidence of metritis and the serum concentration of lipopolysaccharide-binding proteins [105]. Cows in both treatment groups had smaller gravid uterine horns and body sizes at day 14 after calving compared to the control group. The first treatment group had fewer days open, but the second group did not differ from the control group [106]. This experimental setup was also used to evaluate the effect of intravaginal LAB treatment on milk production. The results showed that multiparous cows in both treatment groups had higher milk production and feed efficiency compared to the control group, similar to another study [104], and primiparous cows in the second treatment group also had a higher milk yield than the control group [107].
Other studies found that two intravaginal doses of LAB mixture—L. rhamnosus CECT 278, P. acidilactici CECT 5915 and L. reuteri DSM 20016—per week, starting from week -3 pre-calving, reduced metritis prevalence, whereas an intrauterine treatment on day 1 postpartum did not have such an effect. Both treatment types reduced blood neutrophil gene expression [108,109]. Yang et al. [110] used lactic acid bacteria and stated that their treatment could be an alternative to antibiotics, as most sick cows in the study returned to normal physiological status after the lactic acid bacteria treatment. Lactobacillus species have three fundamental mechanisms against pathogens. They prevent the initial adhesion of pathogens to epithelial cells. They maintain a normal pH level in the vagina, which inhibits the reproduction of pathogenic bacteria. Lactobacillus species can also produce antibacterial substances that can directly or indirectly destroy pathogens [110]. García-Galán et al. [111] also described in vitro the pH acidifier role of Lactobacillus spp. in the bovine vaginal mucus, although a sufficient concentration of the probiotic bacteria is required to achieve significant growth. Peter et al. [112] showed that the administration of Lactobacillus buchneri in utero, even only once, could improve the reproductive performance of healthy cows and cows with subclinical endometritis. This was supposed to be due to the initial stimulatory effect of L. buchneri on the local immune system and defence mechanisms [112]. More recent in vivo studies also reported lowered incidence rates of uterine infections, improved uterine involution, increased fertility, a reduced number of oestrus induction days and increased conception rate in buffalo [113] or cows [114,115].
Table 2. The different probiotic strains used in in vivo studies for treating the reproductive tract and their effects.
Table 2. The different probiotic strains used in in vivo studies for treating the reproductive tract and their effects.
Strains UsedSpeciesTargetEffectsReferences
Lactobacillus sakei FUA 3089
Pediococcus acidilactici FUA 3140
P. acidilactici FUA 3138
cattlevagina, before and after calvingLowered incidence of uterine infections and purulent vaginal discharge, and improved local and systemic immune responses. Multiparous cows had greater milk production and feed efficiency. The concentration of plasma haptoglobin was lower. Increased concentrations of serum progesterone level and earlier cyclicity of ovaries.[104,105,106,107]
L. rhamnosus CECT 278
P. acidilactici CECT 5915
L. reuteri DSM 20016
cattlevagina, before calvingReduced metritis prevalence[108]
L. rhamnosus CECT 278
P. acidilactici CECT 5915
L. reuteri DSM 20016
cattlevagina, before calvingLAB decreases the amount of E. coli in the endometrium ex vivo.[109]
L. buchneri DSM 32407cattleuterus, lactating cows on d 24–30 postpartumStimulatory effect on the local immune system. A higher proportion of cows were pregnant after the first service. The endometrial mRNA expression of several pro-inflammatory factors was lower.[112]
Lactiplantibacillus plantarum KUGBRC
P. pentosaceus GBRCKU
buffalovagina, after calving, with clinical endometritisReduced number of oestrus induction days and lower incidence of endometritis.[113]
L. rhamnosus
P. acidilactici
L. reuteri
cattlevagina, before calvingDecreased incidence of metritis and
increased conception rate in multiparous cows.
[114]
L. farraginis NRIC 0676
L. rhamnosus NBRC 3425
cattlevagina, before and after calvingLowered incidence rates of uterine infections, improved uterine involution and increased fertility[115]
Styková et al. [116] isolated five strains (L. büchneri 5K and 24S8, L. mucosae 29S8, 9/K and 5/Kb) that could be promising candidates for in vivo testing as reproductive tract probiotics. These strains produced hydrogen peroxide and lactic acid and adhered to the vaginal mucus (except for L. büchneri 24S8). They showed an inhibition zone against three uterine pathogens: T. pyogenes, followed by F. necrophorum and Gardnerella vaginalis [116].
The survivability of bacteria in the vagina and the uterus depends on multiple factors, including tolerance for physiological pH levels. Clemmons et al. [117] examined 30 cows and measured vaginal pH levels between 6.15 and 7.44, with a mean of 6.69 ± 0.14. Uterine pH levels ranged from 5.62 to 6.52, with a mean of 6.06 ± 0.09. Swartz et al. [58] also measured vaginal pH of 20 cows and described a range from 6.5 to 8.7, with a mean of 7.3 ± 0.63. On a larger sample size of Holstein-Friesian cows, Beckwith-Cohen et al. [118] found no correlation between vaginal pH and days in milk. While cows maintained a median pH value of 7.50, heifers showed a significant increase, starting at a median pH value of 7.25 before calving, then reaching a median of 7.75 during the first week postpartum, before settling at a median of 7.50 [118].
Further in vivo studies are required to provide extensive knowledge about potential intravaginal probiotic bacterial strains and their optimal application under field conditions. The clinical safety and efficacy of probiotics, focusing on the pharmacological and toxicological aspects, is crucial. Once a particular bacterial strain is chosen, it must undergo different mandatory evaluations, such as safety and innocuity assays and functional and technological characterization, before it can be incorporated into a veterinary medical product. Evaluation from the economic point of view is also unavoidable. Further target animal studies are required to provide extensive knowledge about the potential intravaginal probiotic bacterial strains and their optimal application under field conditions. The major steps in intravaginal probiotic product development are displayed in Figure 3.
Another main concern is antibiotic resistance. Probiotic strains cannot contain transmissible genes that encode resistance to medically important antibiotics or are related to virulence factors. Selected microorganisms must be evaluated based on their ability to adapt to the vaginal ecosystem and be economically included in a pharmaceutical product [119,120].

7. Conclusions

Uterine disease is still a significant health issue on most commercial dairy cattle farms, although it has been investigated in detail, especially following the early 2000s. There are a number of predisposing factors, but not all of them, can be entirely eliminated on a farm, which means that uterine disease cannot be prevented by management tools only. Commonly applied treatment protocols require manual labour, extensive drug usage and repeated follow-up examinations. With the global spread of antibiotic resistance, there is a growing demand for developing alternative treatment options and focusing more on prevention in farm animal medicine. In the case of cattle uterine disease, the most promising new area of research is probiotics. Probiotics have already been successfully used orally in cows. However, in vivo studies involving a more significant number of cows need to be conucted to evaluate the potential of probiotics for uterine disease prevention.

Author Contributions

Conceptualization, Z.V., V.J. and G.C.; writing—original draft preparation, Z.V., V.J., G.C. and Á.C.B.; writing—review and editing, Z.V., V.J., G.C. and Á.C.B.; supervision, V.J. and G.C.; funding acquisition, V.J. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported the National Research, Development and Innovation Office, Budapest, Hungary (Grant No. 2020-1.1.2-PIACI-KFI-2020-00002). VJ was supported by the strategic research fund of the University of Veterinary Medicine Budapest (Grant No. SRF-001).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Gilbert, R.O.; Shin, S.T.; Guard, C.L.; Erb, H.N.; Frajblat, M. Prevalence of endometritis and its effects on reproductive performance of dairy cows. Theriogenology 2005, 64, 1879–1888. [Google Scholar] [CrossRef]
  2. Hadley, G.L.; Wolf, C.A.; Harsh, S.B. Dairy cattle culling patterns, explanations and implications. J. Dairy Sci. 2006, 89, 2286–2296. [Google Scholar] [CrossRef]
  3. Nor, N.M.; Steeneweld, W.; Hogeveen, H. The average culling rate of Dutch dairy herds over the years 2007 to 2010 and its association with herd reproduction, performance and health. J. Dairy Res. 2014, 81, 1–8. [Google Scholar] [CrossRef]
  4. De Vries, A.; Olson, J.D.; Pinedo, P.J. Reproductive risk factors for culling and productive life in large dairy herds in the eastern United States between 2001 and 2006. J. Dairy Sci. 2010, 93, 613–623. [Google Scholar] [CrossRef]
  5. Fodor, I.; Ózsvári, L.; Búza, L. Reproductive management and major fertility parameters of cows in large-scale Hungarian dairy herds. Magy. Állatorv. Lapja. 2016, 138, 653–662. [Google Scholar]
  6. Pérez-Báez, J.; Silva, T.V.; Risco, C.A.; Chebel, R.C.; Cunha, F.; De Vries, A.; Santos, J.E.P.; Lima, F.S.; Pinedo, P.; Schuenemann, G.M.; et al. The economic cost of metritis in dairy herds. J. Dairy Sci. 2021, 104, 3158–3168. [Google Scholar] [CrossRef] [PubMed]
  7. Kern, L.; Fodor, I.; Balogh, O.G.; Ózsvári, L.; Gábor, G. The impact of postpartum uterine diseases on reproductive performance and their economic losses on large Hungarian dairy farms. Magy. Állatorv. Lapja. 2018, 140, 717–726. [Google Scholar]
  8. Sheldon, I.M.; Dobson, H. Postpartum uterine health in cattle. Anim. Reprod. Sci. 2004, 82–83, 295–306. [Google Scholar] [CrossRef] [PubMed]
  9. Sheldon, I.M.; Lewis, G.S.; LeBlanc, S.; Gilbert, R.O. Defining postpartum uterine disease in cattle. Theriogenology 2006, 65, 1516–1530. [Google Scholar] [CrossRef]
  10. Bajcsy, Á.C. Uterine infections affect involution in dairy cows. In Proceedings of the X Scientific Symposium on Domestic Animals Reproduction and Mammary Gland Diseases, Divcibare, Serbia, 10–13 October 2019; pp. 79–100, ISBN 978-86-80446-28-8. [Google Scholar]
  11. Sheldon, I.M.; Cronin, J.; Goetze, L.; Donofrio, G.; Schuberth, H.J. Defining Postpartum Uterine Disease and the Mechanisms of Infection and Immunity in the Female Reproductive Tract in Cattle. Biol. Reprod. 2009, 81, 1025–1032. [Google Scholar] [CrossRef] [PubMed]
  12. LeBlanc, S.J. Postpartum uterine disease and dairy herd reproductive performance: A review. Vet. J. 2008, 176, 102–114. [Google Scholar] [CrossRef]
  13. Goshen, T.; Shpigel, N.Y. Evaluation of intrauterine antibiotic treatment of clinical metritis and retained fetal membranes in dairy cows. Theriogenology 2006, 66, 2210–2218. [Google Scholar] [CrossRef] [PubMed]
  14. Galvao, K.N. Postpartum uterine diseases in dairy cows. Anim. Reprod. 2012, 9, 290–296. [Google Scholar]
  15. Vallejo-Timaran, D.A.; Reyes, J.; Gilbert, R.O.; Lefebvre, R.C.; Palacio-Baena, L.G.; Maldonado-Estrada, J.G. Incidence, clinical patterns, and risk factors of postpartum uterine diseases in dairy cows from high-altitude tropical herds. J. Dairy Sci. 2021, 104, 9016–9026. [Google Scholar] [CrossRef] [PubMed]
  16. Williams, E.J.; Fischer, D.P.; England, G.C.W.; Dobson, H.; Pfeiffer, D.U.; Sheldon, I.M. Clinical evaluation of postpartum vaginal mucus reflects uterine bacterial infection and the inflammatory response to endometritis in cattle. Theriogenology 2005, 63, 102–117. [Google Scholar] [CrossRef] [PubMed]
  17. Szenci, O.; Buják, D.; Bajcsy, Á.C.; Horváth, A.; Han, B.; Szelényi, Z. Diagnosis and treatment of post parturient uterine diseases in dairy cows Literature review. Magy. Állatorv. Lapja. 2015, 137, 271–282. [Google Scholar]
  18. Adnane, M.; Kaidi, R.; Hanzen, C.; England, G. Risk factors of clinical and subclinical endometritis in cattle: A review. Turk. J. Vet. Anim. Sci. 2017, 41, 1–11. [Google Scholar] [CrossRef]
  19. Sheldon, I.M.; Owens, S.E. Postpartum uterine infection and endometritis in dairy cattle. In Proceedings of the 33rd Annual Scientific Meeting of the European Embryo Transfer Association (AETE), Bath, UK, 8–9 September 2017. [Google Scholar] [CrossRef]
  20. Kim, I.H.; Na, K.J.; Yang, M.P. Immune Responses during the Peripartum Period in Dairy Cows with Postpartum Endometritis. J. Reprod. Dev. 2005, 51, 757–764. [Google Scholar] [CrossRef]
  21. Salasel, B.; Mokhtari, A.; Taktaz, T. Prevalence, risk factors for and impact of subclinical endometritis in repeat breeder dairy cows. Theriogenology 2010, 74, 1271–1278. [Google Scholar] [CrossRef]
  22. Pothmann, H.; Prunner, I.; Wagener, K.; Jaureguiberry, M.; de la Sota, R.L.; Erber, R.; Aurich, C.; Ehling-Schulz, M.; Drillich, M. The prevalence of subclinical endometritis and intrauterine infections in repeat breeder cows. Theriogenology 2015, 83, 1249–1253. [Google Scholar] [CrossRef]
  23. Könyves, L.; Szenci, O.; Jurkovich, V.; Tegzes, L.; Tirián, A.; Solymosi, N.; Gyulay, G.; Brydl, E. Risk assessment of postpartum uterine disease and consequences of puerperal metritis for subsequent metabolic status, reproduction and milk yield in dairy cows. Acta Vet. Hung. 2009, 57, 155–169. [Google Scholar] [CrossRef] [PubMed]
  24. Póth-Szebenyi, B.; Varga-Balogh, O.; Kern, L.; Stefler, J.; Ivanyos, D.; Gábor, G. Postpartum involution disorders in cattle especially due to subclinical endometritis. Literature review. Magy. Állatorv. Lapja 2021, 143, 529–540. [Google Scholar]
  25. Hossein-Zadeh, N.G.; Ardalan, M. Cow-specific risk factors for retained placenta, metritis and clinical mastitis in Holstein cows. Vet. Res. Commun. 2011, 35, 345–354. [Google Scholar] [CrossRef] [PubMed]
  26. Gautam, G.; Nakao, T.; Koike, K.; Long, S.T.; Yusuf, M.; Ranasinghe, R.M.; Hayashi, A. Spontaneous recovery or persistence of postpartum endometritis and risk factors for its persistence in Holstein cows. Theriogenology 2010, 73, 168–179. [Google Scholar] [CrossRef] [PubMed]
  27. Potter, T.J.; Guitian, J.; Fishwick, J.; Gordon, P.J.; Sheldon, I.M. Risk factors for clinical endometritis in postpartum dairy cattle. Theriogenology 2010, 74, 127–134. [Google Scholar] [CrossRef] [PubMed]
  28. Karstrup, C.C.; Pedersen, H.G.; Jensen, T.K.; Agerholm, J.S. Bacterial invasion of the uterus and oviducts in bovine pyometra. Theriogenology 2017, 93, 93–98. [Google Scholar] [CrossRef] [PubMed]
  29. Cheong, S.H.; Nydam, D.V.; Galvão, K.N.; Crosier, B.M.; Gilbert, R.O. Cow-level and herd-level risk factors for subclinical endometritis in lactating Holstein cows. J. Dairy Sci. 2011, 94, 762–770. [Google Scholar] [CrossRef]
  30. Dubuc, J.; Duffield, T.F.; Leslie, K.E.; Walton, J.S.; LeBlanc, S.J. Definitions and diagnosis of postpartum endometritis in dairy cows. J. Dairy Sci. 2010, 93, 5225–5233. [Google Scholar] [CrossRef]
  31. McDougall, S.; Macaulay, R.; Compton, C. Association between endometritis diagnosis using a novel intravaginal device and reproductive performance in dairy cattle. Anim. Reprod. Sci. 2007, 99, 9–23. [Google Scholar] [CrossRef]
  32. Pleticha, S.; Drillich, M.; Heuwieser, W. Evaluation of the Metricheck device and the gloved hand for the diagnosis of clinical endometritis in dairy cows. J. Dairy Sci. 2009, 92, 5429–5435. [Google Scholar] [CrossRef]
  33. Denis-Robichaud, J.; Dubuc, J. Determination of optimal diagnostic criteria for purulent vaginal discharge and cytological endometritis in dairy cows. J. Dairy Sci. 2015, 98, 6848–6855. [Google Scholar] [CrossRef]
  34. Wagener, K.; Gabler, C.; Drillich, M. A review of the ongoing discussion about definition, diagnosis and pathomechanism of subclinical endometritis in dairy cows. Theriogenology 2017, 94, 21–30. [Google Scholar] [CrossRef]
  35. Kelly, E.; McAloon, C.G.; O’Grady, L.; Duane, M.; Somers, J.R.; Beltman, M.E. Cow-level risk factors for reproductive tract disease diagnosed by 2 methods in pasture-grazed dairy cattle in Ireland. J. Dairy Sci. 2020, 103, 737–749. [Google Scholar] [CrossRef]
  36. Sun, D.; Wu, R.; He, X.; Wang, S.; Lin, Y.; Han, X.; Wang, Y.; Guo, T.; Wu, G.; Yang, K. Development of a Multiplex PCR for Diagnosis of Staphylococcus aureus, Escherichia coli and Bacillus cereus from Cows with Endometritis. Agric. Sci. China 2011, 10, 1624–1629. [Google Scholar] [CrossRef]
  37. Cheong, S.H.; Nydam, D.V.; Galvão, K.N.; Crosier, B.M.; Ricci, A.; Caixeta, L.S.; Sper, R.B.; Fraga, M.; Gilbert, R.O. Use of reagent test strips for diagnosis of endometritis in dairy cows. Theriogenology 2012, 77, 858–864. [Google Scholar] [CrossRef]
  38. Lima, F.S. Recent advances and future directions for uterine disease diagnosis, pathogenesis, and management in dairy cows. Anim. Reprod. 2020, 17, e20200063. [Google Scholar] [CrossRef]
  39. Kasimanickam, R.; Duffield, T.F.; Foster, R.A.; Gartley, C.J.; Leslie, K.E.; Walton, J.S.; Johnson, W.H. Endometrial cytology and ultrasonography for the detection of subclinical endometritis in postpartum dairy cows. Theriogenology 2004, 62, 9–23. [Google Scholar] [CrossRef] [PubMed]
  40. Kasimanickam, R.; Duffield, T.F.; Foster, R.A.; Gartley, C.J.; Leslie, K.E.; Walton, J.S.; Johnson, W.H. A comparison of the cytobrush and uterine lavage techniques to evaluate endometrial cytology in clinically normal postpartum dairy cows. Can. Vet. J. 2005, 46, 255–259. [Google Scholar] [PubMed]
  41. Pascottini, O.B.; Dini, P.; Hostens, M.; Ducatelle, R.; Opsomer, G. A novel cytologic sampling technique to diagnose subclinical endometritis and comparison of staining methods for endometrial cytology samples in dairy cows. Theriogenology 2015, 84, 1438–1446. [Google Scholar] [CrossRef] [PubMed]
  42. Szenci, O. Recent possibilities for diagnosis and treatment of postparturient uterine diseases in dairy cow. JFIV Reprod. Med. Genet. 2016, 4, 170. [Google Scholar] [CrossRef]
  43. Van Schyndel, S.J.; Pascottini, O.B.; LeBlanc, S.J. Comparison of cow-side diagnostic techniques for subclinical endometritis in dairy cows. Theriogenology 2018, 120, 117–122. [Google Scholar] [CrossRef]
  44. Baranski, W.; Podhalicz-Dziegielewska, M.; Zdunczyk, S.; Janowski, T. The diagnosis and prevalence of subclinical endometritis in cows evaluated by different cytologic thresholds. Theriogenology 2012, 78, 1939–1947. [Google Scholar] [CrossRef]
  45. McDougall, S.; Hussein, H.; Aberdein, D.; Buckle, K.; Roche, J.; Burke, C.; Mitchell, M.; Meier, S. Relationships between cytology, bacteriology and vaginal discharge scores and reproductive performance in dairy cattle. Theriogenology 2011, 76, 229–240. [Google Scholar] [CrossRef]
  46. Sharma, A.; Singh, M.; Kumar, P.; Sharma, A.; Jan, A.M.; Sharma, A.; Kashyap, A.; Thakur, A.; Saini, P.; Gupta, S. Pyometra in a Jersey crossbred cow—Diagnosis and treatment. Explor. Anim. Med. Res. 2018, 8, 97–99. [Google Scholar]
  47. Gomez, D.E.; Galvão, K.N.; Rodriguez-Lecompte, J.C.; Costa, M.C. The cattle microbiota and the immune system—An evolving field. Vet. Clin. N. Am. Food Anim. Pract. 2019, 35, 485–505. [Google Scholar] [CrossRef]
  48. Otero, C.; Saavedra, L.; Silva de Ruiz, C.; Wilde, O.; Holgado, A.R.; Nader-Macías, M.E. Vaginal bacterial microflora modifications during the growth of healthy cows. Lett. Appl. Microbiol. 2000, 31, 251–254. [Google Scholar] [CrossRef] [PubMed]
  49. Quereda, J.J.; Barba, M.; Mocé, M.L.; Gomis, J.; Jiménez-Trigos, E.; García-Muñoz, Á.; Gómez-Martín, Á.; González-Torres, P.; Carbonetto, B.; García-Roselló, E. Vaginal Microbiota Changes During Estrous Cycle in Dairy Heifers. Front. Vet. Sci. 2020, 7, 371. [Google Scholar] [CrossRef] [PubMed]
  50. Ault, T.B.; Clemmons, B.A.; Reese, S.T.; Dantas, F.G.; Franco, G.A.; Smith, T.P.L.; Edwards, J.L.; Myer, P.R.; Pohler, K.G. Bacterial taxonomic composition of the postpartum cow uterus and vagina prior to artificial insemination. J. Anim. Sci. 2019, 97, 4305–4313. [Google Scholar] [CrossRef] [PubMed]
  51. Ault, T.B.; Clemmons, B.A.; Reese, S.T.; Dantas, F.G.; Franco, G.A.; Smith, T.P.L.; Edwards, J.L.; Myer, P.R.; Pohler, K.G. Uterine and vaginal bacterial community diversity prior to artificial insemination between pregnant and nonpregnant postpartum cows. J. Anim. Sci. 2019, 97, 4298–4304. [Google Scholar] [CrossRef] [PubMed]
  52. Westermann, S.; Drillich, M.; Kaufmann, T.B.; Madoz, L.V.; Heuwieser, W. A clinical approach to determine false positive findings of clinical endometritis by vaginoscopy by the use of uterine bacteriology and cytology in dairy cows. Theriogenoogy 2010, 74, 1248–1255. [Google Scholar] [CrossRef] [PubMed]
  53. Udhayavel, S.; Malmarugan, S.; Palanisamy, K.; Rajeswar, J. Antibiogram pattern of bacteria causing endometritis in cows. Vet. World 2013, 6, 100–102. [Google Scholar] [CrossRef]
  54. Knudsen, L.R.V.; Karstrup, C.C.; Pedersen, H.G.; Angen, Ø.; Agerholm, J.S.; Rasmussen, E.L.; Jensen, T.K.; Klitgaard, K. An investigation of the microbiota in uterine flush samples and endometrial biopsies from dairy cows during the first 7 weeks postpartum. Theriogenology 2016, 86, 642–650. [Google Scholar] [CrossRef]
  55. Silva, L.P.; Ramos, S.A.; Cavalcanti Neto, C.C.; dos Santos, T.M.C.; de Oliveira, J.A.C.; dos Santos, M.T.; da Silva, J.M.; Brito Neto, J.S.; Montaldo, Y.C. Vaginal microbiota of nulliparous and multiparous cows and their resistance to antimicrobials. Med. Vet. (UFRPE) Recife 2019, 13, 474–481. [Google Scholar] [CrossRef]
  56. Laguardia-Nascimento, M.; Branco, K.M.; Gasparini, M.R.; Giannattasio-Ferraz, S.; Leite, L.R.; Araujo, F.M.; Salim, A.C.; Nicoli, J.R.; de Oliveira, G.C.; Barbosa-Stancioli, E.F. Vaginal Microbiome Characterization of Nellore Cattle Using Metagenomic Analysis. PLoS ONE 2015, 10, e0143294. [Google Scholar] [CrossRef]
  57. Chen, S.Y.; Deng, F.; Zhang, M.; Jia, X.; Lai, S.J. Characterization of Vaginal Microbiota Associated with Pregnancy Outcomes of Artificial Insemination in Dairy Cows. J. Microbiol. Biotechnol. 2020, 30, 804–810. [Google Scholar] [CrossRef]
  58. Swartz, J.D.; Lachman, M.; Westveer, K.; O’Neill, T.; Geary, T.; Kott, R.W.; Berardinelli, J.G.; Hatfield, P.G.; Thomson, J.M.; Roberts, A.; et al. Characterization of the vaginal microbiota of ewes and cows reveals a unique microbiota with low levels of lactobacilli and near-neutral pH. Front. Vet. Sci. 2014, 1, 19. [Google Scholar] [CrossRef]
  59. Miranda-CasoLuengo, R.; Lu, J.; Williams, E.J.; Miranda-CasoLuengo, A.A.; Carrington, S.D.; Evans, A.C.O.; Meijer, W.G. Delayed differentiation of vaginal and uterine microbiomes in dairy cows developing postpartum endometritis. PLoS ONE 2019, 14, e0200974. [Google Scholar] [CrossRef]
  60. Jeon, S.J.; Vieira-Neto, A.; Gobikrushanth, M.; Daetz, R.; Mingoti, R.D.; Parize, A.C.; de Freitas, S.L.; da Costa, A.N.; Bicalho, R.C.; Lima, S.; et al. Uterine Microbiota Progression from Calving until Establishment of Metritis in Dairy Cows. Appl. Environ. Microbiol. 2015, 81, 6324–6332. [Google Scholar] [CrossRef] [PubMed]
  61. Tasara, T.; Meier, A.B.; Wambui, J.; Whiston, R.; Stevens, M.; Chapwanya, A.; Bleu, U. Interrogating the Diversity of Vaginal, Endometrial, and Fecal Microbiomes in Healthy and Metritis Dairy Cattle. Animals 2023, 13, 1221. [Google Scholar] [CrossRef] [PubMed]
  62. Wang, M.L.; Liu, M.C.; Xu, J.; An, L.G.; Wang, J.F.; Zhu, Y.H. Uterine Microbiota of Dairy Cows with Clinical and Subclinical Endometritis. Front. Microbiol. 2018, 9, 2691. [Google Scholar] [CrossRef] [PubMed]
  63. Bicalho, M.L.S.; Lima, S.; Higgins, C.H.; Machado, V.S.; Lima, F.S.; Bicalho, R.C. Genetic and functional analysis of the bovine uterine microbiota. Part II: Purulent vaginal discharge versus healthy cows. J. Dairy Sci. 2017, 100, 3863–3874. [Google Scholar] [CrossRef]
  64. Pascottini, O.B.; Van Schyndel, S.J.; Spricigo, J.F.W.; Rousseau, J.; Weese, J.S.; LeBlanc, S.J. Dynamics of uterine microbiota in postpartum dairy cows with clinical or subclinical endometritis. Sci. Rep. 2020, 10, 12353. [Google Scholar] [CrossRef] [PubMed]
  65. Wang, J.; Wang, J.; Sun, C.; Liu, C.; Yang, Y.; Lu, W. Comparison of vaginal microbial community structure in healthy and endometritis dairy cows by PCR-DGGE and real-time PCR. Anaerobe 2016, 38, 1–6. [Google Scholar] [CrossRef] [PubMed]
  66. Gonzalez Moreno, C.; Torres Luque, A.; Oliszewski, R.; Rosa, R.J.; Otero, M.C. Characterization of native Escherichia coli populations from bovine vagina of healthy heifers and cows with postpartum uterine disease. PLoS ONE 2020, 15, e0228294. [Google Scholar] [CrossRef] [PubMed]
  67. Rodrigues, N.F.; Kästle, J.; Coutinho, T.J.; Amorim, A.T.; Campos, G.B.; Santos, V.M.; Marques, L.M.; Timenetsky, J.; de Farias, S.T. Qualitative analysis of the vaginal microbiota of healthy cattle and cattle with genital-tract disease. Genet. Mol. Res. 2015, 14, 6518–6528. [Google Scholar] [CrossRef] [PubMed]
  68. Kudo, H.; Sugiura, T.; Higashi, S.; Oka, K.; Takahashi, M.; Kamiya, S.; Tamura, Y.; Usui, M. Characterization of Reproductive Microbiota of Primiparous Cows During Early Postpartum Periods in the Presence and Absence of Endometritis. Front. Vet. Sci. 2021, 8, 736996. [Google Scholar] [CrossRef]
  69. Bicalho, M.L.S.; Santin, T.; Rodrigues, M.X.; Marques, C.E.; Lima, S.F.; Bicalho, R.C. Dynamics of the microbiota found in the vaginas of dairy cows during the transition period: Associations with uterine diseases and reproductive outcome. J. Dairy Sci. 2017, 100, 3043–3058. [Google Scholar] [CrossRef]
  70. Quadros, D.L.; Zanella, R.; Bondan, C.; Zanella, G.C.; Facioli, F.L.; da Silva, A.N.; Zanella, E.L. Study of vaginal microbiota of Holstein cows submitted to an estrus synchronization protocol with the use of intravaginal progesterone device. Res. Vet. Sci. 2020, 131, 1–6. [Google Scholar] [CrossRef]
  71. Pascottini, O.B.; Spricigo, J.F.W.; Van Schyndel, S.J.; Mion, B.; Rousseau, J.; Weese, J.S.; LeBlanc, S.J. Effects of parity, blood progesterone, and non-steroidal anti-inflammatory treatment on the dynamics of the uterine microbiota of healthy postpartum dairy cows. PLoS ONE 2021, 16, e0233943. [Google Scholar] [CrossRef]
  72. Galvao, K.N. Uterine diseases in dairy cows: Understanding the causes and seeking solutions. Anim. Reprod. 2013, 10, 228–238. [Google Scholar]
  73. Sheldon, I.M.; Molinari, P.C.C.; Ormsby, T.J.R.; Bromfield, J.J. Preventing postpartum uterine disease in dairy cattle depends on avoiding, tolerating and resisting pathogenic bacteria. Theriogenology 2020, 150, 158–165. [Google Scholar] [CrossRef]
  74. Pulfer, K.W.; Riese, R.L. Treatment of Postpartum Metritis in Dairy Cows. Iowa State Univ. Vet. 1991, 53, 6. Available online: https://lib.dr.iastate.edu/iowastate_veterinarian/vol53/iss1/6 (accessed on 20 July 2023).
  75. Silva, T.V.; de Oliveira, E.B.; Pérez-Báez, J.; Risco, C.A.; Chebel, R.C.; Cunha, F.; Daetz, R.; Santos, J.E.P.; Lima, F.S.; Jeong, K.C.; et al. Economic comparison between ceftiofur-treated and nontreated dairy cows with metritis. J. Dairy Sci. 2021, 104, 8918–8930. [Google Scholar] [CrossRef]
  76. Negasee, K.A. Clinical metritis and endometritis in dairy cattle: A review. Vet. Med. Open J. 2020, 5, 51–56. [Google Scholar] [CrossRef]
  77. Galvao, K.N.; Frajblat, M.; Brittin, S.B.; Butler, W.R.; Guard, C.L.; Gilbert, R.O. Effect of prostaglandin F2α on subclinical endometritis and fertility in dairy cows. J. Dairy Sci. 2009, 92, 4906–4913. [Google Scholar] [CrossRef]
  78. McDougall, S. Effect of intrauterine antibiotic treatment on reproductive performance of dairy cows following periparturient disease. N. Z. Vet. J. 2001, 49, 150–158. [Google Scholar] [CrossRef]
  79. Brick, T.A.; Schuenemann, G.M.; Bas, S.; Daniels, J.B.; Pinto, C.R.; Rings, D.M.; Rajala-Schultz, P.J. Effect of intrauterine dextrose or antibiotic therapy on reproductive performance of lactating dairy cows diagnosed with clinical endometritis. J. Dairy Sci. 2012, 95, 1894–1905. [Google Scholar] [CrossRef]
  80. Honparkhe, M.; Kumar, A.; Singh, A.K.; Dadarwal, D.; Dhaliwal, G.S. Efficacy of various intrauterine therapies against uterine infections in repeat breeding cattle. Indian Vet. J. 2017, 94, 46–47. [Google Scholar]
  81. Shams-Esfandabadi, N.; Shirazi, A.; Ghasemzadeh-nava, H. Pregnancy rate following post-insemination intrauterine treatment of endometritis in dairy cattle. J. Vet. Med. Ser. A 2004, 51, 155–156. [Google Scholar] [CrossRef]
  82. Haimerl, P.; Arlt, S.; Borchardt, S.; Heuwieser, W. Antibiotic treatment of metritis in dairy cows—A meta-analysis. J. Dairy Sci. 2017, 100, 3783–3795. [Google Scholar] [CrossRef]
  83. Haimerl, P.; Heuwieser, W. Invited review: Antibiotic treatment of metritis in dairy cows: A systematic approach. J. Dairy Sci. 2014, 97, 6649–6661. [Google Scholar] [CrossRef]
  84. Jeon, S.J.; Lima, F.S.; Vieira-Neto, A.; Machado, V.S.; Lima, S.F.; Bicalho, R.C.; Santos, J.E.P.; Galvão, K.N. Shift of uterine microbiota associated with antibiotic treatment and cure of metritis in dairy cows. Vet. Microbiol. 2018, 214, 132–139. [Google Scholar] [CrossRef]
  85. Ma, Z.; Ginn, A.; Kang, M.; Galvão, K.N.; Jeong, K.C. Genomic and Virulence Characterization of Intrauterine Pathogenic Escherichia coli With Multi-Drug Resistance Isolated From Cow Uteri With Metritis. Front. Microbiol. 2018, 9, 3137. [Google Scholar] [CrossRef]
  86. Merenda, V.R.; Lezier, D.; Odetti, A.; Figueiredo, C.C.; Risco, C.A.; Bisinotto, R.S.; Chebel, R.C. Effects of metritis treatment strategies on health, behavior, reproductive, and productive responses of Holstein cows. J. Dairy Sci. 2020, 104, 2056–2073. [Google Scholar] [CrossRef]
  87. Lima, F.S.; Vieira-Neto, A.; Snodgrass, J.A.; De Vries, A.; Santos, J.E.P. Economic comparison of systemic antimicrobial therapies for metritis in dairy cows. J. Dairy Sci. 2019, 102, 7345–7358. [Google Scholar] [CrossRef]
  88. Drillich, M.; Raab, D.; Wittke, M.; Heuwieser, W. Treatment of chronic endometritis in dairy cows with an intrauterine application of enzymes. A field trial. Theriogenology 2005, 63, 1811–1823. [Google Scholar] [CrossRef]
  89. Machado, V.S.; Bicalho, M.L.; Meira Junior, E.B.; Rossi, R.; Ribeiro, B.L.; Lima, S.; Santos, T.; Kussler, A.; Foditsch, C.; Ganda, E.K.; et al. 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 2014, 9, e91734. [Google Scholar] [CrossRef]
  90. Pinedo, P.J.; Caixeta, L.S.; Barrell, E.A.; Velez, J.; Manriquez, D.; Herman, J.; Holt, T. A randomized controlled clinical trial on the effect of acupuncture therapy in dairy cows affected by pyometra. Res. Vet. Sci. 2020, 133, 12–16. [Google Scholar] [CrossRef]
  91. Barragan, A.A.; Bas, S.; Hovingh, E.; Byler, L. Effects of postpartum acetylsalicylic acid on uterine diseases and reproductive performance in dairy cattle. JDS Commun. 2021, 2, 67–72. [Google Scholar] [CrossRef]
  92. Barreto, M.O.; Soust, M.; Moore, R.J.; Olchowy, T.W.J.; Alawneh, J.I. Systematic review and meta-analysis of probiotic use on inflammatory biomarkers and disease prevention in cattle. Prev. Vet. Med. 2021, 194, 105433. [Google Scholar] [CrossRef]
  93. FAO and WHO: Health and Nutrition Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria Cordoba, Argentina, 1–4 October 2001. Available online: https://www.fao.org/3/a0512e/a0512e.pdf (accessed on 25 July 2023).
  94. Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 506–514. [Google Scholar] [CrossRef]
  95. Rosales, E.B.; Ametaj, B.N. Reproductive Tract Infections in Dairy Cows: Can Probiotics Curb Down the Incidence Rate? Dairy 2021, 2, 40–64. [Google Scholar] [CrossRef]
  96. Otero, M.C.; Morelli, L.; Nader-Macías, M.E. Probiotic properties of vaginal lactic acid bacteria to prevent metritis in cattle. Lett. Appl. Microbiol. 2006, 43, 91–97. [Google Scholar] [CrossRef]
  97. Nader-Macías, M.E.; Otero, M.C.; Espeche, M.C.; Maldonado, N.C. Advances in the design of probiotic products for the prevention of major diseases in dairy cattle. J. Ind. Microbiol. Biotechnol. 2008, 35, 1387–1395. [Google Scholar] [CrossRef]
  98. Genís, S.; Sánchez-Chardi, A.; Bach, A.; Fàbregas, F.; Arís, A. A combination of lactic acid bacteria regulates Escherichia coli infection and inflammation of the bovine endometrium. J. Dairy Sci. 2017, 100, 479–492. [Google Scholar] [CrossRef]
  99. Genís, S.; Bach, A.; Fàbregas, F.; Arís, A. Potential of lactic acid bacteria at regulating Escherichia coli infection and inflammation of bovine endometrium. Theriogenology 2016, 85, 625–637. [Google Scholar] [CrossRef]
  100. Liu, M.; Wu, Q.; Wang, M.; Fu, Y.; Wang, J. Lactobacillus rhamnosus GR-1 Limits Escherichia coli-Induced Inflammatory Responses via Attenuating MyD88-Dependent and MyD88-Independent Pathway Activation in Bovine Endometrial Epithelial Cells. Inflammation 2016, 39, 1483–1494. [Google Scholar] [CrossRef]
  101. Wang, Y.; Ametaj, B.N.; Ambrose, D.J.; Gänzle, M.G. Characterisation of the bacterial microbiota of the vagina of dairy cows and isolation of pediocinproducing Pediococcus acidilactici. BMC Microbiol. 2013, 13, 19. [Google Scholar] [CrossRef]
  102. Rodríguez, C.; Cofré, J.V.; Sánchez, M.; Fernández, P.; Boggiano, G.; Castro, E. Lactobacilli isolated from vaginal vault of dairy and meat cows during progesteronic stage of estrous cycle. Anaerobe 2011, 17, 15–18. [Google Scholar] [CrossRef]
  103. Niu, C.; Cheng, C.; Liu, Y.; Huang, S.; Fu, Y.; Li, P. Transcriptome profiling analysis of bovine vaginal epithelial cell response to an isolated Lactobacillus strain. mSystems 2019, 4, e00268-19. [Google Scholar] [CrossRef]
  104. Ametaj, B.N.; Iqbal, S.; Selami, F.; Odhiambo, J.F.; Wang, Y.; Gänzle, M.G.; Dunn, S.M.; Zebeli, Q. Intravaginal administration of lactic acid bacteria modulated the incidence of purulent vaginal discharges, plasma haptoglobin concentrations, and milk production in dairy cows. Res. Vet. Sci. 2014, 96, 365–370. [Google Scholar] [CrossRef]
  105. Deng, Q.; Odhiambo, J.F.; Farooq, U.; Lam, T.; Dunn, S.M.; Ametaj, B.N. Intravaginal Lactic Acid Bacteria Modulated Local and Systemic Immune Responses and Lowered the Incidence of Uterine Infections in Periparturient Dairy Cows. PLoS ONE 2015, 10, e0124167. [Google Scholar] [CrossRef]
  106. Deng, Q.; Odhiambo, J.F.; Farooq, U.; Lam, T.; Dunn, S.M.; Gänzle, M.G.; Ametaj, B.N. Intravaginally administered lactic acid bacteria expedited uterine involution and modulated hormonal profiles of transition dairy cows. J. Dairy Sci. 2015, 98, 1–11. [Google Scholar] [CrossRef]
  107. Deng, Q.; Odhiambo, J.F.; Farooq, U.; Lam, T.; Dunn, S.M.; Ametaj, B.N. Intravaginal probiotics modulated metabolic status and improved milk production and composition of transition dairy cows. J. Anim. Sci. 2016, 94, 760–770. [Google Scholar] [CrossRef]
  108. Genís, S.; Cerri, R.L.A.; Bach, À.; Silper, B.F.; Baylão, M.; Denis-Robichaud, J.; Arís, A. Pre-calving Intravaginal Administration of Lactic Acid Bacteria Reduces Metritis Prevalence and Regulates Blood Neutrophil Gene Expression After Calving in Dairy Cattle. Front. Vet. Sci. 2018, 5, 135. [Google Scholar] [CrossRef]
  109. Genís, S.; Bach, A.; Arís, A. Effects of intravaginal lactic acid bacteria on bovine endometrium: Implications in uterine health. Vet. Microbiol. 2017, 204, 174–179. [Google Scholar] [CrossRef]
  110. Yang, L.; Huang, W.; Yang, C.; Ma, T.; Hou, Q.; Sun, Z.; Zhang, H. Using PacBio sequencing to investigate the effects of treatment with lactic acid bacteria or antibiotics on cow endometritis. Electr. J. Biotechnol. 2021, 51, 67–78. [Google Scholar] [CrossRef]
  111. García-Galán, A.; De la Fe, C.; Gomis, J.; Bataller, E.; Sánchez, A.; Quereda, J.J.; García-Roselló, E.; Gómez-Martín, A. The addition of Lactobacillus spp. negatively affects Mycoplasma bovis viability in bovine cervical mucus. BMC Vet. Res. 2020, 16, 251. [Google Scholar] [CrossRef]
  112. Peter, S.; Gärtner, M.A.; Michel, G.; Ibrahim, M.; Klopfleisch, R.; Lübke-Becker, A.; Jung, M. Infuence of intrauterine administration of Lactobacillus buchneri on reproductive performance and pro-infammatory endometrial mRNA expression of cows with subclinical endometritis. Sci. Rep. 2018, 8, 5473. [Google Scholar] [CrossRef]
  113. Gohil, P.; Nanavati, B.; Patel, K.; Suthar, V.; Joshi, M.; Patil, D.B.; Joshi, C.G. Assessing the efficacy of probiotics in augmenting bovine reproductive health: An integrated in vitro, in silico, and in vivo study. Front. Microbiol. 2023, 14, 1137611. [Google Scholar] [CrossRef]
  114. Madureira, A.M.L.; Burnett, T.A.; Boyd, C.T.; Baylão, M.; Cerri, R.L.A. Use of intravaginal lactic acid bacteria prepartum as an approach for preventing uterine disease and its association with fertility of lactating dairy cows. J. Dairy Sci. 2023, 106, 4860–4873. [Google Scholar] [CrossRef]
  115. El-Garhi, M.S.; El-Bordeny, N.E. Impact of intravaginal probiotics inoculation on reproductive performance of Holstein dairy cattle during transition period. Assiut Vet. Med. J. 2019, 65, 63–70. [Google Scholar] [CrossRef]
  116. Styková, E.; Nemcova, R.; Gancarikova, S.; Valocka, I.; Lauková, A. Bovine vaginal lactobacilli and their adherence to mucus in different phases of the estrous cycle. African J. Microbiol. Res. 2014, 8, 3017–3024. [Google Scholar] [CrossRef]
  117. Clemmons, B.A.; Reese, S.T.; Dantas, F.G.; Franco, G.A.; Smith, T.P.L.; Adeyosoye, O.I.; Pohler, K.G.; Myer, P.R. Vaginal and Uterine Bacterial Communities in Postpartum Lactating Cows. Front. Microbiol. 2017, 8, 1047. [Google Scholar] [CrossRef]
  118. Beckwith-Cohen, B.; Koren, O.; Blum, S.; Elad, D. Variations in Vaginal pH in Dairy Cattle Associated with Parity and the Periparturient Period. Israel J. Vet. Med. 2012, 67, 55–59. [Google Scholar]
  119. Miranda, M.H.; Ficoseco, C.A.; Nader-Macías, M.E.F. Safety, environmental and technological characterization of beneficial autochthonous lactic bacteria, and their vaginal administration to pregnant cows for the design of homologous multi-strain probiotic formulas. Brazil. J. Microbiol. 2021, 52, 2455–2473. [Google Scholar] [CrossRef]
  120. Shridhar, P.B.; Amachawadi, R.G.; Tokach, M.; Patel, I.; Gangiredla, J.; Mammel, M.; Nagaraja, T.G. Whole genome sequence analyses-based assessment of virulence potential and antimicrobial susceptibilities and resistance of Enterococcus faecium strains isolated from commercial swine and cattle probiotic products. J. Anim. Sci. 2022, 100, skac030. [Google Scholar] [CrossRef]
Figure 1. The most important risk factors for cattle uterine disease and which measures can help prevent them.
Figure 1. The most important risk factors for cattle uterine disease and which measures can help prevent them.
Vetsci 11 00066 g001
Figure 2. Mechanisms of action of probiotic bacteria (ProB) that may decrease the possibility of post-puerperal diseases in cows involve direct negative action on pathogen bacteria (PB); by the production of the biofilms (BF) on the surface of epithelial cells (EC), competing for essential nutrients (COMP), production of antimicrobial compounds (AMCs) and maintaining the optimal vaginal pH. The mode of action for probiotic bacteria also includes enhancing epithelial cell barrier functions by increasing the expression of genes involved in the tight junction (TJ) signalling and modulation of the immune system via the activation of toll-like receptors (TLR). Further abbreviations used in the figure: DC: dendritic cells; T: T-lymphocytes; B: B-lymphocytes; P: plasma cells; MP: macrophages. Red arrows represent inhibitory and green arrows represent stimulatory action on the highlighted processes.
Figure 2. Mechanisms of action of probiotic bacteria (ProB) that may decrease the possibility of post-puerperal diseases in cows involve direct negative action on pathogen bacteria (PB); by the production of the biofilms (BF) on the surface of epithelial cells (EC), competing for essential nutrients (COMP), production of antimicrobial compounds (AMCs) and maintaining the optimal vaginal pH. The mode of action for probiotic bacteria also includes enhancing epithelial cell barrier functions by increasing the expression of genes involved in the tight junction (TJ) signalling and modulation of the immune system via the activation of toll-like receptors (TLR). Further abbreviations used in the figure: DC: dendritic cells; T: T-lymphocytes; B: B-lymphocytes; P: plasma cells; MP: macrophages. Red arrows represent inhibitory and green arrows represent stimulatory action on the highlighted processes.
Vetsci 11 00066 g002
Figure 3. Flowchart of intravaginal probiotic product development.
Figure 3. Flowchart of intravaginal probiotic product development.
Vetsci 11 00066 g003
Table 1. The different probiotic strains used in in vitro studies.
Table 1. The different probiotic strains used in in vitro studies.
Strains UsedSpeciesSourceEffectsReferences
76 Lactobacillus spp. strains
7 Streptococcus spp. strains
cattleVaginaAlthough most strains were able to inhibit E. coli due to their acid production, only a few strains were able to inhibit T. pyogenes.[96]
82 Lactobacillus strains;
Lactobacillus fermentum
L. gasseri CRL1412,
L. gasseri CRL1421,
L. delbrueckii subsp. delbrueckii CRL1461
cattlevaginal swab95% produced H2O2; more than 80% produced lactic acid; no strains were bacteriocin producers. Listed isolates were able to inhibit E. coli or T. pyogenes.[97]
Pediococcus acidilactici CECT 5915,
L. sakei DSM 20100,
L. reuteri DSM 20016,
L. rhamnosus CECT 278
cattleobtained from bacterium strain collectionsInhibition of infection with E. coli when inflammation is present.
The combination of L. rhamnosus ratio 25, P. acidilactici ratio 25 and L. reuteri ratio 2 was most effective in reducing E. coli infection with or without basal tissue inflammation compared to single LAB strains.
[98,99]
Lactobacillus rhamnosus GR-1, ATCC 55826cattleobtained from bacterium strain collectionsLimits the inflammatory response to E. coli infection and subsequent endometrial epithelial cell damage.[100]
Pediococcus acidilactici (FUA3138 and FUA3140)cattlevaginal swabProduction of bacteriocin against E. coli.[101]
Lactobacillus spp. (mainly L. plantarum, and L. rhamnosus, L. curvatus, L. delbrueckii delbrueckii, L. acidophilus)cattlevaginal flush13 of 29 strains were characterized by H2O2 production[102]
Lactobacillus strain SQ0048cattlevaginaAdhesion to host cells (endoplasmic reticulum protein processing pathways); Interleukin-17 signalling pathway involved in pathogen inhibition, antigen processing and presentation pathways.[103]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Várhidi, Z.; Csikó, G.; Bajcsy, Á.C.; Jurkovich, V. Uterine Disease in Dairy Cows: A Comprehensive Review Highlighting New Research Areas. Vet. Sci. 2024, 11, 66. https://doi.org/10.3390/vetsci11020066

AMA Style

Várhidi Z, Csikó G, Bajcsy ÁC, Jurkovich V. Uterine Disease in Dairy Cows: A Comprehensive Review Highlighting New Research Areas. Veterinary Sciences. 2024; 11(2):66. https://doi.org/10.3390/vetsci11020066

Chicago/Turabian Style

Várhidi, Zsóka, György Csikó, Árpád Csaba Bajcsy, and Viktor Jurkovich. 2024. "Uterine Disease in Dairy Cows: A Comprehensive Review Highlighting New Research Areas" Veterinary Sciences 11, no. 2: 66. https://doi.org/10.3390/vetsci11020066

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop