Microbial metabolites alleviate Aß-induced alterations of intestinal epithelial barrier and enteric nervous system connectivity

Amyloid-ß (Aß) induced alterations in gut functions, such as reduced motility and compromised barrier integrity contribute to age-related frailty. Therefore, developing fermentation-based products to prevent age-related gut disorders represents a major therapeutic interest. Primary cultures of enteric nervous system and Caco-2 monolayers were exposed to Aß oligomers following pretreatment with individual or a combination of candidate microbial derived metabolites (butyrate, gamma-aminobutyric acid, and indole derivatives), or a candidate metabolite-enriched fermented dairy product that we subsequently developed. Results showed that individual metabolites significantly preserved markers of neuronal connectivity (beta-tubulin III and synaptophysin) and stabilized tight junction proteins (zonula occludens-1 and occludin), reducing Aß-induced dysfunction. Furthermore, enhanced protective effects of the fermented dairy products enriched with microbial metabolites were observed, suggesting a promising dietary strategy for supporting gut health in aging and Alzheimer's disease, although in vivo validation is needed. Left: Pathological aging promotes gut microbiota dysbiosis and amyloid pathology, which increases intestinal epithelial barrier (IEB) permeability and enteric nervous system (ENS) dysconnectivity. Right: normal aging preserves gut microbiota homesostasis and beneficial microbial metabolites, which prevents gut amyloidosis, protects IEB and reinforces ENS connectivity. • Amyloid-ß (Aß) alters enteric nervous system connectivity and intestinal epithelial permeability in vitro. • Butyrate, GABA, and tryptophan derivatives counteract Aß-induced synaptophysin decrease. • A fermented dairy product enriched with indole derivatives, GABA and SCFAs mitigates Aß-induced alterations of ENS connectivity and IEB integrity.