Institute of Neuropathology, University of Freiburg, Freiburg, Germany; Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Neuropathology, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
Cell Metab. 2021 Nov 2;33(11):2260-2276.e7. doi: 10.1016/j.cmet.2021.10.010.
As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
作为中枢神经系统 (CNS) 的组织巨噬细胞，小胶质细胞构成了该器官的关键免疫细胞。小胶质细胞的特征强烈依赖于环境线索，如共生微生物群。众所周知，肠道细菌通过产生短链脂肪酸 (SCFAs) 来不断调节小胶质细胞的成熟和功能。然而，这种串扰的确切机制尚不清楚。在这里，我们确定了无菌 (GF) 小鼠中小胶质细胞的未成熟表型是由与代谢基因相关的 H3K4me3 和 H3K9ac 表观遗传印记的，这些基因与实质性的功能改变有关，包括增加线粒体质量和特定的呼吸链功能障碍。我们确定了乙酸盐是一种必需的微生物衍生的 SCFA，它可以驱动小胶质细胞的成熟，并调节稳态代谢状态，进一步表明它能够调节神经退行性变过程中小胶质细胞的吞噬作用和疾病进展。这些发现表明，在健康和干扰期间，乙酸盐是一种必需的细菌衍生分子，可驱动小胶质细胞的代谢途径和功能。
