The microbiota-microglia axis in the regulation of metabolic homeostasis

项目摘要/摘要 饮食过量会迅速导致炎症的激活和异质性的堆积 下丘脑内侧基底核(MBH)中的髓系细胞群，广泛称为小胶质细胞，是一种关键的 参与调节能量和葡萄糖动态平衡的大脑区域。我们展示了小胶质细胞 在这种情况下，激活足以刺激食物摄取和体重增加，但代谢 启动这一反应的因素仍有待阐明。饮食是影响食物组成的一个主要因素 肠道微生物区系和高脂饮食(HFD)的消费导致了不利的类型和 肠道中共生微生物的比例。这些变化影响了炎症性和 宿主的代谢特性，也可能影响MBH的小胶质细胞功能。为此，小胶质细胞 在无菌(GF)小鼠中，与其他大脑区域(如皮质)相比，MBH中的小鼠处于过度激活状态。 这种小胶质细胞的激活已经表现在新生儿期和定植于孕妇的肠道中。 胎龄16天(E16)的小胶质细胞动态平衡恢复到出生后幼鼠的MBH。 此外，我们还发现，补充短链脂肪酸(SCFAs)是由 细菌发酵不可消化的碳水化合物，足以减少小胶质细胞的激活 高脂饲料喂养小鼠的MBH和体重增加。基于发表的和初步的大量工作， 我们在这里提出了一种假设，即居住在开窗血附近的MBH小胶质细胞 血管受特定微生物代谢物的独特调节，如单链脂肪酸。具体来说，我们的目标是 A)确定SCFA-FFAR2(游离脂肪酸受体2)的细胞和分子机制 信号调节MBH中小胶质细胞的动态平衡，B)决定SCFA-AhR(芳基 碳氢化合物受体)的相互作用调节MBH中的小胶质细胞稳态，以及C)决定 微生物代谢产物调节MBH小胶质细胞的出生后免疫印迹。完成这些任务 AIMS有可能揭示微生物代谢物如何调节的前所未有的机械洞察力 参与调节代谢功能的MBH小胶质细胞的特性和功能，提供新的 代谢性疾病防治的治疗目标。

Project Summary/Abstract Dietary excess rapidly induces the inflammatory activation and accumulation of a heterogeneous population of myeloid cells, broadly termed microglia, in the mediobasal hypothalamus (MBH), a critical brain region involved in the regulation of energy and glucose homeostasis. We showed that microglial activation in this context is sufficient to stimulate food intake and body weight gain, however the metabolic factors initiating this response remain to be elucidated. Diet is a major factor affecting the composition of the gut microbiota, and high-fat diet (HFD) consumption induces unfavorable alterations in the type and proportion of commensal microorganisms in the gut. These changes influence the inflammatory and metabolic properties of the host and may also impact microglial function in the MBH. To this end, microglia in germ-free (GF) mice are hyperactivated in the MBH compared to other brain regions such as cortex. This microglial activation is already manifested during neonatal period and colonizing the gut of pregnant GF dams at embryonic day 16 (E16) restored postnatal microglial homeostasis in the MBH of their pups. Moreover, we found that supplementation of short chain fatty acids (SCFAs), metabolites produced by bacterial fermentation of non-digestible carbohydrates, is sufficient to reduce microglial activation in the MBH and body weight gain in HFD- fed mice. Based on substantial work, both published and preliminary, we propose here to test the hypothesis that MBH microglia, which reside close to fenestrated blood vessels, are uniquely regulated by specific microbial metabolites such as SCFAs. Specifically, we aim to A) determine the cellular and molecular mechanisms by which SCFA-FFAR2 (free fatty acid receptor 2) signaling regulates microglial homeostasis in the MBH, B) determine whether SCFA-AhR (aryl hydrocarbon receptor) interactions regulate microglial homeostasis in the MBH, and C) determine whether microbial metabolites regulate postnatal immunological imprinting of MBH microglia. Completing these aims has the potential to reveal unprecedented mechanistic insights of how microbial metabolites modulate identity and function of MBH microglia engaged in regulating metabolic function, providing novel therapeutic targets for the prevention and treatment of metabolic diseases.