Table 1.
Selected human evidence on gut microbiota in ASD, ADHD, and schizophrenia
| Disorder and study | Design and sample | Main finding relevant to this review | Principal limitation |
|---|---|---|---|
| ASD; Strati et al. [8] | Cross-sectional case-control study in children | Group-level compositional differences; constipation was associated with microbial features | Single cohort; cross-sectional design; gastrointestinal phenotype may explain part of the association |
| ASD; Yap et al., including correction [9,10] | Cohort study of 247 children | Restricted dietary preferences linked the ASD phenotype to microbiome composition; the direct ASD-microbiome association was negligible after relevant modelling | Observational design; correction required reanalysis; residual confounding remains possible |
| ASD; West et al. [11] | Harmonized multi-cohort analysis of 690 participants | Proposed taxonomic differences varied according to age, sex, and bowel function | Heterogeneous source cohorts and metadata; no causal inference |
| ASD/ADHD; Kurokawa et al. [12] | Cross-sectional study of 98 children, including affected groups, siblings, and unrelated controls | Dietary and microbial diversity differed across groups, emphasizing diet-microbiome coupling | Small subgroups; cross-sectional design; multiple comparisons |
| ADHD; Aarts et al. [13] | Case-control study of 19 participants with ADHD and 77 controls | 16S-based prediction of increased phenylalanine-related bacterial gene function and an association with reward anticipation | Function predicted using PICRUSt rather than measured directly; age imbalance; small ADHD group |
| ADHD; Prehn-Kristensen et al. [14] | Case-control study of 14 boys with ADHD and 17 controls | Lower alpha diversity in participants with ADHD | Very small, male-only sample; limited generalizability |
| ADHD; Wan et al. [15] | Case-control study of 17 children with ADHD and 17 controls | Taxonomic differences, but no difference in alpha diversity | Very small sample size; no longitudinal assessment |
| ADHD; Richarte et al. [16] | Case-control study of 100 medication-naive adults with ADHD and 100 controls | Compositional differences; within-dataset classifier sensitivity of 74% and specificity of 71% | No independent external validation; cross-sectional design |
| ADHD; Wang et al. [17] | Systematic review and meta-analysis of eight studies, including 316 participants with ADHD and 359 controls | No stable disorder-specific microbial profile; diversity findings were sensitive to the included studies | Few heterogeneous studies; limited taxon-level replication |
| Psychosis; Schwarz et al. [18] | Case-control study of 28 participants with first-episode psychosis and 16 controls | Preliminary associations with symptom severity and treatment response | Small sample size; exploratory analyses; possible treatment – and life-style-related confounding |
| Schizophrenia; Zhu et al. [19] | Metagenomic study of 90 medication-free patients and 81 controls; external sample of 45 patients and 45 controls | Classifier AUC of 0.896 in the discovery sample and 0.765 in the external sample | Case-control classification does not establish causality or clinical diagnostic utility |
| Schizophrenia; Vasileva et al. [21] | Cross-sectional study of 97 participants with schizophrenia | More pronounced microbiota differences in treatment-resistant and clozapine-treated groups | Effects of treatment, constipation, metabolic status, diet, and illness severity are difficult to disentangle |
Table 2.
Selected clinical evidence for probiotics, synbiotics, and fecal microbiota-based interventions
| Population and study | Intervention and follow-up | Clinical result | Safety and evidential interpretation |
|---|---|---|---|
| Preschool children with ASD; randomized trial, 85 enrolled/63 completed [26] | De Simone Formulation probiotic vs placebo for 6 months | No significant overall between-group effect on the primary ADOS calibrated severity score; subgroup observations were exploratory | No serious adverse events; transient abdominal pain/diarrhea in 2 probiotic recipients; attrition and subgroup analyses limit certainty |
| Children with ASD; meta-analysis of 7 probiotic trials [27] | Heterogeneous products and durations | ASD symptom effect: SMD – 0.24 (95% CI – 0.60 to 0.11; p=0.18) | Small, heterogeneous trials; product-specific safety and efficacy cannot be generalized |
| Children with ASD and gastrointestinal symptoms; open-label MTT, n=18 [28,29] | Vancomycin, bowel cleanse, acid suppression, then intensive and maintenance donor microbiota; 8-week treatment and 2-year observational follow-up | Gastrointestinal and behavioral scores improved over time | No control group; multi-component regimen; same small cohort at follow-up; cannot establish efficacy |
| Children with ASD; single-arm oral lyophilized FMT, n=38 [30] | One FMT course every 4 weeks for 12 weeks; follow-up to week 20 | From baseline: Autism Behavior Checklist – 23%, CARS – 10%, and SRS – 6% at final follow-up | No control group; vomiting/fever in 2 participants, resolving within 24 hours; within-person changes cannot establish efficacy |
| Children with ASD; randomized oral FMT trial, n=103 [31] | Donor-derived capsules vs placebo during two treatment periods; assessment to week 17 | No difference in primary SRS-2 outcome or Aberrant Behavior Checklist; secondary Vineland-3 socialization difference 5.05 points (95% CI 0.31 to 9.79) | Adverse events: 23.1% FMT vs 13.7% placebo; no grade 3/serious events; negative primary outcome governs interpretation |
| Children and adults with ADHD; randomized synbiotic trial, n=182 completed [32] | Synbiotic 2000 vs placebo for 9 weeks | Similar ADHD symptom improvement in both groups; no significant effect on daily functioning | Secondary/subgroup signals do not establish core-symptom efficacy; trial not powered for rare harms |
| Children/adolescents with ADHD; meta-analysis of 7 randomized trials, n=379 [33] | Heterogeneous probiotic formulations, standalone or add-on | Total symptoms SMD 0.25 (p=0.12); inattention 0.14 (p=0.30); hyperactivity/impulsivity 0.08 (p=0.54) | No significant core-symptom benefit; heterogeneity and limited safety power |
| Children with ADHD receiving methylphenidate; randomized trial, modified intention-to-treat n=102 [34] | B. bifidum Bf-688, 5 × 109 CFU/day, vs placebo for 12 weeks | No added benefit on core ADHD rating scales; exploratory attention and gastrointestinal signals | Does not support treatment of core ADHD symptoms; rare harms could not be assessed |
| University students with ADHD; randomized trial, 67 randomized/60 analyzed [35] | Multi-strain probiotic, 8 × 109 CFU/day, vs placebo for 3 months | Signals in selected hyperactivity, gastrointestinal, and functional outcomes | Small single-center trial with multiple outcomes; replication required |
| Adult with ADHD and recurrent C. difficile infection; case report, n=1 [36] | FMT for recurrent C. difficile; microbiome profiling before and after | Coincidental improvement in reported ADHD symptoms | No comparator; treatment was for another indication; no efficacy or safety inference for ADHD |
| Adults with schizophrenia; randomized trial, n=65 [37] | L. rhamnosus GG plus B. animalis Bb12 vs placebo for 14 weeks | No PANSS improvement; lower risk of severe bowel difficulty, HR 0.23 (95% CI 0.09 to 0.61) | Four serious events across both groups; overall AE rates similar; possible gastrointestinal benefit, not antipsychotic efficacy |
| Schizophrenia; systematic review of 3 probiotic studies [38] | Probiotic supplementation vs placebo | Symptoms: SMD – 0.0884 (95% CI – 0.380 to 0.204; p=0.551) | Very small evidence base; no demonstrated benefit for positive, negative, or overall symptoms |
| Schizophrenia; broader systematic review/meta-analysis, 28 trials [39] | 21 antibiotic, 4 other antimicrobial, 3 pre/probiotic, and 0 FMT trials | No effect of probiotics alone on negative symptoms; findings mainly reflected non-probiotic strategies | Does not support routine microbiome-targeted treatment; no human FMT efficacy evidence |
[i] Abbreviations: ADOS, Autism Diagnostic Observation Schedule; AE, adverse event; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CARS, Childhood Autism Rating Scale; CFU, colony-forming units; CI, confidence interval; FMT, fecal microbiota transplantation; HR, hazard ratio; MTT, Microbiota Transfer Therapy; PANSS, Positive and Negative Syndrome Scale; SMD, standardized mean difference; SRS, Social Responsiveness Scale.