A humanized mouse model to analyse the age-dependent impact of gut microbiota on microglial diversity in the brain

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Cognitive decline and dementia are among the most important aging-related health problems worldwide. A key component of aging-associated neurodegeneration is a low-grade systemic inflammation (inflammaging), which in the brain is mainly mediated by activated microglia. Recently, it has been discovered that the microglia receive signals from intestinal microbes as well as their metabolic products and react to them. This highlights microbiota-microglia interactions as an attractive therapeutic target for therapies attenuating inflammaging. The aim of this project is to create a human microbiota-associated mouse model to establish a causal link between the human intestinal microbiota and microglial cell function and diversity. We expect an improvement of cognitive function based on microglial anti-inflammatory and neuro-supportive function in old mice after transfer of microbiota derived from young healthy donors, and vice versa a pro-inflammatory microglial phenotype associated with cognitive dysfunctions in young mice after transfer of microbiota from old donors. Single cell sequencing of hippocampi will determine changes in microglial heterogeneity and gene expression. In particular, microglia will be analysed with respect to the regulation of inflammatory genes and on that basis sorted into cellular subtypes. In addition, we will provide immunohistochemical evidence of their morphological activation state. In order to causally link the microbiota to microglial function and diversity, we will use a novel modelling approach to identify microbiota-produced metabolites that influence microglial heterogeneity. The functional relevance of these peripherally produced metabolites will be validated in cell cultures of primary microglia. In the future, our new pre-clinical animal model and modelling approach should serve as an essential basis for the rational design of microbiome-based therapies to counteract microglia-mediated aging-associated neurodegeneration.