Gut Barrier Dysfunction, Inflammation, and Cognitive Impairment in Aging
Cognitive impairment and Alzheimer disease are increasing with population aging, yet early biological mechanisms remain unclear. Evidence suggests that gut dysbiosis and increased intestinal permeability, or leaky gut, promote systemic inflammation and cognitive decline. We analyzed clinical, inflammatory, and gut microbiome data from 73 older adults in the multi site Microbiome in Aging Gut and Brain (MiaGB) consortium to define links between leaky gut and mild cognitive impairment (MCI). Compared with cognitively healthy controls (n = 43), individuals with MCI (n = 30) showed higher gut permeability markers (LPS binding protein, CD14), increased LPS and toll like receptor 4 activation, and elevated inflammatory markers (IL-6, IL-1 beta, C-reactive protein). MCI was also associated with a distinct gut microbiota profile enriched in pathways related to the microbial metabolite 2 methylcitrate, which correlated with increased gut permeability and reduced cognitive function. These findings support a gut microbiota driven leaky gut inflammation axis contributing to early cognitive impairment and highlight potential biomarkers for early detection and intervention.