Dai LY, Chen RR, Chen HR, Yin JH, Huang ZX, Yin BW, Liu XY. Potential clinical benefits of probiotics, prebiotics, synbiotics, and postbiotics for depression via the microbiota-gut-brain axis. World J Psychiatry 2025; 15(5): 98436 [DOI: 10.5498/wjp.v15.i5.98436]
Corresponding Author of This Article
Xing-Yan Liu, BMed, Professor, Department of General Psychiatry, Wenzhou Seventh People's Hospital, No. 158 Xueshiqian Road, Panqiao Street, Ouhai District, Wenzhou 325000, Zhejiang Province, China. 13645771028@163.com
Research Domain of This Article
Medicine, Research & Experimental
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Dai LY and Chen RR contribute equally to this study as co-first authors; Dai LY and Chen RR acquisition of data, analysis and interpretation of data, drafting the article, final approval; Chen HR acquisition of data, analysis and interpretation of data, drafting the article, final approval; Yin JH interpretation of data, revising the article, final approval; Yin BW interpretation of data, revising the article, final approval; Liu XY conception and design of the study, critical revision, final approval.
Conflict-of-interest statement: The authors deny any conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xing-Yan Liu, BMed, Professor, Department of General Psychiatry, Wenzhou Seventh People's Hospital, No. 158 Xueshiqian Road, Panqiao Street, Ouhai District, Wenzhou 325000, Zhejiang Province, China. 13645771028@163.com
Received: August 20, 2024 Revised: February 6, 2025 Accepted: April 7, 2025 Published online: May 19, 2025 Processing time: 253 Days and 0.4 Hours
Abstract
BACKGROUND
Depression is a common mental-health disorder worldwide. Several studies have demonstrated the effects of gut microbiota-targeting interventions, such as probiotics, prebiotics, synbiotics, and postbiotics (PPSP), on depression.
AIM
To assess the potential benefits of PPSP on patients diagnosed with depressive disorder.
METHODS
A literature search of the PubMed, Web of Science, and Elsevier Science Direct databases for relevant studies published from database inception to March 2024 was performed. Studies that used a randomized controlled trial design and evaluated differences in depression between PPSP and placebo were included. Depressive symptoms were assessed using a validated scale. Analysis was performed using Review Manager version 5.4 (The Cochrane Collaboration, 2020).
RESULTS
Fourteen studies comprising 906 patients with depressive symptoms were included. PPSP improved depression compared with placebo [SMD: -0.39 (95%CI: -0.60 to -0.17); P < 0.001]. PPSP resulted in significant reductions in Hamilton Depression Rating Scale [MD: -1.72 (95%CI: -2.57 to -0.88); P < 0.001] and Beck Depression Inventory [MD: -2.69 (95%CI: -4.67 to -0.71); P < 0.001] scores. Sub-analysis confirmed the antidepressant effects of probiotics on depressive symptoms [SMD: -0.32 (95%CI: -0.48 to -0.16); P < 0.001], with prebiotics exerting no apparent effect [SMD: -0.08 (95%CI: -0.39 to -0.23); P = 0.62], and synbiotics exerting statistically significant benefits [SMD: -1.09 (95%CI: -1.45 to -0.73); P < 0.001].
CONCLUSION
PPSP effectively alleviates depressive symptoms, and subgroup analysis supports the benefits of probiotics and synbiotics. Nevertheless, evidence supporting the use of PPSP for the treatment of depression remains insufficient.
Core Tip: The present study evaluated the effect of probiotics, prebiotics, synbiotics, and postbiotics (PPSP)-based treatment on depressive symptoms by analyzing data from 14 studies comprising 906 participants. Results indicated that PPSP could significantly improve symptoms in patients with depression compared with placebo, while subgroup analysis confirmed the apparent effects of probiotics and synbiotics in improving depressive symptoms. Larger randomized controlled trials, nevertheless, are required to further explore the benefits of PPSP in treating depression.
Citation: Dai LY, Chen RR, Chen HR, Yin JH, Huang ZX, Yin BW, Liu XY. Potential clinical benefits of probiotics, prebiotics, synbiotics, and postbiotics for depression via the microbiota-gut-brain axis. World J Psychiatry 2025; 15(5): 98436
Depression, a complex neuropsychiatric condition caused by various external and internal factors, has become a leading cause of disability related to mental health problems, posing a global mental health challenge[1]. The lifetime risk for depression is estimated to be approximately 15%-18%, which means that nearly one in five individuals experience an episode at some point in their lifetime[2]. The overall 12-month incidence of depression worldwide is approximately 6%[2]. Depression is a lifelong illness with a high probability of recurrence, with almost 80% of patients experiencing ≥ 1 episode(s) in their lifetime[3,4]. The frequency of recurrence increases with each episode, and the prognosis worsens with an older age of onset[2].
Although currently available pharmacological and psychosocial interventions are effective in treating depression, these methods have some limitations, including delayed onset of action, potential side effects, and the need for multiple medications[5]. As such, there is an urgent need to develop new, targeted interventions for patients diagnosed with refractory depression. Recently, investigators have explored interventions targeting the gut microbiota, which acts through the gut-brain axis to regulate the secretion of neuromodulators closely associated with the modulation of mood and psychological function[6]. Probiotics are living microorganisms that confer health benefits when administered in sufficient amounts[7]. Prebiotics are substrates that promote the proliferation of health-promoting bacteria[8]. Several studies have demonstrated that prebiotics have effective antidepressant effects, acceptable safety, and ease of industrialization and storage, making them promising candidates for probiotic alternatives or in combination with probiotics[8,9]. Synbiotics, defined as a combination of probiotics and prebiotics, have also been shown to improve mental health[10]. Postbiotics, defined as heat-killed probiotics, paraprobiotics, and metabiotics, are the byproducts of prebiotics by probiotics[11,12]. Recent studies have indicated the involvement of postbiotics in the regulation of the brain[11].
As such, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) may represent a new strategy for the treatment of psychiatric disorders through the gut–brain axis; compared with traditional pharmacological treatments, PPSP may yield unique advantages in terms of efficacy, safety, and other measurable outcomes, making in-depth research of significant importance[13].
Although many clinical studies have demonstrated the effects of PPSP in patients with depression, studies reporting the effects of PPSP in small sample sizes do not provide strong evidence, and data from randomized controlled trials (RCTs) are scarce and unconvincing. Therefore, it is necessary to pool independent clinical trials to improve the precision and confidence levels of the findings. Accordingly, we conducted an updated meta-analysis to assess the potential effects of PPSP on depressive disorders.
MATERIALS AND METHODS
Search strategy and study selection
A literature search of the PubMed, Web of Science, and Elsevier Science Direct databases for relevant studies published from database inception to April 2024 was performed. Search terms included “probiotics”, “prebiotics”, “synbiotics”, “postbiotics”, “heat-killed probiotics”, “paraprobiotics”, “metabiotics”, “depression”, “microbiota”, and “microbiome”. The same search strategy was applied to all databases. In addition, the reference lists of the retrieved studies were manually screened to identify other, potentially eligible studies that were not captured in the databases.
Inclusion and exclusion criteria
The inclusion criteria were based on the “PICOS” principle, as follows: Population, patients with depressive symptoms; intervention, probiotics, prebiotics, synbiotics, postbiotics, heat-killed probiotics, paraprobiotics, or metabiotics; comparator, comparative studies investigating PPSP and placebo; outcome, results assessed using validated rating scales for depression; and study design, RCT.
Duplicate studies, investigations with incomplete data, and reviews, case reports, and conference abstracts were excluded.
Data extraction
The following data were extracted from the included studies: Clinical trial characteristics, including first author, publication year, country, study design, intervention and comparator group details, intervention duration, and trial number; patient characteristics, including diagnostic criteria, sample size, age, and sex; and endpoints and depressive symptoms measured using validated rating scales.
Quality assessment
Two independent reviewers evaluated the risk of bias in the included studies using the Cochrane Collaboration’s Risk-of-Bias tool. Assessment of overall bias involved seven domains: Randomization process; allocation concealment; blinding of participants; outcome measurements; missing outcome data; selection of reported results; and other biases. All the domains were assessed as having a low, unclear, or high risk of bias.
Statistical analysis
Data transformation, as described in the Cochrane Handbook for Systematic Reviews of Interventions, was performed to make the data usable for analysis. To overcome the unit of analysis error in single studies with two interventions, the sample sizes of the control group were halved, and the mean and standard deviation were unchanged. Pooled results were calculated as MD or SMD with corresponding 95%CI for each outcome. Heterogeneity was examined using the I2 statistic. If studies indicated statistical homogeneity (P > 0.1, I2 < 50%), a fixed-effects model was used; otherwise, a random-effects model was used. Subgroup analysis was performed to assess the heterogeneity and factors influencing the outcomes. Funnel plots were used to detect potential publication bias. Sensitivity analysis was performed to examine the robustness of the results. Analysis was performed using Review Manager version 5.4 (The Cochrane Collaboration, 2020). Differences with P < 0.05 were considered to be statistically significant.
RESULTS
Study selection and characteristics
A flow diagram illustrating the literature search process is presented in Figure 1. After removing duplicate and ineligible studies, 14 studies[14-27] comprising 906 patients were ultimately included. The intervention and placebo groups consisted of 507 and 399 patients, respectively. The assessment scales for depression symptoms varied across studies and included the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI). Characteristics of the included trials and patients are summarized in Table 1.
The effects of PPSP on depression were analyzed in 14 studies comprising 906 patients with depressive symptoms. Results of analysis revealed significant improvement in depression scores in PPSP-treated patients compared with placebo [SMD: -0.39 (95%CI: -0.60 to -0.17); P < 0.001; Figure 2A], supporting the effectiveness of PPSP. However, the I2 statistic suggested slightly high heterogeneity among the included studies (I2 = 59%, P < 0.001). Significant heterogeneity was observed (I2 = 59%); accordingly, a sensitivity analysis was performed by removing each study “one-at-a-time” and re-analyzing the remaining studies, which did not alter the direction of the effect. Analyses based on different rating scales also indicated that PPSP was more effective than placebo in alleviating depressive symptoms [HDRS, MD: -1.72 (95%CI: -2.57 to -0.88), P < 0.001 (Figure 2B); BDI: MD -2.69 (95%CI: -4.67 to -0.71), P < 0.001 (Figure 2C)]. There was significant heterogeneity in studies using the HDRS (I2 = 50%, P = 0.05) but not in those using the BDI (I2 = 0%, P = 0.94).
Figure 2 Forest plot of the pooled effect of probiotics, prebiotics, synbiotics, and postbiotics on depression symptoms.
A: Overall effect of probiotics, prebiotics, synbiotics, and postbiotics (PPSP); B: Effect of PPSP based on Hamilton Depression Rating Scale; C: Effect of PPSP based on Beck Depression Inventory. PPSP: Probiotics, prebiotics, synbiotics, and postbiotics.
Subgroup analysis of different gut microbiota-targeting interventions
A subgroup analysis was used to evaluate the effects of different interventions on the outcomes. Results of the subgroup analyses of probiotics, prebiotics, and synbiotics are reported in Figure 3. Eleven studies compared probiotics with a placebo, with pooled results suggesting that probiotics were effective in improving depressive disorders [SMD: -0.32 (95%CI: - 0.48 to -0.16); P < 0.01]. No significant heterogeneity was observed in the probiotic subgroup (I2 = 36%, P = 0.11). However, for the three studies reporting prebiotic intervention, there was no significant reduction in depressive symptoms [SMD: -0.08 (95%CI: -0.39 to 0.23); P = 0.62] or apparent heterogeneity (I2 = 0%, P = 0.92). For intervention with synbiotics, in three studies, there was a significant reduction in depressive symptom scores compared with the placebo group [SMD: -1.09 (95%CI: -1.45 to 0.73); P < 0.001], with nonsignificant heterogeneity (I2 = 48%, P = 0.14). Subgroup analysis for postbiotics was not performed because only 1 study compared postbiotics with placebo. Heterogeneity among the 3 groups was significant (I2 = 89.5%, P < 0.001).
Figure 3 Forest plot of sub-analysis of different gut microbiota-targeting interventions.
Risk of bias and sensitivity analysis
Results of the risk-of-bias analysis are presented in Figure 4. Most studies had a low risk of bias in their approach to measurements in multiple domains. Funnel plots for publication bias assessment are presented in Figure 5. Results revealed no significant publication bias because the included studies were symmetrically distributed. In the sensitivity analysis, no single study had a significant effect on the overall results.
Figure 5 Funnel plot for publication bias.
A: Overall effect of probiotics, prebiotics, synbiotics, and postbiotics (PPSP); B: Effect of PPSP based on Hamilton Depression Rating Scale; C: Effect of PPSP based on Beck Depression Inventory.
DISCUSSION
Results of the present meta-analysis suggested that the PPSP intervention had a significant antidepressant effect compared with placebo in patients diagnosed with depression. Although significant improvement in depressive symptoms was confirmed only with probiotics and synbiotics in the subgroup analysis, the potential benefits of PPSP in the treatment of depression are promising, although further studies are required to confirm these results.
The gut-brain axis is a bidirectional communication system that connects the enteric and central nervous systems[28]. The gut microbiota comprises a variety of microorganisms residing in the gastrointestinal tract, including bacteria, archaea, protists, and fungi[29]. These gut microorganisms synthesize various products, such as neurotransmitters, lactate, bile acids, choline, and vitamins, which may affect depressive behavior through multiple signaling pathways[30]. Accumulating clinical evidence has shown that the gut microbiota has a substantial and far-reaching impact on the gut–brain axis[6]. In the past decade, most clinical trials have suggested the beneficial effect of probiotics in the treatment of depression and anxiety[31]. A recent meta-analysis concluded that patients with mild to moderate depression could benefit from prebiotic, probiotic, and synbiotic treatments[32]. In terms of postbiotics, Lactobacillus gasseri CP2305 intake alleviated anxiety and depressive symptoms compared with placebo, as assessed according to the Hospital Anxiety and Depression Scale questionnaire[25]. Moreover, Lactobacillus paracasei MCC1849 has been demonstrated to have the potential to support a desirable mood state under stressful conditions[33].
The present study was an updated meta-analysis of the effects of PPSP on depressive symptoms using data from 14 studies comprising 906 participants. Compared with placebo, the PPSP intervention yielded significant improvement in depression, with a significant reduction in HDRS and BDI scores. Subgroup analysis confirmed the significant antidepressant effects of probiotics and synbiotics on depression; however, this effect was not demonstrated for prebiotics. The effects of postbiotics could not be assessed due to insufficient data for a proper sub-analysis.
Future research should investigate specific mechanisms of action within the microbiota-gut-brain axis. Understanding the biochemical pathways through which gut microbiota-derived metabolites influence neurotransmitter synthesis and signaling could help elucidate their antidepressant properties. For example, research could investigate how short-chain fatty acids, produced by the fermentation of dietary fibers by gut bacteria, modulate neuroinflammatory responses and affect mood regulation. Additionally, studies should focus on specific subpopulations, such as individuals with treatment-resistant depression or distinct age cohorts, to assess the differential efficacy of PPSP interventions across diverse demographic groups.
Despite these promising results, the present analysis study had some limitations, the first of which was the relatively small number and sample sizes of the included studies, particularly those evaluating prebiotics, synbiotics, or postbiotics, which may have influenced the generalizability of the results. Second, different microbiomes, interventions, durations, assessment times, and outcome measurements across studies may have affected the results. Third, the number of patients in the placebo groups of studies that involved two interventions was halved to accomplish a pooled analysis, which may not have completely overcome the unit of analysis error. As such, more precise and larger studies are required to confirm the evidence supporting PPSP treatment.
CONCLUSION
The present study provided evidence that PPSP effectively alleviates depressive symptoms. Therefore, PPSP may be a potential treatment option for patients with depressive symptoms in clinical practice. However, there is insufficient evidence to support the inclusion of PPSP-based interventions in current depression treatment guidelines. Further studies are required to support the potential effects and underlying mechanisms of action of PPSP to inform the development of interventions targeting the gut microbiota.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C, Grade C
Novelty: Grade C, Grade C
Creativity or Innovation: Grade B, Grade C
Scientific Significance: Grade B, Grade C
P-Reviewer: Liu X S-Editor: Lin C L-Editor: A P-Editor: Yu HG
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