Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease

The immune cells of the central nervous system (CNS) comprise parenchymal microglia and at the CNS border regions meningeal, perivascular, and choroid plexus macrophages (collectively called CNS‐associated macrophages, CAMs). While previous work has shown that microglial properties depend on environmental signals from the commensal microbiota, the effects of microbiota on CAMs are unknown. By combining several microbiota manipulation approaches, genetic mouse models, and single‐cell RNA‐sequencing, we have characterized CNS myeloid cell composition and function. Under steady‐state conditions, the transcriptional profiles and numbers of choroid plexus macrophages were found to be tightly regulated by complex microbiota. In contrast, perivascular and meningeal macrophages were affected to a lesser extent. An acute perturbation through viral infection evoked an attenuated immune response of all CAMs in germ‐free mice. We further assessed CAMs in a more chronic pathological state in 5xFAD mice, a model for Alzheimer’s disease, and found enhanced amyloid beta uptake exclusively by perivascular macrophages in germ‐free 5xFAD mice. Our results aid the understanding of distinct microbiota–CNS macrophage interactions during homeostasis and disease, which could potentially be targeted therapeutically.