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

研究影响子宫粘膜免疫机制的牛模型：代谢状态和子宫微生物组的作用。

• 批准号: RGPIN-2020-06632
• 负责人: Dadarwal, Dinesh
• 金额: $ 2.04万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=718403
• 关键词: Bovine; model; study; mechanisms; affect

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.

产后期是奶牛生产周期中最重要的时期，因为子宫会经历产犊后的修复性变化（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%的产后肉牛和奶牛会出现子宫粘膜持续性炎症（子宫内膜炎），导致下一次妊娠的环境不利。有趣的是，在所有乳房炎病例中分离出的细菌都是属于奶牛生殖道肠道微生物群落的机会致病菌。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、子宫微生物群和免疫系统成分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，可能是由于代谢应激较低（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，奶牛比肉牛更常见代谢紊乱。最近，我们已经表明，产后奶牛持续性子宫炎有失调的表达细胞因子在子宫粘膜，尽管有类似的代谢状态相比，那些奶牛解决子宫炎症。此外，观察到的有或没有子宫内膜炎的产后奶牛子宫微生物组的差异表明，牛子宫的共生微生物也可以调节子宫炎症。因此，我对所提出的项目的工作假设是，在不同代谢状态的奶牛中，子宫内细菌与子宫防御机制的相互作用不同，从而导致子宫内膜炎的消退或持续。具体来说，我的短期目标是了解1）围产期乳制品与牛肉的外周免疫状态和子宫微生物组的时间变化（分别为较高与较低代谢应激）奶牛，2）免疫调节剂对产后奶牛的外周和子宫免疫应答的影响和3）益生菌输注物的子宫内输注对微生物，产后牛子宫的细胞和分子微环境。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）来解决子宫炎症并使产后子宫恢复正常。我们期望确定新的益生菌以及管理（针对不同生产状态的营养）策略，以供将来用于预防和治疗奶牛和肉牛的子宫炎症，以帮助减轻对动物源性食品相关的抗菌素耐药性的担忧。