The microbiota-microglia axis in the regulation of metabolic homeostasis

微生物群-小胶质细胞轴在代谢稳态调节中的作用

基本信息

批准号：
10567163
负责人：
Martin Valdearcos
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-23 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567163
关键词：
Affect Agonist Aryl Hydrocarbon Receptor Automobile Driving Blood Vessels Body Weight Brain region Carbohydrates Cells Chromatin Chronic Consumption Coupled Data Data Set Diet Eating Embryo Exhibits FFAR2 gene Fermentation Gene Expression Profile Germ-Free Goals Health Heterogeneity High Fat Diet Homeostasis Hypothalamic dysfunction Hypothalamic structure Immune Immunologics Inflammatory Inflammatory Response Knowledge Life Ligands Mediating Mediator Metabolic Metabolic Control Metabolic Diseases Microglia Molecular Molecular Mechanisms of Action Mucosal Immunity Mus Myeloid Cells Neurons Obesity Pathogenesis Pathologic Pathway Analysis Pathway interactions Peptide Initiation Factors Peripheral Phenotype Population Population Heterogeneity Predisposition Prevention Process Property Publishing Receptor Signaling Regulation Role Signal Transduction Supplementation Testing Transcript Volatile Fatty Acids Weaning Weight Gain Weight maintenance regimen Work aryl hydrocarbon receptor ligand blood glucose regulation dietary dietary excess epigenomics genetic approach glial activation gut microbiota histone modification imprint insight interest microbial microbiota microorganism multiple omics neonatal period new therapeutic target novel postnatal postnatal development pregnant prevent public health relevance pup receptor response restraint single cell technology transcriptomics

项目摘要

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.

项目概要/摘要饮食过量会迅速诱导炎症激活和异质物质的积累下丘脑内侧基底层 (MBH) 中的髓样细胞群（广义上称为小胶质细胞）是一个关键的细胞参与能量和葡萄糖稳态调节的大脑区域。我们证明了小胶质细胞在这种情况下的激活足以刺激食物摄入和体重增加，但是代谢引发这种反应的因素仍有待阐明。饮食是影响人体成分的主要因素肠道微生物群和高脂肪饮食 (HFD) 的摄入会导致肠道菌群类型和肠道内共生微生物的比例。这些变化会影响炎症和宿主的代谢特性也可能影响 MBH 中的小胶质细胞功能。为此，小胶质细胞与其他大脑区域（例如皮质）相比，无菌（GF）小鼠的 MBH 过度活跃。这种小胶质细胞的激活在新生儿期和妊娠期肠道中已经表现出来 GF 母鼠在胚胎第 16 天 (E16) 恢复了幼仔 MBH 的出生后小胶质细胞稳态。此外，我们发现补充短链脂肪酸（SCFA），即由不可消化碳水化合物的细菌发酵足以减少小胶质细胞的活化 HFD 喂养小鼠的 MBH 和体重增加。基于已发表的和初步的大量工作，我们在这里建议检验 MBH 小胶质细胞的假设，它靠近有孔的血液血管受到特定微生物代谢物（例如短链脂肪酸 SCFA）的独特调节。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传导调节 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，并且 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。完成这些目标有可能揭示微生物代谢物如何调节的前所未有的机制见解 MBH 小胶质细胞参与调节代谢功能的身份和功能，提供了新的预防和治疗代谢性疾病的治疗靶点。