Microglial cells are located behind the blood brain-barrier in the so-called immune-privileged brain. Until recently it was unclear, whether environmental factors could control their maturation and activation status under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. These effects were mainly mediated through short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products. Now, our aim is to determine the impact of host microbiota on microglial morphological and transcriptional profiles in young, adult animals and during the aging process by using mice of different age, which differ in their microbiome (germ-free, specific-pathogen free, altered Schaedler flora, recolonized GF mice, respectively). We will further focus on how host microbiota is influencing brain function and cognitive processing in young and aged mice. Besides characterizing normal, non-pathological aging processes, we will address the impact of GF conditions on age-dependent neurodegenerative diseases like Alzheimer’s disease (AD). During AD, microglia get activated and secret potential neurotoxic cytokines, such as IL1β, TNFα or IL-6. Since the immune response of microglia is impaired in GF mice, we will determine the influence of host microbiota on microglia in 5xFad transgenic mice, which recapitulate major features of AD.
With the new findings of this project we will be able to determine a) whether age-dependent learning and memory decline under pathological- and non-pathological conditions can be attributed to narrowing in microbial diversity and b) whether impaired cognitive abilities can be restored by targeting microbiota or their communication between the gut and brain.