Abstract
BACKGROUND: Functional recovery from ischemic stroke (IS), the main cause of adult disability worldwide, is influenced by many factors, and a portion of interindividual variability remains unexplained. METHODS: Observational study in a tertiary stroke centre of patients with IS analyzed using shotgun metagenomic sequencing (January 2020-March 2022). Functional outcomes were assessed according to modified Rankin Scale (mRS) scores 3-months post-IS, considering 0-2 favorable and 3-6 unfavorable. The causal relationship between several bacteria and post-IS outcomes was explored via two-sample Mendelian randomization (MR) analyses using Genome-Wide Association Analysis (GWAS) summary statistics. RESULTS: Comparing 128 patients with favorable and unfavorable post-IS functional outcomes, β-diversity analysis showed a separation in microbial structure, and α-diversity measures revealed greater bacterial richness in the favorable outcomes group. Taxonomic profiling of the samples showed that a greater abundance of pathogenic bacteria (e.g., Pseudomonas, Finegoldia, Porphyromonas) was associated with an unfavorable outcome. Functional profiling of the samples revealed differences in the ethylbenzene degradation pathway and in 16S rRNA (uracil1498-N3)-methyltransferase. MR confirmed increased pyruvate levels to be causally associated with post-IS favorable outcomes (β = -0.50, 95% CI: -0.91, -0.10). CONCLUSIONS: Our study points to gut microbiota differences in patients with unfavorable versus favorable 3-month post-IS outcomes. Patients with unfavorable outcomes presented gut microbiota dysbiosis and alterations in multiple metabolic pathways. TRIAL REGISTRATION: This study was registered on 3 October 2021 with https://clinicaltrials.gov. Access number: NCT04795687.