Microbial tryptophan metabolites modulate blood-brain and gut barriers in vitro

The gut microbiota influences brain function via the gut-brain axis, but the underlying molecular processes remain unclear. Critical to this communication are barrier systems, such as the epithelial gut and the blood-brain barrier, which mediate the interface between circulating signals and gut-brain communication. Microbial metabolites are key mediators of the gut microbiota that can influence barrier integrity. In this study, we used well-established in vitro models of the blood-brain and gut barriers and exposed them to a wide range of physiologically relevant stress-associated microbial metabolites, including tryptophan-derived metabolites with and without lipopolysaccharide (LPS) as a disrupting insult. We demonstrated that indole, indole-3-acetate, indole-3-propionate and tryptamine can modulate both gut and brain barriers in a dose- and cell-type dependent manner. Our findings suggest that specific indole metabolites should be further evaluated as promising novel therapeutic interventions to regulate barrier integrity along the microbiota-gut-brain axis.