Gut microbiota transmission induces cognitive impairment through amyloid pathology in wild-type mice.

Abstract

Alzheimer's disease (AD), the leading cause of dementia, is predominantly sporadic and influenced by non-genetic factors, including the gut microbiota. Cohabitation studies have shown microbial transmission between AD transgenic (Tg) and wild-type (WT) mice, leading to cognitive impairment; however, the mechanisms during early-life co-housing exposure remain largely undetermined. Here, one-month-old WT mice were housed with age-matched AD Tg (5XFAD) mice for 3 months. Gut microbiota composition was profiled by 16S rRNA sequencing, while brain amyloid-β 42 (Aβ42) levels were quantified by enzyme-linked immunosorbent assay (ELISA) and a nanoplasmonic sensor, respectively. Cognitive function was assessed by the Morris water maze and Barnes maze, and a probiotic intervention with Lactobacillus reuteri and Bifidobacterium pseudolongum was tested for therapeutic efficacy. WT mice co-housed with AD Tg mice (defined as ADWT) developed gut dysbiosis with microbial community shifts resembling those of AD Tg mice, accompanied by elevated brain Aβ42 and cognitive impairment. Finally, probiotic treatment reshaped gut microbial profiles and reduced cortical and hippocampal Aβ42 levels in ADWT mice. Together, these findings indicate that microbiota transfer through early-life co-housing induces gut dysbiosis, amyloid pathology, and cognitive deficits in WT mice, while targeted probiotic intervention mitigates these effects, supporting a microbiota-driven, non-genetic pathway in AD pathogenesis.