Abstract DP094: Targeting Age-Related Microbiota Dysbiosis with Akkermansia to Improve Post-Stroke Outcomes in the Elderly

Background: Elderly stroke patients experience markedly worse neurological recovery and higher mortality than younger patients, yet the mechanisms remain unclear. Gut microbiota–brain communication is increasingly recognized as a key regulator of post-stroke repair. Our 16S rDNA sequencing identified a marked age-related depletion of Akkermansia muciniphila (AKK)—a beneficial mucin-degrading bacterium—suggesting that AKK loss may contribute to poor outcomes. We hypothesized that restoring a “youthful” microbiota or supplementing AKK could improve recovery in aged stroke. Methods: Male C57BL/6 mice (young: 2–3 months; aged: 18–20 months) underwent distal middle cerebral artery occlusion (dMCAo). To enable donor microbiota engraftment, aged mice received an antibiotic cocktail (neomycin, streptomycin, vancomycin) for 3 weeks before fecal microbiota transplantation (FMT) from either young or aged donors. A separate aged cohort received oral AKK for 30 days pre-stroke. Neurological and cognitive outcomes, gut barrier integrity, and inflammatory profiles were evaluated for 28 days post-stroke. Gut microbiota composition was assessed by 16S sequencing; brain and gut tissues underwent immunohistochemistry, qPCR, Western blot, and ELISA. Results: 16S analysis confirmed significantly higher AKK abundance in young donors and recipients, with pronounced depletion in aged mice. Aged mice exhibited worse neurological scores and cognitive deficits than young mice after stroke. FMT from aged donors failed to improve recovery, whereas young donor FMT enhanced neurological function, suppressed neuroinflammation, reduced gut inflammation, and restored tight junction proteins (ZO-1, occludin). Oral AKK alone reproduced these benefits, enriching beneficial taxa (e.g., Bifidobacterium, Lactobacillus) and reducing pro-inflammatory/pathogenic taxa (e.g., Enterobacteriaceae, Desulfovibrio). AKK also lowered circulating LPS, IL-1β, IL-6, and TNF-α, and improved gut barrier integrity. Conclusions: Gut microbiota from young hosts or targeted AKK supplementation significantly improves post-stroke recovery in aged mice by rebalancing the microbiome, restoring beneficial species, reducing harmful taxa, and attenuating systemic and neuroinflammation. Age-related AKK depletion may be a critical driver of poor outcomes, supporting microbiome-targeted strategies—particularly AKK therapy—as promising interventions to improve recovery in the elderly stroke population.