Agathobacter rectalis attenuates post-stroke cognitive impairment by suppressing Indole-3-acetic acid–mediated AhR/NF-κB neuroinflammation

Post-stroke cognitive impairment (PSCI) limits neurological recovery, but its mechanisms and targeted therapies remain unclear. We enrolled 58 patients with acute ischemic stroke and integrated fecal metagenomics, metabolomics, and a middle cerebral artery occlusion mouse model to investigate the gut microbiota–metabolite–neuroinflammation axis in PSCI. Patients with PSCI exhibited gut dysbiosis characterized by depletion of Agathobacter rectalis and enrichment of pro-inflammatory taxa. Metabolomics revealed disrupted tryptophan metabolism with marked elevation of indole-3-acetic acid (IAA) in feces and serum, which correlated with poorer cognitive scores and higher interleukin-6 and interleukin-1β levels. In mice, oral A. rectalis supplementation lowered systemic IAA, reduced hippocampal inflammatory responses, and improved spatial memory. Mechanistically, IAA activated the aryl hydrocarbon receptor (AhR)/NF-κB signaling pathway in human microglia, promoting pro-inflammatory cytokine production in a dose-dependent manner. These findings support a functional link between reduced A. rectalis abundance, increased IAA exposure, and neuroinflammation in PSCI, suggesting that modulation of this axis may warrant further investigation as a microbiome-based strategy.