Gut microbiome perturbations influence brain amyloidosis only in the presence of microglia in APPPS1‐21 mice

Abstract

AbstractBackgroundIn prior efforts, we demonstrated reduced amyloidosis and altered microgliosis in long‐term antibiotics (abx)‐treated APPPS1‐21 male mice. Restoration of the gut microbiome into abx‐treated male mice by fecal microbiota transfer (FMT) established a causality between the gut microbiome and amyloidosis. We have used FMT studies using our current short‐term abx APPPS1‐21 mice to evaluate the microbiome‐microglia‐amyloidosis axis.MethodShort‐term, postnatal abx (4mg/ml Kanamycin, 0.35mg/ml Gentamicin, 8500U/ml Colistin, 2.15mg/ml Metronidazole, 0.45mg/ml Vancomycin: post‐natal day 14 to day 21) was performed. To establish causality, we performed FMT (200µl of 5mg/ml fecal slurry daily gavage) into abx‐treated APPPS1‐21 male mice. Pathogenicity of the gut microbiome in WT or Tg mice were confirmed using age‐matched FMT from WT and Tg controls into abx‐treated male mice. We performed total RNAseq transcriptome analysis to evaluate potential mechanism(s). The role of microglial cells were evaluated in PLX6522 (CSF‐1 receptor inhibitor)‐treated FMT‐transplanted abx‐treated APPPS1‐21 male mice. Nine weeks old GF APPPS1‐21 were used to characterize the amyloidosis and glial cells in both genders.ResultAn early life abx treatment resulted in gut microbiota changes in a sex‐dependent manner. Only male mice showed reduced amyloidosis and altered microglial phenotypes. Age matched Tg FMT or WT FMT resulted in higher amyloidosis in abx‐treated male mice. RNAseq analysis of total cortical RNA showed significantly different mRNA levels that occurred in a sex‐specific manner and changes in abx‐treated male mice were restored with FMT. GO term analysis showed gliogenesis and microglia development as significantly altered pathways in abx‐treated male group only. To confirm the exact role of the microglia in this model, we employed PLX6522 in FMT‐treated ABX‐male mice. Microglia depletion did not result in an FMT‐dependent increase in amyloidosis in abx‐treated male mice. Finally, germ‐free APPPS1‐21 mice showed reduced amyloidosis that occurs in a sex‐specific manner.ConclusionFrom GF APPPS1‐21 and FMT‐treated abx‐male APPPS1‐21 studies, we conclude that gut microbiome plays a critical role in modulating amyloidosis in APPPS1‐21 mice. Furthermore, microglia mediates the effects of early life gut microbiota perturbations, which results in altered amyloidosis in APPPS1‐21 male mice.