University thesis:
Dissertation, Universität Freiburg, 2021
Footnote:
Description:
Abstract: The mammalian-microbial partnership constitutes a long-standing mutualistic relationship which ensures the survival of both partners by exchanging of vital components. The host microbiota is a source of a plethora of molecules, nutrients and metabolites which benefit the physiology of the host organism and in exchange the host provides a safe harbor for a variety of microbial species. It is widely appreciated that the host microbiome, especially in the gut, plays an instrumental role in the development and homeostasis of various organs, including the central nervous system (CNS). In the CNS, microglia cells, the embryonically-derived, long-lived tissue resident macrophages, are responsible for maintaining the neural network and responding rapidly to tissue insults. It has been recognized that the host microbiota has a vital impact on the maturation and function of these immune cells primarily under homeostasis and disease. The present thesis sought to investigate the underlying mechanisms by which the gut microbiome influences microglia physiology under steady-state conditions. In particular, the impact of the complex commensal microbiome and selected microbial molecules on microglia metabolism and development was investigated.<br>The current study employed a battery of metabolic assays adapted for ex vivo isolated murine microglia cells to reliably reflect the in vivo environment and better assess the gut microbiome-microglia interactions. The use of axenic germ-free mice revealed that in the absence of commensal microbial flora, microglia display compromised metabolic fitness associated with increased number of mitochondria, reduced mitochondrial membrane potential and attenuated mitochondrial complex II activity. The dysfunctional mitochondrial phenotype in microglia was successfully rescued by recolonization of germ-free mice with the complete specific-pathogen free microbiome. Interestingly, supplementation of the microbial short-chain fatty acid acetate in germ-free mice was able restore the metabolic deficits of microglia highlighting the impact of defined microbial molecules on the cellular metabolism of these brain macrophages. In addition, this study addressed the influence of temporally and biologically defined microbial exposure during murine embryogenesis on microglia development and response to the 5xFAD model of Alzheimer’s disease (AD). Transient maternal colonization with the Escherichia coli HA107 strain during early gestation, revealed the microglia plasticity of the offspring under steady-state conditions. Surprisingly, despite the minute effect of this early microbial exposure on homeostatic microglia development, activation of the cells in the context of the AD model led to altered disease burden. <br>Taken together, the current study provides novel insights on microglia metabolism and their interaction with the host microbiome which could be the basis for better understanding of the microglia physiology and opens new avenues for therapeutic interventions of uncurable CNS disorders