Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease

被引:257
作者
Erny, Daniel [1 ,2 ]
Dokalis, Nikolaos [1 ,3 ]
Mezoe, Charlotte [1 ,3 ]
Castoldi, Angela [4 ]
Mossad, Omar [1 ,3 ]
Staszewski, Ori [1 ]
Frosch, Maximilian [1 ]
Villa, Matteo [4 ]
Fuchs, Vidmante [1 ,3 ]
Mayer, Arun [1 ]
Neuber, Jana [1 ,3 ]
Sosat, Janika [1 ,3 ]
Tholen, Stefan [5 ]
Schilling, Oliver [5 ]
Vlachos, Andreas [6 ,9 ]
Blank, Thomas [1 ]
de Agueero, Mercedes Gomez [7 ]
Macpherson, Andrew J. [7 ]
Pearce, Edward J. [3 ,4 ,8 ,11 ]
Prinz, Marco [1 ,9 ,10 ]
机构
[1] Univ Freiburg, Inst Neuropathol, Freiburg, Germany
[2] Univ Freiburg, Fac Med, Berta Ottenstein Programme, Freiburg, Germany
[3] Univ Freiburg, Fac Biol, Freiburg, Germany
[4] Max Planck Inst Immunobiol & Epigenet, Dept Immunometab, Freiburg, Germany
[5] Univ Freiburg, Med Ctr, Inst Surg Pathol, Freiburg, Germany
[6] Univ Freiburg, Fac Med, Inst Anat & Cell Biol, Dept Neuroanat, Freiburg, Germany
[7] Univ Bern, Maurice E Muller Labs, Dept Biomed Res DBMR, Univ Clin Visceral Surg & Med,Inselspital, Bern, Switzerland
[8] Univ Freiburg, CIBSS Ctr Integrat Biol Signalling Studies, Freiburg, Germany
[9] Univ Freiburg, Fac Med, Ctr Basics NeuroModulat NeuroModulBasicas, Freiburg, Germany
[10] Univ Freiburg, Signalling Res Ctr BIOSS & CIBSS, Freiburg, Germany
[11] Johns Hopkins Sch Med, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD 21287 USA
基金
瑞士国家科学基金会;
关键词
CENTRAL-NERVOUS-SYSTEM; CHAIN FATTY-ACIDS; MICROGLIA FUNCTION; MYELOID CELLS; ACETYLATION; ENVIRONMENT; ACTIVATION; ROLES;
D O I
10.1016/j.cmet.2021.10.010
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 micro biota. 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.
引用
收藏
页码:2260 / +
页数:25
相关论文
共 71 条
  • [1] The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis
    Amit, Ido
    Winter, Deborah R.
    Jung, Steffen
    [J]. NATURE IMMUNOLOGY, 2016, 17 (01) : 18 - 25
  • [2] Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice
    Babcock, Alicia A.
    Ilkjaer, Laura
    Clausen, Bettina H.
    Villadsen, Birgitte
    Dissing-Olesen, Lasse
    Bendixen, Anita T. M.
    Lyck, Lise
    Lambertsen, Kate L.
    Finsen, Bente
    [J]. BRAIN BEHAVIOR AND IMMUNITY, 2015, 48 : 86 - 101
  • [3] A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease
    Baik, Sung Hoon
    Kang, Seokjo
    Lee, Woochan
    Choi, Hayoung
    Chung, Sunwoo
    Kim, Jong-Il
    Mook-Jung, Inhee
    [J]. CELL METABOLISM, 2019, 30 (03) : 493 - +
  • [4] Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells
    Benakis, Corinne
    Brea, David
    Caballero, Silvia
    Faraco, Giuseppe
    Moore, Jamie
    Murphy, Michelle
    Sita, Giulia
    Racchumi, Gianfranco
    Lingo, Lilan
    Pamer, Eric G.
    Iadecola, Costantino
    Anrather, Josef
    [J]. NATURE MEDICINE, 2016, 22 (05) : 516 - 523
  • [5] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING
    BENJAMINI, Y
    HOCHBERG, Y
    [J]. JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) : 289 - 300
  • [6] Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination
    Berer, Kerstin
    Mues, Marsilius
    Koutrolos, Michail
    Al Rasbi, Zakeya
    Boziki, Marina
    Johner, Caroline
    Wekerle, Hartmut
    Krishnamoorthy, Gurumoorthy
    [J]. NATURE, 2011, 479 (7374) : 538 - U266
  • [7] Potential roles of gut microbiome and metabolites in modulating ALS in mice
    Blacher, Eran
    Bashiardes, Stavros
    Shapiro, Hagit
    Rothschild, Daphna
    Mor, Uria
    Dori-Bachash, Mally
    Kleimeyer, Christian
    Moresi, Claudia
    Harnik, Yotam
    Zur, Maya
    Zabari, Michal
    Brik, Rotem Ben-Zeev
    Kviatcovsky, Denise
    Zmora, Niv
    Cohen, Yotam
    Bar, Noam
    Levi, Izhak
    Amar, Nira
    Mehlman, Tevie
    Brandis, Alexander
    Biton, Inbal
    Kuperman, Yael
    Tsoory, Michael
    Alfahel, Leenor
    Harmelin, Alon
    Schwartz, Michal
    Israelson, Adrian
    Arike, Liisa
    Johansson, Malin E. V.
    Hansson, Gunnar C.
    Gotkine, Marc
    Segal, Eran
    Elinav, Eran
    [J]. NATURE, 2019, 572 (7770) : 474 - +
  • [8] Microglia metabolism in health and disease
    Borst, Katharina
    Schwabenland, Marius
    Prinz, Marco
    [J]. NEUROCHEMISTRY INTERNATIONAL, 2019, 130
  • [9] A roadmap for interpreting 13C metabolite labeling patterns from cells
    Buescher, Joerg M.
    Antoniewicz, Maciek R.
    Boros, Laszlo G.
    Burgess, Shawn C.
    Brunengraber, Henri
    Clish, Clary B.
    DeBerardinis, Ralph J.
    Feron, Olivier
    Frezza, Christian
    Ghesquiere, Bart
    Gottlieb, Eyal
    Hiller, Karsten
    Jones, Russell G.
    Kamphorst, Jurre J.
    Kibbey, Richard G.
    Kimmelman, Alec C.
    Locasale, Jason W.
    Lunt, Sophia Y.
    Maddocks, Oliver D. K.
    Malloy, Craig
    Metallo, Christian M.
    Meuillet, Emmanuelle J.
    Munger, Joshua
    Noeh, Katharina
    Rabinowitz, Joshua D.
    Ralser, Markus
    Sauer, Uwe
    Stephanopoulos, Gregory
    St-Pierre, Julie
    Tennant, Daniel A.
    Wittmann, Christoph
    Vander Heiden, Matthew G.
    Vazquez, Alexei
    Vousden, Karen
    Young, Jamey D.
    Zamboni, Nicola
    Fendt, Sarah-Maria
    [J]. CURRENT OPINION IN BIOTECHNOLOGY, 2015, 34 : 189 - 201
  • [10] Metabolism and acetylation in innate immune cell function and fate
    Cameron, Alanna M.
    Lawless, Simon J.
    Pearce, Edward J.
    [J]. SEMINARS IN IMMUNOLOGY, 2016, 28 (05) : 408 - 416