Bovine model to study the mechanisms that affect uterine mucosal immunity: role of metabolic status and uterine microbiome.

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The postpartum period is the most important period in a cow's production cycle as the uterus undergoes post-calving reparative changes (uterine involution) - an inflammatory process that must be resolved in a timely manner. Up to 20% and 37% of postpartum beef and dairy cows, respectively, experience persistent inflammation of the uterine mucosa (endometritis) resulting in an unfavorable environment for the next pregnancy. Interestingly, bacteria isolated in all cases of endometritis are opportunistic pathogens that belong to the commensal microbial community of the cow's genital tract. The long-term goal of my research program is to determine the metabolic, cellular and molecular mechanisms that influence persistence or resolution of uterine inflammation. My overall hypothesis is that complex interactions between the metabolic state of the cow, uterine microbiota and components of the immune system determines the resolution or persistence of inflammatory response in the postpartum uterus. Endometritis incidence is lower in postpartum beef cows than dairy cows potentially due to lower metabolic stress (lower milk production than dairy cows). Clinically, metabolic disorders are more common in dairy than beef cows due to differences in milk production demands and management. Recently, we have shown that postpartum dairy cows with persistent endometritis have a dysregulated expression of cytokines in the uterine mucosa despite having similar metabolic status compared to those cows that resolve uterine inflammation. Furthermore, observed differences in the uterine microbiome of postpartum cows with or without endometritis indicate that commensal microbes of the bovine uterus could also modulate uterine inflammation. Thus, my working hypothesis for the proposed project is that commensal bacteria interact differentially with the uterine defense mechanisms in cows of different metabolic status which results in either resolution or persistence of endometritis. Specifically, my short-term objectives are to understand 1) temporal changes in the peripheral immune status and uterine microbiome of peripartum dairy versus beef (higher versus lower metabolic stress, respectively) cows, 2) the effects of an immunomodulant agent on the peripheral and uterine immune response of postpartum cows and 3) the effects of intrauterine infusion of probiotic bacteria infusion on the microbial, cellular and molecular microenvironment of postpartum bovine uterus. We will use a non-antibiotic immunomodulator (administered subcutaneously or locally) and probiotic bacteria (administered locally) to resolve the uterine inflammation and bring the postpartum uterus to normalcy. We anticipate to identifying novel probiotics as well as managemental (nutrition targeting different production status) strategies for future use to prevent and treat uterine inflammation both in dairy and beef cattle to help mitigate concerns about antimicrobial resistance related to food of animal origin.