Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes

We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-beta (A beta) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)(SWE)/presenilin 1 (PS1)(Delta E9) transgenic model of A beta amyloidosis. We now show that in an independent, aggressive APP(SWE)/PS1(L166P) (APPPS1-21) mouse model of A beta amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in A beta pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice. Furthermore, ABX treatment lead to alterations in levels of selected microglial expressed transcripts indicative of the M0 homeostatic state in male but not in female mice. Finally, we found that transplants of fecal microbiota from age-matched APPPS1-21 male mice into ABX-treated APPPS1-21 male restores the gut microbiome and partially restores A beta pathology and microglial morphology, thus demonstrating a causal role of the microbiome in the modulation of A beta amyloidosis and microglial physiology in mouse models of A beta amyloidosis.