The microbiota-microglia axis in the regulation of metabolic homeostasis

项目总结/摘要 饮食过量迅速诱导炎症激活和异质性蛋白的积累， 在下丘脑中基底核（MBH）中的髓样细胞群，广泛称为小胶质细胞，是一个关键的 参与能量和葡萄糖稳态调节的大脑区域。我们发现小胶质细胞 在这种情况下，激活足以刺激食物摄入和体重增加，然而，代谢激活是不可能的。 引发这种反应的因素仍有待阐明。饮食是影响营养成分的主要因素。 肠道微生物群和高脂饮食（HFD）消耗诱导了类型和 肠道中微生物的比例。这些变化影响炎症和 在MBH中，小胶质细胞的功能可能与宿主的代谢特性有关，也可能影响小胶质细胞的功能。为此，小胶质细胞 在无菌（GF）小鼠中，与其他脑区如皮质相比，MBH中的神经元被过度激活。 这种小胶质细胞的激活在新生儿时期就已经表现出来，并在孕妇的肠道中定植。 GF母鼠在胚胎第16天（E16）恢复出生后的小胶质细胞在其幼崽的MBH的稳态。 此外，我们发现，补充短链脂肪酸（SCFA），代谢产物产生的 细菌发酵的非消化性碳水化合物，足以减少小胶质细胞的活化， HFD喂养小鼠的MBH和体重增加。根据已发表和初步的大量工作， 我们在这里提出的假设，MBH小胶质细胞，居住在接近开窗血液， 血管，是由特定的微生物代谢产物，如SCFA独特的调节。具体而言，我们的目标是 A）确定SCFA-FFAR 2（游离脂肪酸受体2） 信号转导调节MBH中的小胶质细胞稳态，B）确定SCFA-AhR（芳基 碳氢化合物受体）相互作用调节MBH中的小胶质细胞稳态，和C）确定是否 微生物代谢产物调节MBH小胶质细胞的出生后免疫印记。完成这些 aims有可能揭示微生物代谢物如何调节 MBH小胶质细胞参与调节代谢功能的身份和功能，提供了新的 用于预防和治疗代谢疾病的治疗靶点。

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.