Precision Glycans Enhance Gamma-Aminobutyric Acid Production in Human Gut Model

Background: Prebiotics, substrates selectively utilized by host microorganisms to confer health benefits, can induce the production of microbial metabolites involved in regulating host biological functions. Several of these metabolites, including gamma-aminobutyric acid (GABA), play a crucial role in regulating neural activity and can be linked to a variety of neurological as well as physiological disorders. While GABA is primarily synthesized in the brain, emerging evidence suggests that the gut microbiome can also contribute to systemic GABA levels. Abiotic glycans, synthesized oligosaccharides containing structures not typically found in nature, are a promising candidate for increasing systemic GABA levels through the targeted modulation of the gut microbiome via the enrichment of GABA-producing microorganisms.Results: In this study, we investigated the impact of abiotic oligosaccharides on human fecal microbiota and GABA production. We identified a specific glycan, SG-Glc, that significantly increases GABA levels in ex vivo fermentation experiments wherein the constituent simple sugar had no impact on GABA levels. We find Bifidobacterium adolescentis is a key species driving this increase. Further analysis revealed that B. adolescentis possesses both genes required for GABA production and a unique CAZyme (carbohydrate-active enzyme) profile enabling it to utilize SG-Glc for growth while producing GABA, unlike other Bifidobacterium species.Conclusions: Our findings highlight the potential of abiotic oligosaccharides to modulate the gut microbiome and enhance GABA production, offering an expanded toolbox for targeting the gut-brain axis. By understanding the specific mechanisms underlying these effects, we may develop innovative strategies for improving overall brain function with possible impacts on both mental and physiological health and well-being.