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The high neuroactive potential of metabolites produced by gut microbes has gained traction over the last few years, with metagenomic-based studies suggesting an important role of microbiota-derived γ-aminobutyric acid (GABA) in modulating mental health. Emerging evidence has revealed the presence of the glutamate decarboxylase (GAD)-encoding gene, a key enzyme to produce GABA, in the prominent human intestinal genus  Bacteroides . Here, we investigated GABA production by  Bacteroides  in culture and metabolic assays combined with comparative genomics and phylogenetics. A total of 961  Bacteroides  genomes were analyzed  in silico  and 17 metabolically and genetically diverse human intestinal isolates representing 11 species were screened  in vitro . Using the model organism  Bacteroides thetaiotaomicron  DSM 2079, we determined GABA production kinetics, its impact on milieu pH, and we assessed its role in mitigating acid-induced cellular damage. We showed that the GAD-system consists of at least four highly conserved genes encoding a GAD, a glutaminase, a glutamate/GABA antiporter, and a potassium channel. We demonstrated a high prevalence of the GAD-system among  Bacteroides  with 90% of all  Bacteroides  genomes (96% in human gut isolates only) harboring all genes of the GAD-system and 16 intestinal  Bacteroides  strains producing GABA  in vitro  (ranging from 0.09 to 60.84 mM). We identified glutamate and glutamine as precursors of GABA production, showed that the production is regulated by pH, and that the GAD-system acts as a protective mechanism against acid stress in  Bacteroides , mitigating cell death and preserving metabolic activity. Our data also indicate that the GAD-system might represent the only amino acid-dependent acid tolerance system in  Bacteroides . Altogether, our results suggest an important contribution of  Bacteroides  in the regulation of the GABAergic system in the human gut.

GABA Production by Human Intestinal Bacteroides spp.: Prevalence, Regulation, and Role in Acid Stress Tolerance