Stroke survivors face an elevated risk of developing Alzheimer's disease (AD), yet the biological mechanisms linking these conditions remain poorly defined. Here, we show that a stroke-induced gut microbiome is a key driver of AD-related pathology. Fecal microbiota transplantation (FMT) from stroke patients into young triple-transgenic Alzheimer's disease (3xTg-AD) mice accelerated tau phosphorylation, increased neuroinflammation, and disrupted metabolic homeostasis in both the brain and gut, compared with FMT from healthy donors. Mice receiving stroke-derived microbiota exhibited persistent, donor-specific dysbiosis and broad metabolic reprogramming involving redox balance, nucleotide metabolism, and energy pathways in cecal contents and brain tissue. These metabolic disturbances were accompanied by widespread and region-specific transcriptional changes revealed by single-cell spatial transcriptomics, including glial activation, impaired neuron-glia communication, and dysregulation of mitochondrial, amyloid-processing and inflammatory pathways across cortical and hippocampal regions. Collectively, these findings identify post-stroke gut dysbiosis as a mechanistic contributor to heightened neurodegenerative vulnerability and AD risk, highlighting the gut-brain axis as a potentially modifiable target for preventing post-stroke dementia.
Aware et al. (Tue,) studied this question.