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

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

NORT

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

β-diversity

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

MWAS

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

GOGAT

ELISA

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

α-diversity

PICRUSt analysis

β-diversity altered  →  decreased phylum

 Mainly Firmicutes (Clostridia, Streptococcus, etc.)

β-diversity

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

↑ SCFAs

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

SOD

qRT-PCR

hs-CRP

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

ELISA

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

ELISA

qRT-PCR

Kyn/KynA pathway of Tr degradation

Extracellular DA in PFC, 5-HT in HPC