Impact of early postpartum uterine disease (metritis) on the functional regeneration of endometrial glands in lactating dairy cows
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"The biological mechanisms that govern the establishment of mammalian pregnancy have been extensively investigated over the past century. Despite the advances, female fertility is continuously challenged by many intrinsic and extrinsic factors that are yet to be elucidated. A linear population increase is estimated to occur globally from the year 2000 to 2050 (Alexandratos et al., 2006). Unsurprisingly, these trends are expected to compel livestock production systems to accompany the growing demand for food, given that predictive metrics estimate that 68 percent and 57 percent of the global population will consume meat and milk, respectively, by the year of 2030 (Steinfeld and Gerber, 2010). The increasing populational demand for food poses a challenge for livestock producers across all food animal systems to maintain an efficient herd. The efficiency of livestock production systems typically relies on herd-level turnover rates as its single indicator; however, these only provide a broader picture of a variety of events that culminate into that single outcome. Given that, the demand for superior efficiency could be met by increasing the productive lifespan of production animals at an individual level, closely redirecting efforts towards the maintenance of consistent genetic progress alongside optimal health and reproduction (Vries, 2020). Currently, the productive lifespan of cattle destined to milk production remains suboptimal (? 3 lactations) in most large dairy systems across the United States, mostly due to the high incidence of health disorders and reproductive failure affecting lactating cows (Phuong et al., 2016; De Vries and Marcondes, 2020). A cascade of physiological, morphological, and metabolic adaptations during the transition from pregnancy to parturition and subsequent lactation create a significant challenge for dairy cows. Successful completion of early postpartum events is relevant to early postpartum milk production as well as optimal reproductive performance during the breeding period at later postpartum stages (Lucy, 2019; Sheldon et al., 2019). Amongst these events is the process of uterine involution, which is characterized by the functional reestablishment of the uterus to support subsequent pregnancies (Buch et al., 1955; Sheldon, 2004). Despite the success achieved by reproductive programs, fertility in lactating dairy cows remains suboptimal, with first service conception rates ranging between 30 percent to 40 percent (Fricke and Wiltbank, 2022; Sartori et al., 2023), mostly attributed to early lactation disorders that contribute to early embryonic loss (Ribeiro et al., 2016a; Wiltbank et al., 2016; Ribeiro and Carvalho, 2017). Amongst these disorders is metritis, an early postpartum uterine disease that affects approximately 25 to 40 percent of lactating dairy cows (Bromfield et al., 2015; LeBlanc, 2023; Bruinjé et al., 2024). Metritis is characterized by the presence of a red-brownish, watery and fetid uterine discharge, typically detected between 5-10 days postpartum (dpp) and often associated with clinical signs of systemic illness (e.g. pyrexia, cachexia and decreased milk production) (Sheldon et al., 2009) and other periparturient disorders (i.e. retention of fetal membranes; dystocia; vulvovaginal lacerations) (Vergara et al., 2014; Vieira-Neto et al., 2016). Caused by the dysbiosis of pathogenic bacteria within the postpartum uterus (i.e. Fusobacterium necrophorum; Bacteroides spp.; T. pyogenes), treatment options for cows diagnosed with metritis rely mostly on the administration of systemic antibiotic drugs (e.g. ceftiofur), which have been demonstrated to efficiently alleviate the systemic signs of infection (Galvão et al., 2019; Machado et al., 2020; Pinedo et al., 2020; Silva et al., 2023). Regardless of the significant rates of clinical cure associated to antibiotic treatment (Lima et al., 2014), the cost of metritis per case in the U.S. currently ranges from $156 to $948, and may vary based on treatment and fertility-related culling (Pérez-Báez et al., 2021), presenting a significant economic impact to the dairy industry, estimated at $1 billion per year. Failure to resolve bacterial infection and associated inflammation occurs in approximately half of the cows that are diagnosed with early postpartum metritis (Sheldon et al., 2020). Chronic bacterial infection results in the development of endometritis, a disease characterized by the presence of purulent content within the uterine lumen between 21 to 35 days in milk (DIM) and often associated with the presence of a purulent vaginal discharge (PVD), which may go undiagnosed and is greatly associated with the presence of pyogenic bacteria (e.g. T. pyogenes) (Sheldon et al., 2006; Pascottini et al., 2020). Microscopically, endometritis is characterized by an exacerbated innate immune response, evidenced by the presence of neutrophils and macrophages within the uterine lumen, frequently found infiltrated within the endometrial luminal epithelium (LE) and underlying stroma (stratum compactum) as well, in addition to the presence of lymphocytic foci (T and B cells) within the stratum compactum (Bonnett et al., 1993; Dadarwal et al., 2017). Early postpartum uterine disease is associated with a greater risk for pregnancy losses and a lengthened calving-to-conception interval, both often found to be correlated with a delayed resumption of cyclicity (i.e. ovulation) (Giuliodori et al., 2013b; a; Bruinjé et al., 2024). Despite the known association, the intrinsic mechanisms through which metritis and endometritis reduce fertility remain under investigated. A proposed mechanism for the association of uterine disease with poor fertility outcomes has recently emerged when researchers discovered that the outer membrane components of Gram-negative bacteria (lipopolysaccharide, LPS) are found within the follicular fluid of cows that experience early postpartum uterine disease further until 60 DIM, when cows are expected to undergo their first artificial insemination (Piersanti et al., 2019). Using an experimentally induced endometritis model in non-lactating dairy cows (i.e. T. pyogenes + E. coli), these studies demonstrated that bacterial induced inflammation impaired the developmental capacity of oocytes when fertilized in vitro (Dickson et al., 2020), and postulated that disease may impact fertility through a mechanism that disrupts ovarian homeostasis, and consequently, its germ cell pool. Nonetheless, the successful establishment of pregnancy extends past the phenomena of fertilization, requiring a functional endometrium that is permissive to the newly formed embryo. Following parturition, the uterus must undergo extensive remodeling in order to reestablish the endometrial histoarchitecture and cellular homeostasis prior to subsequent pregnancy attempts (Kiracofe, 1980; Salamonsen et al., 2021; Spooner et al., 2021). Accordingly, latest developments evidenced that experimentally induced endometrial inflammation (T. pyogenes + E. coli) in lactating dairy cows compromised the development of conceptuses as far as 16 days post- conception, suggesting that inflammation may compromise the embryotropic capacity of the endometrium during early lactation (Husnain et al., 2023). Given that, we hypothesized that early postpartum uterine disease may delay or permanently impact the reestablishment of a functional endometrial histoarchitecture, which could explain lower fertility in cows that experience early postpartum uterine disease. Given that a functional uterus is comprised of functional endometrial glands, which are essential for fertility (i.e. early embryonic development) (Spencer et al., 2019), we aimed to investigate the mechanisms through which uterine glands are reestablished at both physiological and pro-inflammatory conditions following parturition in lactating dairy cows."--Introduction.
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M.S.