Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner

Abstract

SummaryMicroglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.

Microglia heterogeneity along a spatio–temporal axis: More questions than answers

“…Our recent study confirmed previous suggestions (Schwarz, Sholar, & Bilbo, 2012;Hanamsagar & Bilbo, 2016) that the transcriptional signature of microglia diverges between adult males and females (Thion et al, 2018). Microglia exist in a heightened immune-activated state in females compared with males, which is in line with previous studies showing that females produce a stronger innate and adaptive immune response than males (Klein & Flanagan, 2016).…”

The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system

“…Much of the evidence suggests that eutherian foetuses reside in a sterile environment and that they are colonised at birth . However, the evidence also suggests that foetuses are exposed to microbial products and metabolites from the maternal microbiota during pregnancy . Transient colonisation of pregnant female mice using genetically engineered Escherichia coli HA107 showed that the maternal microbiota shapes the immune system of the offspring .…”

Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development

“…These structural differences, at least in the hippocampus, are likely related to observations of increased rates of hippocampal neurogenesis in both germ‐free (Ogbonnaya et al, ) and antibiotic‐treated mice (Möhle et al, ). Microbiota‐related structural brain changes are not limited to the neuronal architecture; germ‐free and antibiotic‐induced microbiota depletion also leads to changes in microglia maturation (more immature microglia; Erny et al, ; Thion, Low, et al, ) and levels of myelination (hypermyelination of the prefrontal cortex; Gacias et al, ; Hoban, Stilling, et al, ), while white matter integrity was associated with diet‐induced changes in the gut microbiota in rats (Ong et al, ).…”

“…Germ‐free animals exhibit profound alterations in both innate and adaptive immunity (Strauch et al, ), while specific commensal bacteria can regulate the maturation of and balance between different types of T cells in vitro and in vivo (Baba et al, ; Ivanov et al, ; Sudo et al, ). Microbiota manipulations can alter both circulating and central levels of cytokines (Burokas et al, ; Luczynski et al, ; O'Mahony et al, ; Sudo et al, ) as well as microglia development (Erny et al, ; Thion, Low, et al, ). Moreover, there is a growing realization of a link between immune/allergic sensitivity and alterations in the microbiota–gut–brain axis (Berni Canani et al, ).…”

“…For example, prenatal stress has more profound effects on the developing male microbiota (Jašarević et al, , ), while germ‐free males but not females exhibit hypermyelination of the prefrontal cortex (Hoban, Stilling, et al, ) and disruption of the hippocampal serotonergic system (Clarke et al, ). Similarly, maternal germ‐free status had a substantially greater impact on the microglia of males during embryonic development (>1,000 genes differentially expressed in male microglia vs. 20 genes in females), although this sex difference was reversed in adulthood (Thion, Low, et al, ). Following a fecal microbiota transplant from children with ASD, stronger behavioral deficits were observed in male recipient mice than in females (Sharon et al, ).…”