Psychobiotic interventions for anxiety in young people: a systematic review and meta-analysis, with youth consultation

The study investigates whether psychobiotic interventions (probiotics and prebiotics targeting the gut microbiota) reduce anxiety and stress in youth aged 10–24 years. Rationale stems from evidence that the gut-brain axis influences psychological function and that adolescence is a sensitive neurodevelopmental window when microbiota may shape stress responsivity and mental health. Preclinical work links specific bacterial strains and prebiotics to neuroactive processes (e.g., GABA, serotonin) and anxiolytic effects, suggesting a potential preventive or therapeutic avenue during youth. The review aims to evaluate translational efficacy in humans by systematically synthesizing controlled trials measuring anxiety and stress outcomes in this age range.

Preclinical and emerging human literature suggests psychobiotics can modulate neurochemical pathways and behavior. Probiotics such as Lactobacillus and Bifidobacterium strains can influence GABA and serotonin pathways; for instance, Bifidobacterium is linked to GABA expression, Enterococcus and Streptococcus to serotonin, and Lactobacillus to GABA and acetylcholine. Animal studies show specific strains (e.g., L. rhamnosus, L. brevis, B. dentium) alter central GABA receptor expression, reduce corticosterone, and lessen anxiety-/depression-like behaviors, with effects emerging after several weeks and sometimes constrained by developmental timing (e.g., adolescent germ-free recolonization not reversing anxiety-like behavior). Prebiotics (e.g., fructooligosaccharides [FOS], galactooligosaccharides [GOS]) selectively nourish beneficial gut bacteria, modulate hippocampal/hypothalamic gene expression, and shift SCFAs, correlating with reduced stress responses and improved anxiety-like behaviors in rodents. Adolescence appears a critical window: early-life and periadolescent interventions (e.g., Lactobacillus helveticus exposure, multi-strain lactococci/lactobacilli around inflammatory challenge) can buffer immediate and later-life stress responsivity. These mechanistic and animal findings motivate testing psychobiotics for anxiety reduction in human youth, while cautioning that sensitive periods may differ across species.

Design: Systematic review and meta-analysis following PRISMA guidelines. Protocol and registration: Conducted per PRISMA; checklist provided in Appendix 5. Data sources and search: Six databases (PubMed, Embase, Cochrane, Scopus, Ovid, Web of Science) searched between May 30 and June 10, 2020, using predefined terms (Appendix 1) with no date restrictions. Eligibility criteria: Controlled human trials with at least one active psychobiotic (probiotic or prebiotic) arm and one comparator (placebo or treatment-as-usual); mean age 10–24 years; healthy or clinical samples; pre- and post-intervention measures; peer-reviewed publications. Excluded: synbiotic interventions, unpublished/non–peer-reviewed data, duplicates, samples with mean age outside 10–24. Outcomes: Primary—anxiety symptom change (questionnaire/interview). Secondary—behavioral anxiety indices (e.g., emotional Stroop), stress measures (e.g., salivary cortisol, immunoglobulin A, alpha-amylase, metanephrine; blood pressure; pulse rate; serum/urinary biomarkers; self-reported stress; behavioral performance). Study selection and data extraction: 5416 records identified; duplicates (n=1549) removed in EPPI-Reviewer4. Titles/abstracts screened independently by two reviewers (MB, PK); disagreements resolved with a third (KCK). Full texts assessed for eligibility; qualitative data extracted (author, year, intervention type and delivery, active compound, dose, frequency, duration, sample characteristics, outcomes) and quantitative data entered into RevMan 5. Authors contacted when needed for missing data. Risk of bias: Assessed with Cochrane RoB 2 for randomized trials across standard domains (randomization, allocation concealment, blinding, incomplete data, selective reporting, other). Excel RoB2 tool used to support judgments and figure creation. Funnel plot generated in RevMan 5 to assess potential biases. Statistical analysis: Effect sizes extracted as standardized mean differences (SMDs) with 95% CIs. Random-effects meta-analysis used to pool effects; heterogeneity quantified with I^2. Sensitivity analyses conducted excluding studies at high risk of bias.

- Study yield: 5416 records identified; 14 studies included in the systematic review (9 probiotic, 5 prebiotic); 10 studies included in the meta-analysis comprising 324 experimental and 293 control participants. - Meta-analytic effect: Pooled SMD = −0.03 (95% CI −0.21 to 0.14) with low heterogeneity (I^2 = 12%), indicating no overall effect of psychobiotics on anxiety in youth. - Risk of bias: Of included studies in the meta-analysis, 1 had low risk, 5 high risk, and 4 unclear risk of bias. Sensitivity analysis excluding high-risk studies yielded SMD = −0.16 (95% CI −0.38 to 0.07), suggesting minimal efficacy at best. - Probiotic outcomes: Considerable methodological heterogeneity (strains, doses 10^9–10^11 CFU; durations 14–56 days; diverse anxiety/stress measures). Five of six probiotic studies assessing anxiety found no significant effect; one study reported improvement on worry (PSWQ) only at a high dose (50×10^9 CFU). Some studies in student exam-stress paradigms reported reductions in salivary cortisol and self-reported stress with L. casei Shirota; another reported reduced stress in sleep-deprived students with B. bifidum. Approximately half of stress-focused probiotic studies found no significant effects; adverse findings included increased pulse rate with Saccharomyces boulardii and increased BAI scores in one study. - Prebiotic outcomes: Fewer studies (n=5) using GOS, FOS, omega-3 PUFA, and fermented ginseng. Doses typically 1.8–5.5 g/day over 8–56 days (some up to 84 days). Evidence remains limited and mixed, with several studies reporting non-significant effects on stress/anxiety measures. Overall conclusion of results: Current evidence does not support a reliable anxiolytic effect of psychobiotics in youth, though isolated strain- and context-specific signals exist.

The review directly addresses whether modulating the gut microbiota via psychobiotics reduces anxiety in youth. Despite compelling mechanistic and preclinical data and the developmental salience of adolescence, pooled human evidence shows no significant anxiolytic effect, with minimal effect sizes after accounting for high-risk studies. Heterogeneity in strains, doses, treatment durations, populations (often non-clinical student samples), and outcome measures likely dilutes detectable effects and complicates synthesis. Findings suggest any benefits may be strain-specific, dose-dependent, and context-bound (e.g., exam stress), underscoring the need for targeted selection of psychobiotic agents tied to mechanistic hypotheses (e.g., GABAergic modulation) and standardized, validated anxiety outcomes. The work emphasizes moving beyond correlational or secondary stress outcomes toward adequately powered, rigorously blinded RCTs specifying mechanisms in human models, assessing causal pathways, and considering developmental timing. Youth consultation indicates acceptability and interest, suggesting implementation potential if efficacy is established.

This systematic review and meta-analysis finds limited evidence that psychobiotic interventions reduce anxiety in young people, with an overall null pooled effect and only minimal effects after excluding high-risk studies. The field is characterized by methodological heterogeneity and mixed results, particularly among probiotic trials, while prebiotic evidence remains sparse. Future research should be multidisciplinary and mechanism-led, focusing on: (1) precise strain and prebiotic selection based on hypothesized neurobiological pathways; (2) standardized, clinically relevant anxiety measures and biomarkers; (3) rigorous trial designs with adequate power, blinding, and risk-of-bias controls; (4) developmental considerations regarding timing and duration of interventions; and (5) contextual factors influencing acceptability and adherence. Such advances could clarify causal effects and identify subgroups or conditions under which psychobiotics may benefit youth anxiety.

- High methodological heterogeneity across included studies (varied strains/compounds, doses, delivery methods, treatment durations, and outcome measures) limits comparability and synthesis. - Many trials assessed stress or anxiety as secondary outcomes (e.g., exam-stress paradigms), potentially underpowering anxiety effects and reducing specificity. - Risk of bias was high or unclear in most studies included in the meta-analysis, affecting confidence in observed effects. - Limited number of eligible trials, particularly for prebiotics and for clinical youth populations, constrains generalizability and precision. - Variability in measurement tools (e.g., BAI, STAI, PSWQ; diverse physiological stress markers) complicates interpretation and pooling.