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

产后期是奶牛生产周期中最重要的时期，因为子宫在产后经历修复性变化(子宫复旧)--这是一个必须及时解决的炎症过程。分别有高达20%和37%的产后牛肉和奶牛经历了持续的子宫粘膜炎症(子宫内膜炎)，导致不利于下一次怀孕的环境。有趣的是，在所有子宫内膜炎病例中分离出的细菌都是机会性病原体，属于奶牛生殖道共生微生物群落。我的研究计划的长期目标是确定影响子宫炎症持续或消退的代谢、细胞和分子机制。我的总体假设是，奶牛的代谢状态、子宫微生物区系和免疫系统组件之间的复杂相互作用决定了产后子宫炎症反应的消退或持续。产后肉牛子宫内膜炎的发病率低于奶牛，可能是由于代谢压力较低(产奶量低于奶牛)。在临床上，由于牛奶生产需求和管理的差异，代谢紊乱在乳制品中比肉牛更常见。最近，我们发现患有持续性子宫内膜炎的产后奶牛与那些缓解子宫炎症的奶牛相比，尽管具有相似的代谢状态，但子宫粘膜中细胞因子的表达存在异常。此外，观察到患有和不患有子宫内膜炎的产后奶牛子宫微生物群的差异表明，牛子宫的共生微生物也可以调节子宫炎症。因此，我对拟议项目的主要工作假设是，在不同代谢状态的奶牛中，共生细菌与子宫防御机制存在不同的相互作用，从而导致子宫内膜炎的解决或持续。具体地说，我的短期目标是了解1)围产期奶牛(分别是高代谢应激奶牛和低代谢应激奶牛)外周免疫状态和子宫微生物群的动态变化；2)一种免疫调节剂对产后奶牛外周和子宫免疫反应的影响；3)宫内注入益生菌对产后牛子宫微生物、细胞和分子微环境的影响。我们将使用非抗生素免疫调节剂(皮下或局部给药)和益生菌(局部给药)来化解子宫炎症，使产后子宫恢复正常。我们预计将确定新的益生菌以及未来用于预防和治疗奶牛和肉牛子宫炎症的管理(针对不同生产状态的营养)策略，以帮助缓解与动物性食品相关的抗菌素耐药性的担忧。

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.