What's GABA got to do with it? A potential link between the microbiome, schizophrenia, and the endo-cannabinoid system

The microbiome has been linked to numerous neurological and psychiatric diseases, including schizophrenia. Nevertheless, correlating microbial perturbations to pathophysiological aspects of schizophrenia remains elusive, as study participants are typically medicated when sampled, complicating mechanistic investigation. Here we explored specific microbial and metabolic alterations in schizophrenia patients, while explicitly considering their medications. We recruited 30 patients and 14 healthy controls. Fecal and serum samples were collected for microbiota and (untargeted) metabolome characterization, respectively. While significant differences were detected between microbiome of controls and schizophrenia patients overall, patients not taking GABA-enhancing drugs had profiles similar to the control group. This pattern was preserved, but to a lesser extent, when comparing metabolomes. Several key metabolic pathways differed between patients and controls, even after filtering out those directly related to pharmaceuticals and their metabolism, and the citric acid cycle and amino acid biosynthesis pathways were enriched in the group prescribed antipsychotics without GABA-enhancers. Administration of exogenous GABA affected overall patient homeostasis, not just disease course, supporting our hypothesis that microbiota play a part in cognitive, emotional, and mental function, and that this role must be considered in the full context of an individual's state, including medication.