Stroke-induced gut microbiome dysbiosis accelerates Alzheimer's disease progression.

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.