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The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice

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Zheng P et al. Science Advances. Vol. 5, no. 2, eaau8317.

COMMENT: This work analyzes possible relationships between the gut microbiome from patients with schizophrenia (SCZ) and the schizophrenic symptoms. Interesting results were obtained transferring gut microbiota from patients with schizophrenia to germ free mices. Behavioral tests showed that these transplanted mice had some schizophrenic symptoms. The differences between healthy and transplanted mice microbiomes were studied using 16S, shotgun metagenomics and metabolomics assays. The studies detected differences in taxonomic profiles and differences in glutamate-glutamine-GABA metabolites especially in glutamate-rich brain regions (hippocampus and cortex) that are implicated in the disruptions of these metabolites in schizophrenia.

These were the differences in the bacterial composition detected between healthy controls (HC) and transplanted with gut from schizophrenic patients:

Stepwise regression analysis showed that the most significant discrimination between these two groups was attributable to the bacterial families Aerococcaceae and Rikenellaceae, and their combined microbial markers could completely discriminate the SCZ microbiota recipient mice from their HC counterparts with an AUC of 1, which represents 100% discrimination accuracy. Furthermore, identical changes in Aerococcaceae and Rikenellaceae composition were seen in both patients with SCZ and the SCZ microbiota recipient mice.

These were the results of the metabolomics studies:

We identified the differentially expressed metabolites between the two groups (table S3, A to C). Of particular relevance to SCZ, we measured differences in central nervous system and peripheral glutamate-glutamine–GABA (Gamma-AminoButyric Acid) metabolism, and in the SCZ microbiota compared to the HC microbiota recipient mouse samples, we found elevated glutamine in the serum and hippocampus, decreased glutamate (glutamic acid) in the stool and hippocampus, and increased GABA in the hippocampus 

Significant differences between HC and SCZ subjects were seen in these three metabolites in cortex, but not in cerebellum or striatum, thus confirming that the observed metabolic disturbances are localized to the glutamate-rich brain regions (i.e., hippocampus and cortex) that are most consistently implicated in glutamate-glutamine-GABA disruptions in SCZ and that are relevant to the behavioral endophenotypes observed 

CONCLUSIONS:

Together, we provide seminal evidence that SCZ is associated with changes in gut microbiota composition that are both specific to SCZ and correlated with symptom severity. Moreover, we found that changes in the gut microbiota resulting from human SCZ fecal microbiome transfer to mice lead to hypoglutamatergia and onset of SCZ-relevant behaviors characteristic of SCZ rodent models, accompanied by gut-brain axis metabolic changes. Our findings provide a novel framework for understanding the mechanisms of SCZ through the MGB axis and may lead to new diagnostic and treatment strategies

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Raquel Tobes