Regulation of Gut Microbiota-Derived GABA: Impact of Intestinal pH, Osmolality, and Microbial Consumption

Abstract The production of gamma-aminobutyric acid (GABA) by the gut microbiota has garnered attention due to its potential role in the gut-brain axis. However, the regulatory mechanisms governing microbiota-derived GABA under physiologically relevant conditions remain unclear. Here, using the model GABA-producing gut microbe Bacteroides thetaiotaomicron, we identified intestinal environmental factors that modulate GABA production. We demonstrate that low pH and high osmolality promote GABA production by driving changes in the expression of the glutamate decarboxylase system. Notably, pH emerged as a critical factor for enhancing GABA production across diverse gut microbes. However, in complex microbial communities, such as the cecum of specific pathogen-free mice and an ex vivo human colon model, GABA levels did not increase under acidic conditions. This was partly due to GABA consumption by GABA-utilizing bacteria. Consistently, reducing cecal pH increased GABA levels in Oligo-MM12 mice, a gnotobiotic model lacking GABA-consuming strains. Our findings highlight the intricate balance between microbial GABA production, consumption, and environmental factors such as pH and osmolality.