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Table 1 Evidence for a role of gut microbiota in SCZ from human and animal studies

From: Schizophrenia, the gut microbiota, and new opportunities from optogenetic manipulations of the gut-brain axis

References Subject type Investigated actors Methods Results
Pyndt Jørgensen et al. [22] Rats Cognitive abilities (memory performances) Sub-chronic PCP model to induce SCZ-like behaviors SubPCP model impaired NORT
Increased locomotor sensitivity up to 6 weeks after washout
16S rRNA gene MiSeq-based high throughput sequencing
Locomotor activity Gut microbiota profiles correlated to SCZ-like memory performance
Administration of ampicillin (restoring gut microbiota) abolished the subPCP-induced memory deficit
Gut microbiota
Nguyen et al. [30] Human α-diversity Stool sampling Phylum level
16S rRNA amplicon extraction protocol  ↓ Proteobacteria in SCZ vs HC
Illumina primers to target the V4 region of the 16S ribosomal RNA gene
Genus level
 ↑Anaerococcus in SCZ
 ↓Haemophilus, Sutterella, and Clostridium in SCZ
Within SCZ
 Ruminococcaceae correlated with low negative symptoms
Zheng et al. [85] Human, mice Gut microbiota of SCZ and HC 16S rRNA gene sequencing ↓ Microbiome α-diversity index in SCZ
↓ Disturbances of gut microbiota composition
Veillonellaceae and Lachnospiraceae associated with SCZ severity
Human-to-mice Gut microbiota transplant
SCZ-relevant behavioral phenotypes in GF mice
Whole-genome shotgun sequencing of cecum GF mice receiving SCZ microbiome
 HPC ↓glutamate and ↑glutamine and GABA
Non-targeted metabolomics analysis
SCZ vs HC mice microbiota analysis
SCZ-relevant behaviors similar to those with GLU hypofunction
Severance et al. [90] Human Plasma biomarkers for general inflammation and gut microbiota derived inflammation: hs-CRP, LBP, sCD14 409 SCZ individuals Multivariate regression models
 GI and endocrine conditions was additive for LBP, with associations only when both conditions were present compared to when were absent
Multivariate and univariate regression models  hs-CRP strongly associated with primarily endocrine conditions
Univariate comparisons
 S. cerevisiae IgG levels were elevated only in GI problematic persons
IgG antibodies to S. Cerevisiae, bovine milk casein, and wheat gluten
Babulas et al. [91] Human Maternal G/R infections prenatal exposure and SCZ relationship in offspring 7794 offspring reported maternal G/R infections from obstetric records Exposure to G/R infections during the periconceptional period is associated with increased SCZ risk, with adjustment for maternal race, education, age, and mental illness
Diagnosed 71 cases of SCZ and SCZ spectrum disorders
Dunphy-Doherty et al. [92] Rats Social isolation/altered gut microbiota correlation Behavioral testing: OF/NORT, EPM, CFR, restraint SI rats showed a few signs of anxiety phenotype (↑ locomotion, ↓ defecation, ↓ CFR). No differences in NORT and EPM
ELISA No changes in corticosterone after stress
HPC neurogenesis and brain cytokine levels 16S rRNA gene MiSeq-based high throughput sequencing ↓ BrdU/NeuN in dentate gyrus
Post-mortem caecal microbiota composition Cytokine and mTOR analysis ↓ Il-6 and IL-10 in HPC
Kannan et al. [93] Human, mice T. gondii-induced infection in mice and human cohorts Mice received 2 T. gondii strains, or NaCl (HC) i.p. injections In mice
Serum collection from blood tail 20 weeks post infection  T. gondii infection produced sustained, strain-specific, anti-NMDAR immune responses
Enzyme-linked immunosorbent assays In humans (USA and Germany cohorts)
IgG class antibodies to the NMDAR  ↑ NMDAR IgG levels in T. gondii-seropositive SCZ vs HC
Serum IgG antibodies (T. gondii, NMDAR subunit)
Humans: 2 cohorts (USA, Germany) with
T. gondii and NMDAR antibody seropositivity   =  NMDAR IgG levels in medicated T. gondii-seropositive SCZ vs HC
 Blood sampling
 Subject selection with RBANS
Maes et al. [94] Human Plasma IgA/IgM against 5 g-negative bacteria Recruitment (80 SCZ, 38 HC) IgA/IgM values
 IgA values associated with the SCZ Deficit Phenotype
SDS screening (40 out of 80 SCZ)  No associations between IgM and the 5 Gram-negative bacteria
IgM MDA and azelaic acid
Assessments (MINI, PANSS, BPRS) Low IgM to MDA and azelaic acid in SCZ deficit phenotype
Immunoassays for
 IgA and IgM against 5 g-negative bacteria
SCZ deficit phenotype  IgM-mediated autoimmune responses directed against MDA and azelaic acid
Xu et al. [95] Human GMEs Recruitment (84 SCZ  +  HC) MWAS found 19 different taxonomies in SCZ vs HC; and 12 were increased in SCZ
Stool sampling and analysis
↑ MD index in SCZ vs HC
MEs analysis
↑ MEs diversity in SCZ,  +  correlation with the MD index
Gut microbiota taxonomies 16S rRNA gene MiSeq-based high throughput sequencing
↑ GOGAT in the SCZ guts
ROC analysis showed that MD index, IgA and GOGAT reached AUC 0.86  →  potential gut markers of SCZ
MD index
Correlation and regression analysis
MD analysis
ROC analysis
Shen et al. [96] Human SCZ and HC gut microbiota 16S rRNA gene MiSeq-based high throughput sequencing Similar α-diversity SCZ vs HC
ROC analysis β-diversity altered  →  increased phylum
 Proteobacteria, Fusobacteria, Firmicutes, Bacteroidetes
PICRUSt analysis β-diversity altered  →  decreased phylum
 Mainly Firmicutes (Clostridia, Streptococcus, etc.)
Olde Loohuis et al. [97] Human Microbial communities composition in the blood Recruitment (192 with SCZ, ALS, BPD)  +  HC ↑ Microbial diversity in SCZ vs ALS, BPD, HC
High-quality unmapped RNA sequencing reads
↑ Microbial diversity is inversely correlated with estimated abundance of antigenic CD8  +  T cells in HC
Kanayama et al. [98] Human Gut microbiota of a SCZ patient after ECT Stool sampling before and after ECT After ECT
 ↓ Scores in BPRS and BFCRS
Gut microbiota differences before and after ECT
Assessments (BPRS, BFCRS)  ↓ Clostridium
 ↑ Lactobacillus
ECT (14 sessions)
 ↑ Bacteroides
He et al. [99] Human Gut microbiota differences Stool sampling ↑ Clostridiales, Lactobacillales, and Bacteroidales in UHR vs HR and HC
MRS scans
Recruitment (81 HR SCZ, 19 UHR SCZ, 69 HC) ↑ ACC choline in UHR vs HR and HC
Choline concentrations in the ACC
Yuan et al. [100] Human Metabolic parameters Recruitment (41 SCZ, 41 HC) Bifidobacterium, E. Coli, and Lactobacillus in SCZ vs HC
Assessment (PANSS) ↑ Clostridium
Post 24-weeks risperidone
 ↑ Body weight, BMI, hs-CRP, SOD, HOMA-IR
Blood and stool sampling
 ↑ Bifidobacterium and E. Coli
 ↓ Clostridium and Lactobacillus
Only changes in Bifidobacterium correlated with changes in weight and BMI
Standard enzymatic methods  +  electro-chemiluminescence immunoassay
Automatic biochemical analyzer
Particle-enhanced assay  +  chemical colorimetric assay
QIAamp fast DNA stool mini kit
Gut microbiota
Metabolic/microbiota changes relationship
24-weeks risperidone treatment
Schwarz et al. [101] Human Fecal microbiota Assessment (extended BPRS, SANS, GAF, food habits, physical activity) Similar α-diversity SCZ vs HC
Difference in β-diversity
 ↑ and ↓ different strains of Phyla (Proteobacteria, Fusobacteria, Firmicutes, Bacteroidetes)
Stool sampling In active SCZ patients:
 ↑ Lactobacillaceae
 ↓ Veillonellaceae
SCZ-first episode, HC qRT-PCR
Okubo et al. [102] Human B. breve A-1 effects on SCZ-anxiety/depression, and the immune system 4-weeks B. breve A-1 admin ↑ HADS and PANSS scores after B. Breve A1
Assessment (HADS, PANSS)
↑ Relative abundance of gut Parabacteroides after in B. breve A1
Blood test findings
Fecal microbiota composition
Flowers et al. [103] Human AAP treatment Starch tolerability assessment =  overall microbiota composition at baseline between AAP vs non-AAP
Stool sampling
↑ Alistipes in non-AAP
AAP-microbiome varied with resistant starch admin
↑ Actinobacteria phylum in AAP-treated
PowerMag soil DNA isolation kit
16S rRNA gene MiSeq-based high throughput sequencing
6 months prebiotics (resistant starch) Illumina expression array
Recruitment (37 SCZ, BPD)
Ghaderi et al. [104] Human Effects of vitamin D/probiotic combination on metabolic and clinical SCZ symptoms Assessment (PANSS, BPRS) Vitamin D
Vitamin D3/probiotic every 2 weeks or placebo (12 weeks)  ↑ PANSS scores
Vitamin D/probiotic co-supplementation
 ↑ TAC
 ↓ MDA, hs-CRP
 ↓ Fasting plasma glucose, QUICKI, HOMA-IR
Fasting blood sampling
Antioxidant markers (TAC, GSH, MDA)
Insulin markers (HOMA-IR, QUICKI)
Enzymatic kits
Zhu et al. [105] Human, mice FMT from SCZ humans to HC mice Behavioral testing (OF, RSIT, TCST, NORT, FST, EPM, BM, TST) SCZ-transplanted mice showed behavioral (cognitive and locomotor) impairments up to 10 days post FMT
Cognitive and motor abilities in SCZ-induced mice Mice stool sampling
↑ Kyn/KynA pathway of Tr degradation in both periphery and brain
16S rRNA gene MiSeq-based high throughput sequencing Increased DA in PFC, and 5-HT in HPC
Kyn/KynA pathway of Tr degradation
Extracellular DA in PFC, 5-HT in HPC
  1. The table provides a summary of the most relevant studies cited in the manuscript related to the role of the gut microbiota in the onset and development of SCZ
  2. PCP phencyclidine; SCZ schizophrenia; NORT novel object recognition test; HC healthy controls; GF germ free; GLU glutamate; OF open field; EPM elevated plus maze; DA dopamine; 5-HT serotonin; qRT-PCR quantitative real time-PCR; PFC prefrontal cortex; HPC hippocampus; Tr tryptophan; Kyn kynurenine; KynA kynurenic acid; hs-CRP high-sensitivity C-reactive protein; LBP lipopolysaccharide-binding protein; SCD14 soluble CD14; GI gastrointestinal; G/R genital/reproductive; CFR conditioning freezing response; SI social isolation; RBANS repeated battery for the assessment of neuropsychological status; MDA malondialdehyde; SDS schedule for deficit syndrome; MINI mini international neuropsychiatric interview; PANSS positive and negative syndrome scale; BPRS brief psychiatric rating scale; GMEs gut-microbiota associated epitopes; MD microbial dysbiosis; GOGAT glutamate synthase; MWAS metagenomic-wide association study; ROC receiver operating characteristic; BPD bipolar disorder; ECT electroconvulsive therapy; BFCRS Bush–Francis catatonia rating survey; ACC anterior cingulate cortex; MRS magnetic resonance spectroscopy; HR high risk; UHR ultra high risk; SCFA short-chain fatty acids; SOD antioxidant superoxide dismutase; HOMA-IR homeostasis model of assessment-insulin resistance; SANS assessment of negative symptoms; GAF global assessment of functions; HADS hospital anxiety and depression scale; AAP atypical antipsychotics; TAC total antioxidant capacity; GSH total glutathione; QUICKI quantitative insulin sensitivity check index; RSIT reciprocal social interaction test; TCST three-chamber social test; BM Barnes maze; FST forced swimming test; TST tail suspension test