Research ArticleNEUROSCIENCE

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

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Science Advances  06 Feb 2019:
Vol. 5, no. 2, eaau8317
DOI: 10.1126/sciadv.aau8317
  • Fig. 1 Gut microbial characteristics of SCZ.

    (A) α-Phylogenetic diversity analysis showed that patients with SCZ were characterized by lower microbial richness (Chao, *P < 0.05) and diversity (Shannon, **P < 0.01) indices relative to HCs. (B) At the OTU level, partial least-squares discriminant analysis (PLS-DA) showed that gut microbiota composition of patients with SCZ was greatly different from that of HCs. (C) Heat map of the 77 discriminative OTU abundances between patients with SCZ and HCs; 23 up-regulated OTUs in SCZ are arranged on the left part of the image, and 54 decreased OTUs are arranged on the right part. The taxonomic assignment of each OTU is provided on the right column. (D) OTUs related to SCZ symptom severity (quantitation with PANSS). The red line designates negative correlation between PANSS and microbes, while the green line shows positive correlation. Lachnospiraceae and Ruminococcaceae are shown twice because they both had two different OTUs correlated with PANSS (see Results). (E) ROC analysis showed that the combination of Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae can distinguish patients with SCZ from HCs with an AUC of 0.769.

  • Fig. 2 Behavioral comparisons between the SCZ microbiota recipient mice and the HC microbiota recipient mice.

    (A and B) Open-field test. Compared to the HC microbiota recipient mice, the total distance (A) and proportion (B) of central distance traveled in 30 min were significantly increased in the SCZ microbiota recipient mice (HC, n = 24; SCZ, n = 25). (C) Forced swimming test. Compared to the HC microbiota recipient mice, the duration of immobility was significantly decreased in the SCZ microbiota recipient mice (n = 20 per group). (D) Y-maze test. There was no difference in the alteration rate between the two groups (n = 20 per group). (E and F) Sociability and social novelty preference test. In the sociability test (E) and social novelty preference tests (F), the time investigating the chamber containing a novel mouse versus the time investigating both chambers was indistinguishable between the two groups (HC, n = 24; SCZ, n = 23). (G and H) Prepulse inhibition (PPI) test. (G) The SCZ microbiota recipient mice displayed an exaggerated startle response to high-decibel tones (120 db) relative to the HC microbiota recipient mice. (H) Increasing prepulse intensity led to increased PPI magnitude in both microbiota recipient groups; however, the PPI magnitude did not differ between the two groups. All data were presented as means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 using nonparametric tests).

  • Fig. 3 Metagenomic analysis identified differential KEGG pathways between SCZ microbiota and HC microbiota recipient mice.

    The altered differential KEGG Orthologs (KOs) were mainly involved in 33 disturbed metabolic pathways. Seven of 33 pathways were down-regulated, and the remaining pathways were up-regulated in the SCZ microbiota recipient mice compared to HC microbiota recipient mice (n = 8 per group). tRNA, transfer RNA.

  • Fig. 4 Altered metabolites in stool, serum, and hippocampus.

    (A to C) Key metabolites glutamine (A), glutamate (B), and GABA (C) related to glutamatergic neurotransmission metabolism were significantly changed in the SCZ microbiota mice (n = 10 per group). All data were presented as means ± SEM. *P < 0.05 using Student’s t test. (D) A heat map shows the altered metabolites in stool, serum, and hippocampus. Functional clustering analysis showed that these differentially expressed fecal, serum, and hippocampal metabolites were consistently involved in amino acid and lipid metabolism (n = 10 per group).

  • Fig. 5 The workflow diagram for this study.

    SCZ is associated with dysbiosis of gut microbial composition, which is distinct from that seen in major depressive disorder (MDD). This alteration can result in host gut-brain axis metabolic and neurobehavioral changes relevant to SCZ.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/2/eaau8317/DC1

    Fig. S1. Gut microbial composition differences between patients with SCZ and HC subjects.

    Fig. S2. Impact of confounding variables on global gut microbial phenotypes.

    Fig. S3. Comparison of microbial markers between patients with SCZ and major depressive disorder.

    Fig. S4. Comparison of gut microbial characteristics between SCZ microbiota and HC microbiota recipient mice.

    Fig. S5. Metabolomic analysis of fecal, serum, and hippocampal samples obtained from SCZ microbiota and HC microbiota recipient mice.

    Fig. S6. IPA shows that differentially expressed fecal, serum, and hippocampus metabolites were consistently involved in amino acid metabolism, especially glutamate metabolism.

    Fig. S7. Levels of glutamine, glutamic acid, and GABA in SCZ microbiota and HC microbiota recipient mice.

    Table S1. Detailed clinical characteristics of participants.

    Table S2A. Discriminatory OTUs between patients with SCZ and HC subjects.

    Table S2B. Discriminatory KEGG pathways between SCZ microbiota and HC microbiota recipient mice.

    Table S3A. Differential fecal metabolites between SCZ microbiota and HC microbiota recipient mice.

    Table S3B. Differential serum metabolites between SCZ microbiota and HC microbiota recipient mice.

    Table S3C. Differential hippocampus metabolites between SCZ microbiota and HC microbiota recipient mice.

  • Supplementary Materials

    This PDF file includes:

    • Fig. S1. Gut microbial composition differences between patients with SCZ and HC subjects.
    • Fig. S2. Impact of confounding variables on global gut microbial phenotypes.
    • Fig. S3. Comparison of microbial markers between patients with SCZ and major depressive disorder.
    • Fig. S4. Comparison of gut microbial characteristics between SCZ microbiota and HC microbiota recipient mice.
    • Fig. S5. Metabolomic analysis of fecal, serum, and hippocampal samples obtained from SCZ microbiota and HC microbiota recipient mice.
    • Fig. S6. IPA shows that differentially expressed fecal, serum, and hippocampus metabolites were consistently involved in amino acid metabolism, especially glutamate metabolism.
    • Fig. S7. Levels of glutamine, glutamic acid, and GABA in SCZ microbiota and HC microbiota recipient mice.
    • Table S1. Detailed clinical characteristics of participants.
    • Table S2A. Discriminatory OTUs between patients with SCZ and HC subjects.
    • Table S2B. Discriminatory KEGG pathways between SCZ microbiota and HC microbiota recipient mice.
    • Table S3A. Differential fecal metabolites between SCZ microbiota and HC microbiota recipient mice.
    • Table S3B. Differential serum metabolites between SCZ microbiota and HC microbiota recipient mice.
    • Table S3C. Differential hippocampus metabolites between SCZ microbiota and HC microbiota recipient mice.

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    Correction (21 June 2019): The last column on the ID: ko00532 line in table S2B, in the Supplementary Materials, incorrectly displayed "Down" instead of "Up".

    The original version is accessible here.

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