Plasma and feces multiomics unveil cognition-associated perturbations of chronic inflammatory pathways of the gut-microbiota-brain axis

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.