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BackgroundThe mechanisms underlying the protective effect of the e2 variant of the APOE gene (APOEe2) against Alzheimer’s disease (AD) have not been elucidated. We altered the microbiota of 3xTgAD mice by fecal microbiota transplantation from a human APOEe2 donor (e2-FMT) and tested the effect of microbiota perturbations on brain AD pathology.MethodsFMT of bacteria isolated from stools of untreated 3xTgAD mice (M-FMT) or e2-FMT were transplanted in 15-month-old 3xTgAD mice. FMT was done alone or in combination with antibiotic and proton-pump inhibitor following the Microbiota Transfer Therapy protocol (MTT). The effect of donor (M or e2) and transplantation protocol (FMT or MTT) on hippocampal amyloid, tau pathology and neuroinflammation were assessed at the end of the treatment.Resultse2-FMT reduced amyloid, and tau pathology as well as increased neuroinflammation as compared with M-FMT. MTT was associated with reduced number of Aβ40+ plaques and tau pathology. Low levels of amyloid were associated with high levels of pro-inflammatory molecules in e2-FMT mice. These associations were partially attenuated by MTT.ConclusionBacteria from a human APOEe2 donor reduced AD pathology and increased neuroinflammation in mice suggesting that the gut microbiota may be a mediator of the protective effect of APOEe2.

Abstract House flies (Musca domestica) are widespread, synanthropic filth flies commonly found on decaying matter, garbage, and feces as well as human food. They have been shown to vector microbes, including clinically relevant pathogens. Previous studies have demonstrated that house flies carry a complex and variable prokaryotic microbiota, but the main drivers underlying this variability and the influence of habitat on the microbiota remain understudied. Moreover, the differences between the external and internal microbiota and the eukaryotic components have not been examined. To obtain a comprehensive view of the fly microbiota and its environmental drivers, we sampled over 400 flies from two geographically distinct countries (Belgium and Rwanda) and three different environments—farms, homes, and hospitals. Both the internal as well as external microbiota of the house flies were studied, using amplicon sequencing targeting both bacteria and fungi. Results show that the house fly’s internal bacterial community is very diverse yet relatively consistent across geographic location and habitat, dominated by genera Staphylococcus and Weissella. The external bacterial community, however, varies with geographic location and habitat. The fly fungal microbiota carries a distinct signature correlating with the country of sampling, with order Capnodiales and genus Wallemia dominating Belgian flies and genus Cladosporium dominating Rwandan fly samples. Together, our results reveal an intricate country-specific pattern for fungal communities, a relatively stable internal bacterial microbiota and a variable external bacterial microbiota that depends on geographical location and habitat. These findings suggest that vectoring of a wide spectrum of environmental microbes occurs principally through the external fly body surface, while the internal microbiome is likely more limited by fly physiology.