Molecular docking of GAD to gut pathogen targets: New prospects for probiotic therapy in post-traumatic stress disorder
Abstract
The human gut microbiome is increasingly understood as a central regulator of brain function through the complex bidirectional system known as the gut - brain axis. One of the most influential microbial metabolites involved in this communication is gamma-aminobutyric acid, a neurotransmitter that plays a critical role in regulating anxiety and stress responses. Probiotics that are capable of producing gamma-aminobutyric acid, also called psychobiotics, are now regarded as promising candidates for innovative therapeutic approaches in trauma-related psychiatric conditions, including post-traumatic stress disorder. The findings of this study reveal that probiotic-derived glutamate decarboxylase, the enzyme responsible for gamma-aminobutyric acid synthesis, exhibits selective and high-affinity interactions with enzymes originating from pathogenic microorganisms in the gut. Strong binding was observed with dihydrofolate reductase and beta-lactamases, which are essential for pathogen survival and resistance. These interactions were stabilized through salt bridges, hydrogen bonds, and aromatic stacking involving conserved residues such as glutamate-25, arginine-42, and phenylalanine-20. In contrast, the interactions with enzymes from commensal gut bacteria were weak, transient, and non-inhibitory, suggesting that the probiotic enzyme selectively targets pathogens while sparing beneficial microbial species. In addition, probiotic strains capable of producing glutamate decarboxylase demonstrated pronounced antagonism against members of the Ent e robacteriaceae family, a group strongly associated with microbial imbalance and psychiatric comorbidities. This dual effect – direct antimicrobial activity together with enhancement of gamma-aminobutyric acid availability in the gut – points to an important role for probiotic glutamate decarboxylase in both microbiota restoration and modulation of neuroimmune communication. Taken together, these results highlight the therapeutic promise of gamma-aminobutyric acid-producing probiotics. Their ability to simultaneously suppress pathogenic bacteria and increase neuroactive metabolite levels, without disrupting commensal populations, underscores their potential as safe and effective psychobiotic interventions. Future investigations should focus on confirming these effects in vivo and on translating them into clinical strategies for trauma-related mental health disorders.References
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