What this is
- This meta-analysis evaluates the impact of probiotics on cognitive and depressive symptoms in patients with depression.
- Seven randomized control trials were analyzed to assess the efficacy of probiotics compared to placebo.
- Findings indicate significant improvements in both cognitive function and depressive symptoms with probiotic supplementation.
Essence
- Probiotic supplementation significantly alleviates cognitive symptoms and depressive symptoms in patients with depression compared to placebo.
Key takeaways
- Probiotics led to a significant reduction in cognitive symptoms (SMD, -0.90; p = 0.01) compared to placebo.
- Depressive symptoms also showed significant improvement with probiotics (SMD, -0.55; p = 0.03) compared to placebo.
Caveats
- High heterogeneity was observed in the studies, indicating variability in results across trials.
- Most included studies had a male-to-female ratio of 0.48:1, limiting generalizability to female populations.
AI simplified
Introduction
Psychiatric illness, especially depression, is becoming a global burden for causes of morbidity in patients, affecting 264 million individuals worldwide, and is known to be one of the major causes of disability in patients (Lam et al. 2014). The estimated lifetime risk of a severe depressive episode in the United States is currently close to 30% (Kessler et al. 2012), and it is estimated that 50% of suicidal events have background of mood disorders such as depression and bipolar disorder (Henriksson et al. 1993). Depressive illnesses can present with cognitive dysfunction, which may last long after the patient experiences symptom remission. Cognitive dysfunction can hinder and limit a patient's functioning in various domains and severely degrade its quality as they are enduring signs of depression (Czerwińska and Pawłowski 2020). In basic neuroscience studies, depression‐like behaviors and chronic stress have been linked to deficits in neuroplasticity, including synapse loss and neuronal atrophy in the hippocampus and medial prefrontal cortex (mPFC). As a multidomain neurobiological, cognitive, and psychological construct, neuroplasticity is relevant to depression and other disorders associated with negative affect, such as anxiety (Price and Duman 2020). Notably, a possible premorbid sign of depression is a decrease in verbal episodic memory. Ironically, in the context of contemporary therapeutic techniques, cognitive disorders are often ignored, despite their tremendous impact on daily functioning (Sousa et al. 2021).
The effectiveness of conventional major depressive disorder (MDD) treatments, which include psychotherapy and antidepressant drugs (7), in improving depression‐related cognitive impairment has been shown to be quite effective (Tiller 2013). However, there remains a need to develop novel and more effective treatment approaches that may simultaneously address both the emotional and cognitive aspects of depression at the same time. In this context, probiotics have emerged as viable intervention options (Liu et al. 2023). Studies have shown that probiotics can be a potential treatment for alleviating cognitive and depressive symptoms in patients with mild to severe forms of depression (Kim et al. 2021).
A peculiar group of probiotics known as psychobiotics impact immunological, humoral, neurological, and metabolic networks that regulate the gut–brain axis (GBA) and related behaviors and functions of the central nervous system (CNS) to enhance not just gastrointestinal (GI) function but also the ability to function as an antidepressant and anxiolytic (Jha et al. 2023).
Research on animals and rodents has demonstrated that the gut microbiota interacts with the host through immunological, neuroendocrine, and neurological pathways. These pathways are components of the brain–gut–microbiota axis, and preclinical studies have suggested that the microbiota uses this two‐way communication system to regulate behavior, brain development, and function (Kelly et al. 2016).
The objective of this meta‐analysis and systematic review was to thoroughly assess the impact of probiotic supplementation on cognition and associated brain functions in individuals with depression which was based on the evidence from the newer studies and provides the latest insight on this topic. We also aimed to evaluate the impact of probiotics on symptoms and indicators of depression in this population. This review offers a thorough and evidence‐based analysis of the possible advantages and restrictions of probiotic therapies for depression by synthesizing data from current clinical trials.
Methods
This review followed the PRISMA 2020 reporting guidelines (Page et al. 2021). Additionally, this review was registered on PROSPERO (CRD42024543034). No deviations from the registered protocol occurred.
Eligibility Criteria
This meta‐analysis examined only randomized control trials (RCTs) to evaluate the effect of probiotic supplementation on cognition and depressive symptoms in patients with depression. The inclusion criteria were as follows: (1) Participants with either a definite diagnosis of depression or any other psychiatric disorder with available data for the depression subgroup. (2) Studies should evaluate cognitive parameters such as memory, executive functionality, emotional process, and depression in patients. (3) A wide range of probiotics were identified in the search strategy, and all those affecting cognition and related brain functions were included. RCTs were excluded on the basis of the following criteria: (1) Observational studies, case reports, and all types of non‐randomized studies were excluded because of their potential for bias. (2) Studies conducted on species other than humans, and all in vitro studies were excluded. (3) Randomized trials that did not correspond to our PICOS framework were excluded.
Search Strategy and Data Sources
The search was conducted for randomized controlled trials published in 2023. Only studies published in English were included. A systematic protocol for the database search was developed to ensure a thorough review of the relevant literature. The search spanned databases such as PubMed, Google Scholar, and Embase. The search strategy was based on the use of Boolean operators (AND, OR) in conjunction with Medical Subject Headings keywords and free text terms. Tableshows the search string that was applied on PubMed. The goal of combining these terms was to find studies that focused on probiotics, depression, and cognition. First, we started with titles and abstracts of the compiled data to identify studies of potential relevance. A rigorous analysis of the full texts of the selected publications was then undertaken. This analysis was conducted independently by two researchers to determine their eligibility for inclusion in the meta‐analysis. In instances where disparities emerged, deliberations with a third researcher were conducted to achieve a consensus (Table). S1 S1
Risk of Bias Assessment
Two selected researchers carefully evaluated the potential bias in randomized studies using the Cochrane Collaboration technique. This method was used to conduct an official evaluation of the quality of the chosen studies. The examination of bias included elements such as outcome blinding, accessibility of outcome data, exclusive reporting of outcomes in some circumstances, and the discovery of any other sources of bias. Studies were divided into three categories by evaluation: low risk of bias, high risk of bias, and unclear risk of bias because of incomplete data. When studies with a score higher than 1 were designated as "high risk," a sensitivity analysis was also conducted to ensure the robustness of the findings. To address the possibility of publication bias, visual depiction using a funnel plot was employed. This comprehensive approach ensures meticulous evaluation of study quality and potential biases, leading to trustworthy and unbiased results (Figure 1).
Risk of bias summary via traffic lights: review authors' judgments about each risk of bias item for each included study.
Data Extraction
We gathered the baseline information, information related to intervention, patient number, and continuous data from the chosen RCT. Information on the evaluated cognitive parameters and the influence of probiotics on cognition was collected. This encompassed specifics of any noted alterations in cognitive performance, such as enhancements in memory, attention, and emotional processing. Data regarding the effects of probiotic supplementation on depression and depressive symptoms were compiled, including changes in depression scores and symptom severity. The overall conclusions or deductions made by each study regarding the correlation between probiotic supplementation, cognition, and depression were recorded.
Statistical Analysis
RevMan (Review Manager Version 5) was used to evaluate the data in this meta‐analysis. For every statistical analysis, a random‐effects model was used. The main aim of this study was to evaluate the effectiveness of probiotics in promoting favorable cognitive and behavioral changes related to depressive symptoms and signs in participants of the chosen clinical trials using quantitative methods. For cognitive and depressive symptom outcomes, we determined the mean difference (MD) and standard deviation (SD) values from each individual trial that was part of the review. These MD values were then input into RevMan 5. We computed the risk difference (RD) or relative risk (RR) using a 95% confidence interval (CI). We used the MD and 95% CI for continuous data. Statistical significance was set at p < 0.05. To visualize the data and evaluate statistical heterogeneity, we used a forest plot and χ2 and I2 tests (Higgins et al. 2003). If the p value was less than 0.05 or the I2 exceeded 50%, significant heterogeneity was deemed to exist. When there was a lot of variation, we used a leave‐one‐out method to determine where it came from. This methodical approach guarantees the precision of our findings and fosters trust in their interpretation.
Publication Bias
To evaluate the possibility of publication bias in the included studies, we employed the Egger linear regression test. This statistical technique measures the asymmetry of the funnel plot based on the assumption that a lack of bias would result in a symmetrical funnel plot. A significant outcome suggests the presence of potential bias. It is important to note that the effectiveness of this test is limited when the number of studies is less than 10, so the results should be interpreted with care.
Results
Search and Selection Process
This process included a systematic approach to extract relevant studies for inclusion in our meta‐analysis. First, a detailed comprehensive search strategy was advanced involving keywords across multiple databases, including PubMed, Google Scholar, and the Cochrane Library. The initial search strategy gave 1291 results. Titles and abstracts of the recovered studies were screened to evaluate their acceptability according to predefined inclusion and exclusion criteria. After initial screening and removing 1275 irrelevant studies, full‐text articles of 16 conceivable related studies were obtained and further assessed for eligibility. Any disparities and differences in opinions were resolved through discussion and concurrence. Moreover, reference lists of the included studies were also searched manually to identify any significant studies missed during the initial search. Eventually, three reports fulfilling the inclusion criteria were selected, whereas those not meeting the criteria were excluded (13 trials). After merging the new RCTs with the parent meta‐analysis studies, we included a total of seven RCTs in our analysis. The entire search and selection process was supervised according to the PRISMA guidelines to certify pellucidity and transparency in study selection (Figure 2).
PRISMA flow chart of the included studies.
Quality Assessment
We placed a high priority on ensuring a thorough assessment of study quality in all our research initiatives. We have specifically used the Cochrane Table of Risk of Bias for RCTs, as the graphical and tabular presentations are provided in Tableand Figure. S2 S1
Study Characteristics
The detailed characteristics of the studies included in the meta‐analysis can be reviewed in Table 1 which evaluates the effect of probiotics in persuading participants of productive changes in cognition and signs and symptoms of depression. It also encompasses details about the country, design, interventional group, control group, patients' characteristics, and outcomes of the respective study. Our sample size included both males and females with a mean age between 22 and 39 years, covering an extensive range of age distribution. The total number of participants was 402, with a female‐to‐male ratio of 131:271 (0.48:1). This gender difference emphasizes the significance of sex‐related variance in the response of probiotic efficacy in reducing depression. Our study intervention included different multispecies probiotics for separate time periods in all studies, whereas the control group was placebo in all studies.
| Author | Year | Country | Design | Interventional group | Control group | Patients | Outcomes |
|---|---|---|---|---|---|---|---|
| Nikolova et al. () [2023] | 2023 | London, the United Kingdom | RCT | Multistrain probiotic (8 billion colony‐forming units per day) containing 14 strains of,,,,,,subsp. bulgaricus,,,,,,, and(Bio‐Kult Advanced; ADM Protexin)Bacillus subtilisBifidobacterium bifidumBifidobacterium breveBifidobacterium infantisBifidobacterium longumLactobacillus acidophilusLactobacillus delbrueckiiLactobacillus caseiLactobacillus plantarumLactobacillus rhamnosusLactobacillus helveticusLactobacillus salivariusLactococcus lactisStreptococcus thermophilus | Placebo daily for 8 weeks | Adults aged 18–55 years with MDD taking antidepressant medication but having an incomplete response were studied | Probiotic group received greater improvements in depressive (HAMD‐17 scores) and anxiety (Hama scores) symptoms compared to placebo |
| Zhu et al. () [2023] | 2023 | China | RCT | JYLP‐326 twice per day for 3 weeksLactobacillus plantarum | Placebo (maltodextrin) twice per day for 3 weeks | Sixty anxious students were enrolled and randomly allocated to the placebo group and the probiotic group and thirty unanxious students with no treatments were assigned to a regular control group | jylp‐326 reduced anxiety, depression, and insomnia symptoms in test‐anxious college studentsLactobacillus plantarumPlacebo group showed higher gut microbiota, whereas jylp‐326 partly restored itPlacebo group had increasedandbut decreasedand, partially reversed by jylp‐326. Test anxiety correlated with altered fecal metabolites, which jylp‐326 assisted normalize. Changes in gut microbiota and fecal metabolites were related to anxiety symptoms, indicating a potential mechanism for the interventional group effectivenessBacteroidesRoseburiaPrevotellaBifidobacterium |
| Gawlik‐Kotelnicka et al. () [2023] | 2023 | Poland | RCT | Participants received a probiotic preparation containingRosell‐52 andRosell‐175 over 60 daysLactobacillus helveticusBifidobacterium longum | Placebo consumed one daily | Sixty adult patients with depressive disorders were included in the study | The maintenance proportion within the probiotic vs. Placebo was 78.8% vs. 81.5%, with comparative dropout reasons. Adherence was full among all members, with no genuine side effects. For instance, minor antagonistic impacts like diarrhea were detailed more within the probiotic group. The statistical investigation included 44 members for psychometric scales, 46 for metabolic parameters, and 43 for inflammation markers. Baseline characteristics were the same and certifying study comparability. Metabolic and psychometric appraisals appeared potential change with probiotic mediation |
| Baião et al. () [2023] | 2022 | The United Kingdom | RCT | Multispecies probiotics (,,,,,,ssp. bulgaricus,PXN,,,,,ssp. lactis,PXN) given for 4 weeksBacillus subtilisBifidobacterium bifidumBifidobacterium breveBifidobacterium infantisBifidobacterium longumLactobacillus acidophilusLactobacillus delbrueckiiLactobacillus caseiLactobacillus plantarumLactobacillus rhamnosusLactobacillus helveticusLactobacillus salivariusLactococcus lactisStreptococcus thermophilus | Placebo | 71 depressed patients were included | Probiotic intake improved emotional processing a little bit and reduced depression and affect specific cognitive changes positively |
| Chahwan et al. () [2019] | 2019 | Australia | RCT | Probiotic group, were provided two sachets for each day of the trial, containing 2 g of freeze‐dried probiotic powder mixture (,,,,,,, and)Bifidobacterium bifidumBifidobacterium lactisLactobacillus acidophilusLactobacillus brevisLactobacillus caseiLactobacillus salivariusLactococcus lactisLactococcus | Placebo | 71 patients with depressive symptoms were recruited and allocated sequentially over 12 months | Probiotic intake reduced cognitive irritability and improved depressive symptoms to some extent. Although it did not significantly change gut microbiota, it affects a psychological variable related to depression |
| Rudzki et al. () [2019] | 2019 | Poland | RCT | SSRI with the probiotic299v (LP299v) ( = 40) for a period of 8 weeksLactobacillus plantarumn | SSRI with the placebo of the probiotic ( = 39) for 8 weeksn | 79 patients with MDD were randomized and allocated to a double‐blind, placebo‐controlled trial | Improved attention and verbal memory (apt and cvlt) in lp299v group; decreased kynurenine (kyn) concentration; increased 3hkyn: kyn ratio; interaction for anthranilic acid (aa) concentration; no significant change in TNF‐α, IL‐6, IL‐1b, and cortisol concentrations. Improvement in cognitive functions; biochemical changes related to depression; no significant change in proinflammatory cytokines and cortisol. Overall, lp299v supplementation might have enhanced cognitive functions and modulated biochemical parameters related to depression without affecting proinflammatory markers |
| Schneider et al. () [2023] | 2023 | Switzerland | RCT | A probiotic supplement (,NCIMB 30441,,,,,, andsubsp and Thermophilus) was administered over 31 days in addition to treatment as usual for depressionStreptococcus thermophilusBifidobacterium breveBifidobacterium lactisBifidobacterium infantisLactobacillus acidophilusLactobacillus plantarumLacticaseibacillus. paracaseiLactobacillus delbrueckii | Indistinguishable placebo containing maltose was administered over 31 days in addition to treatment as usual for depression | Sixty patients with MDD, of whom 43 entered modified intention‐to‐treat analysis | Improved immediate recall in verbal learning memory test (vlmt) in probiotic group; time × group interaction in hippocampus activation during working memory processing. Improvement in verbal episodic memory; remediated hippocampus function. Overall, probiotic supplementation with various strains enhanced verbal episodic memory and affected neural mechanisms underlying impaired cognition in MDD |
Outcomes
According to the defined PICO criteria, the outcomes of our study were the effect of probiotics on persuading productive changes in cognitive status and reduction in depressive signs and symptoms in the selected participants.
Effect of Probiotics and Productive Changes in Cognitive Status
During the meta‐analysis of our study, we analyzed four out of seven studies to assess the changes in cognitive status of individuals (Baião et al. 2023; Chahwan et al. 2019; Rudzki et al. 2019; Schneider et al. 2023). Our analysis results show that the study by Baião et al. delineated an MD of −1.23, with 95% CI of (−1.83, −0.62), favoring the probiotic group in improving cognitive function with a statistically significant CI. Chahwan et al. delineated an MD of −0.38, with a 95% CI of (−0.85, 0.09), favoring the probiotic group in improving cognitive function, but without statistical significance. Rudzki et al. delineated an MD of −0.26, with a 95% CI of (−0.81, 0.29), again favoring the probiotic group in improving cognitive function, but without statistical significance. Schneider et al. delineated an MD of −1.89, with 95% CI of (−2.62, −1.16) showing a significant improvement in cognitive functions in the probiotic group. The overall pooled effect of the four studies showed an MD of −0.90, with a 95% CI of (−1.59, −0.21), delineating the moderate improvement of cognitive function in participants assigned to the probiotic group. However, the most important result is that the overall pooled effect was statistically significant, as proved by the Z value of 2.56 (p = 0.01), explaining that the improvement in cognitive function in the probiotic group is of great significance. Additionally, a heterogeneity test was performed, which refers to the variation in study outcomes between studies (Chi2 = 17.05, degrees of freedom [df] = 3, p = 0.0007), indicating high heterogeneity (I2 = 82%). However, for high heterogeneity, a sensitivity analysis was performed to assess the risk of bias using the leave‐one‐out method. Figure 3 demonstrates the forest plot that explains the MD and its 95% CI regarding the effect of probiotics on cognitive function.
Forest plot of the effect of probiotics in improving cognitive function in the selected participants of the individual study.
Effect of Probiotics and Reduction in Depressive Signs and Symptoms
Six studies were included in the analysis, which predicts reduction in depressive signs and symptoms in probiotic group compared to placebo (Chahwan et al. 2019; Gawlik‐Kotelnicka et al. 2023; Nikolova et al. 2023; Rudzki et al. 2019; Schneider et al. 2023; Zhu et al. 2023). Interpreting the data obtained from six studies, the study by Chahwan et al. (2019) indicated an MD of −0.20, with a 95% CI of (−0.67, 0.26), suggesting a reduction in depressive signs and symptoms in the probiotic group, but with a statistically insignificant CI. Nikolova et al. (2023) reported standard MD of −0.59 with 95% CI of (−1.16, −0.02), advocating reduction in depressive signs and symptoms in probiotic group with statistically significant CI. Rudzki et al. (2019) denoted a standard MD of −0.66, with a 95% CI of (−1.18, −0.14), recommending a minor decrease in depressive signs and symptoms in the probiotic group with statistical significance. Schneider et al. (2023) demonstrated standard MD of −0.09 with 95% CI of (−0.69, 0.52), suggesting insignificant decrease in reducing depressive signs and symptoms comparing both groups. Thuluva et al. (Gawlik‐Kotelnicka et al. 2023) delineated standard MD of −0.01 with 95% CI of (−0.60, 0.58), explaining negligible decrease in depressive symptoms with statistically insignificance. Zhu et al. (2023) displayed standard MD of −1.78 with 95% CI of (−2.38, −1.18), favoring reduction in depressive signs and symptoms in probiotic group with statistically significant CI. The overall effect of pooled analysis is the standard MD of −0.55, with a 95% CI of (−1.04, −0.06), clearly favoring the probiotic group in reducing depressive signs and symptoms in the included participants. More importantly, the overall effect is statistically significant, as manifested by the Z value of 2.18 (p = 0.03), showing that the reduction in depressive signs and symptoms are statistically significant. Moreover, heterogeneity test was also performed, which detects the variation among studies, demonstrating a chi‐squared value of 23.78 with 5 df and p value of 0.0002, showing high heterogeneity (I2 = 79%), indicating statistically significant results but inconsistency between individual studies. Due to high heterogeneity, sensitivity analysis was performed to rule out any risk of bias using the leave‐one‐out method, which significantly drops to low heterogeneity. Figure 4 presents the forest plot, which illustrates the MD and its 95% CI regarding the effect of probiotics on depressive signs and symptoms.
Forest plot of the effect of probiotics in reducing depressive signs and symptoms in the selected participants of the individual study.
Leave One Out of the Analysis and Publication Bias
Effect of Probiotics and Productive Changes in Cognitive Status
The pooled analysis of four studies showed a standard MD of −0.60 (95% CI −1.16, −0.05; Chi2 = 6.38, df = 2, p = 0.04; I2 = 69%). As the heterogeneity was high, a leave‐one‐out analysis was performed, which lowered the heterogeneity from high to moderate with significant results. Schneider et al. (2023) was ruled out as the cause of high heterogeneity. Nevertheless, a small sample size and small number of studies can hinder the validity of the results. Figure 5a illustrates the forest plot of the leave‐one‐out analysis. Funnel plot for effect of probiotics and productive changes in cognitive status as visual depiction of the bias (see Figure S2).
(a) Leave one out the analysis of the effect of probiotics in improving cognitive functions in the selected participants of the individual study. (b) Leave one out the analysis of the effect of probiotics in reducing depressive signs and symptoms in the selected participants of the individual study.
Effect of Probiotics and Reduction in Depressive Signs and Symptoms
The pooled analysis of six studies revealed a standard MD of −0.32, with a 95% CI of (−0.57, −0.07), indicating results of the heterogeneity test as a chi‐squared value of 4.38, with 4 df, p value of 0.36, specifying low heterogeneity I2 = 9%. As described above, heterogeneity was high, which significantly dropped to low. Zhu et al. (2023) was ruled out as the cause of heterogeneity. However, the small size and number of studies can disrupt the certainty of the results. Figure 5b shows the forest plot of the leave‐one‐out analysis. Funnel plot for effect of probiotics and reduction in depressive signs and symptoms, as visual depiction of the bias (See Figure S3).
Discussion
Our meta‐analysis is an enhancement of the study titled "Effect of probiotic supplementation on cognition and depressive symptoms in patients with depression" (He et al. 2023) that was published in 2023. The primary objective of our analysis was to delve deeper into the impact of probiotics on depression and various cognitive aspects, such as memory, executive functionality, and emotional processing.
In our study (Nikolova et al. 2023; Zhu et al. 2023), we observed a marked improvement in the signs and symptoms of depression in the intervention group. Similarly, probiotics also appeared to aid cognitive functions, such as face recognition (Rudzki et al. 2019; Schneider et al. 2023), in the intervention group.
Several theories explain how probiotics could potentially alleviate depressive symptoms. One of the key hypotheses is that probiotics aid in reducing inflammation, which in turn brings about positive changes in the gut–brain connection. This helps maintain emotional well‐being and alleviate depressive symptoms (Schneider et al. 2023). Some studies have shown that changes in the gut microbiota brought about by probiotics are helpful in alleviating depression. Antibiotics, which also affect the gut microbiota, have been observed to exacerbate depression in some patients, supporting the relationship between gut biota, neurotransmitters, and ultimately, depression (Xu et al. 2023). Cognition, the second outcome addressed in our meta‐analysis, was also found to be positively affected in patients on probiotics versus those in the control group (Xiang et al. 2022). It has been found that probiotics, which bring about changes in the gut microbiota, decrease the concentration of kynurenine in plasma, thereby helping improve cognitive functions (Handajani et al. 2023; Rudzki et al. 2019). The impact of probiotics on the intestinal barrier and permeability, along with a decrease in intestinal translocation (Zareie et al. 2006), modulation of indoleamine activity, and reduction in inflammation, all contribute to a decrease in kynurenine concentration (Ağagündüz et al. 2023; Rudzki et al. 2019).
Furthermore, the hippocampus, which is a crucial structure for depression‐related cognitive decline, is strongly associated with gut microbiota. This association influences hippocampus‐dependent learning, behavior, and memory, making it a significant point of discussion when establishing a relationship between cognitive function and probiotics (Salami and Soheili 2022). Probiotics are said to enhance learning and memory by raising butyrate, which raises BDNF and lowers the levels of proinflammatory cytokines in the hippocampal regions (Romo‐Araiza et al. 2018).
Our meta‐analysis builds on previous research and provides further evidence supporting the potential benefits of probiotics in managing depression and improving cognitive function. However, further research is needed to fully understand the mechanisms involved and determine the most effective types and doses of probiotics for these purposes.
In essence, our meta‐analysis contributes to a growing body of evidence that favors the use of probiotics in clinical practice when dealing with depression and cognitive function. If further research is carried out, it can be helpful, especially in treating patients suffering from mild and moderate intensities of depression and having new onset of symptoms. Patients suffering from depression have postdepression cognitive decline that includes decreases in concentration, learning, memory, and executive functionality that add to the misery they are going through (Roberts et al. 2022). Using probiotics has been shown to be advantageous for these patients and can potentially help them recover swiftly. We think that adding probiotics to treat these two conditions can open new doors to look into the GBA and potentially assist us to understand in more detail the cause of disease and give us a new treatment approach to encounter them. This also allows us to look into the depression symptoms people confront in everyday life, and how just by bringing up a little modification in diet can aid us in raising our mood. However, further research is needed to discover what type of microbiota brings these changes, the dosage and nature of probiotics to be used, and how to monitor their effect when used in the general population.
The efficacy of probiotics has been a significant topic of interest in recent years, with a wealth of research underscoring their potential benefits in the treatment of depression. Studies have consistently shown that probiotics are more effective than prebiotics, leading to notable improvements in depressive symptoms (Liu et al. 2019). Age appears to play a crucial role in the efficacy of probiotics, with positive results observed in individuals under 60 years of age, whereas those over 65 years of age show no significant benefits (Tsai et al. 2023).
Our study echoes these findings, focusing on patients younger than 60 years and highlighting the pronounced effects of probiotics on this age group. It is important to note, however, that some studies have not observed changes in depression severity, which may be attributed to the variety of depression scales used. Our research, utilizing the Depression Anxiety Stress Scales (DASS) and Hamilton Rating Scale, found significant improvements, suggesting that the choice of scale can influence the outcomes. In terms of cognitive function, studies involving patients with Alzheimer's disease and minimal cognitive impairment have shown promising results, aligning with our analysis (Den et al. 2020). However, there are also studies that report no cognitive improvements following probiotic, prebiotic, or fermented food interventions (Marx et al. 2020). This finding indicates the need for more nuanced research to understand the full impact of these interventions on mental health.
In our comprehensive study, we encountered a notable degree of heterogeneity, which we have determined is largely due to the diverse formulations, strains, and dosages of probiotics utilized across different trials. This variability is a critical factor in the interpretation of results. Moreover, inconsistency in the measurement scales, such as the Hamilton Rating Scale of Depression in most studies (Nikolova et al. 2023; Zhu et al. 2023), is used for depression assessment, whereas the DASS scaling system is used with the Beck Depression Index (BDI‐II) and Beck Anxiety Inventory (BAI) (Chahwan et al. 2019) to report outcomes across the studies further compounds this heterogeneity, making it challenging to draw uniform conclusions.
To address this issue methodically, we implemented a "leave‐one‐out" analytical approach. This technique involves sequentially removing one study at a time to assess the impact on overall heterogeneity. Notably, when we excluded the study conducted by Schneider in 2023, we observed a significant reduction in heterogeneity. This suggests that the particular methodology or population used in Schneider's study may differ substantially from the others. Similarly, the removal of Zhu's 2023 study from the analysis also resulted in a marked decrease in heterogeneity levels, especially when examining depressive signs and symptoms within the intervention group. Additionally, the studies involved people from different races and regions and did not consider the comorbidities that patients have and can potentially affect the results.
These findings underscore the complexity of synthesizing data from multiple sources and highlight the importance of standardization methodologies in future research. Refining our approach to account for these variations can enhance the reliability of our meta‐analysis and provide clearer guidance for clinical practice. Because earlier studies were not re‐searched (as they were included in the parent meta‐analysis), some relevant older data may not have been reassessed. Most study participants were male (female‐to‐male ratio 0.48:1), limiting generalizability. Probiotic effects may vary by sex; therefore, the findings must be interpreted with caution. Although subgroup/meta‐regression was considered, the limited number of included studies prevented formal analysis. Through such meticulous scrutiny and adaptation, we can pave the way for more targeted and effective interventions for the treatment of depression and its cognitive manifestations.
Conclusion
In conclusion, research has demonstrated that probiotic supplementation can be a highly effective supplementary treatment for depression by effectively addressing psychological symptoms and cognitive problems. Its therapeutic potential in clinical settings should be explored by additional research to better understand its mechanisms.
Author Contributions
Screening was performed by Shafin Bin Amin and Laksh Kumar. Extraction and analysis were done by Syed Ali Arsal and Aashish Kumar. Muhammad Aniq Amir, Muhammad Abrar Amir, Umer Iqbal, and Suhaib Ahmed wrote manuscript. Editing and compilation were done by Muhammad Ashir Shafique and Oluwatobiloba Israel Popoola. Conceptualization was done by Syed Ali Arsal during the whole process. Supervision and critical thinking were done by Inibehe Ime Okon.
Funding
The authors have nothing to report.
Ethics Statement
The authors have nothing to report.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Transparency Statement
The lead author, Inibehe Ime Okon, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects have been omitted; and that any discrepancies from a study as planned (and, if relevant, registered) have been explained.