Abstract
INTRODUCTION: Gut-microbiota dysbiosis has been linked to cognitive decline. Given its role in metabolism, immunity, and environmental interactions, broader molecular signaling alterations are likely. METHODS: We analyzed gut microbiota composition, plasma and fecal metabolites, and inflammatory cytokines across cognitive stages, from healthy controls to dementia. RESULTS: Alpha diversity declined with increasing cognitive impairment severity. Short-chain fatty acid-producing Firmicutes and Bacteroidota decreased from 76% and 17% in controls to 59% and 11% in dementia, respectively. Proteobacteria (e.g., Escherichia-Shigella) rose from < 2% to 4%, and Verrucomicrobiota from 3% to 11%. Despite overall Firmicutes decline, Ruminococcus gnavus, a mucus-degrading species, increased in dementia. These shifts correlated with elevated plasma cytokines, suggesting a link between gut dysbiosis and systemic inflammation. Bacteria-associated metabolites, including bile acids, trimethylamine N-oxide, oxylipins, sugars, and fatty acids were significantly altered. Changes were seen as early as subjective cognitive decline. DISCUSSION: Larger studies are needed to validate these findings and explore microbiome-based interventions. HIGHLIGHTS: Examined gut microbiota, inflammation, and metabolic changes in cognitive impairment stages Early metabolic changes in feces detected before plasma alterations Observed shifts in gut microbiota and inflammation associated with cognitive decline Suggests potential for early biomarkers based on gut metabolites Calls for larger, longitudinal studies to validate findings.