Multiomics Analyses Reveal Microbiome–Gut–Brain Crosstalk Centered on Aberrant Gamma-Aminobutyric Acid and Tryptophan Metabolism in Drug-Naïve Patients with First-Episode Schizophrenia

Abstract

Background and Hypothesis Schizophrenia (SCZ) is associated with complex crosstalk between the gut microbiota and host metabolism, but the underlying mechanism remains elusive. Investigating the aberrant neurotransmitter processes reflected by alterations identified using multiomics analysis is valuable to fully explain the pathogenesis of SCZ. Study Design We conducted an integrative analysis of multiomics data, including the serum metabolome, fecal metagenome, single nucleotide polymorphism data, and neuroimaging data obtained from a cohort of 127 drug-naïve, first-episode SCZ patients and 92 healthy controls to characterize the microbiome–gut–brain axis in SCZ patients. We used pathway-based polygenic risk score (PRS) analyses to determine the biological pathways contributing to genetic risk and mediation effect analyses to determine the important neuroimaging features. Additionally, a random forest model was generated for effective SCZ diagnosis. Study Results We found that the altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including gamma-aminobutyric acid (GABA), tryptophan, and short-chain fatty acids. Further structural and functional magnetic resonance imaging analyses highlighted that gray matter volume and functional connectivity disturbances mediate the relationships between Ruminococcus_torgues and Collinsella_aerofaciens and symptom severity and the relationships between species Lactobacillus_ruminis and differential metabolites l-2,4-diaminobutyric acid and N-acetylserotonin and cognitive function. Moreover, analyses of the Polygenic Risk Score (PRS) support that alterations in GABA and tryptophan neurotransmitter pathways are associated with SCZ risk, and GABA might be a more dominant contributor. Conclusions This study provides new insights into systematic relationships among genes, metabolism, and the gut microbiota that affect brain functional connectivity, thereby affecting SCZ pathogenesis.

Ileal Dysbiosis Is Associated with Increased Acoustic Startle in the 22q11.2 Microdeletion Mouse Model of Schizophrenia

“…However, the abundance of this ASV was negatively correlated with the acoustic startle response across all mice, suggesting that the reduced abundance of this microbe is indeed related to the SCZ phenotype. This preliminary evidence of a gut-brain relationship may mirror findings in humans, where symptom severity score was negatively correlated with the abundances of several microbes and their metabolites, including Streptococcus salivarius [36].…”

Association of gut dysbiosis with first‑episode psychosis (Review)

“…In addition, an elevated amount of Purpureocillium was shown to be associated with more severe SCH symptomatology and poorer cognitive ability in subjects with SCH, while an elevated amount of Aspergillus was found to be associated with an improved cognitive ability. Wang et al ( 43 ) found that an altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including GABA, tryptophan and short-chain fatty acids. They underlined the association between Ruminococcus torgues and Collinsella aerofaciens and symptom intensity, and the associations between Lactobacillus ruminis and the differential metabolites, l-2,4-diaminobutyric acid and N-acetylserotonin, and cognitive ability ( 43 ).…”

“…Wang et al ( 43 ) found that an altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including GABA, tryptophan and short-chain fatty acids. They underlined the association between Ruminococcus torgues and Collinsella aerofaciens and symptom intensity, and the associations between Lactobacillus ruminis and the differential metabolites, l-2,4-diaminobutyric acid and N-acetylserotonin, and cognitive ability ( 43 ). Alterations in GABA and tryptophan neurotransmitter pathways were found to be associated with the risk of developing SCH ( 43 ).…”

“…They underlined the association between Ruminococcus torgues and Collinsella aerofaciens and symptom intensity, and the associations between Lactobacillus ruminis and the differential metabolites, l-2,4-diaminobutyric acid and N-acetylserotonin, and cognitive ability ( 43 ). Alterations in GABA and tryptophan neurotransmitter pathways were found to be associated with the risk of developing SCH ( 43 ). Finally, Sen et al ( 33 ), in subjects with FEP, found an increase in the amounts of Bifidobacterium adolescentis, Prevotella copri and Turicibacter sanguinis along with abnormalities in deoxyribonucleotide biosynthesis, branched-chain amino acid biosynthesis, the tricarboxylic acid cycle and fatty acid elongation and biosynthesis.…”