Efficacy of probiotics in patients with cognitive impairment: A systematic review and meta-analysis

Miaomiao Ma; Bo Li; Zhi Qu; Shejuan Liu; Sisi Li

doi:10.1371/journal.pone.0321567

. 2025 May 2;20(5):e0321567. doi: 10.1371/journal.pone.0321567

Efficacy of probiotics in patients with cognitive impairment: A systematic review and meta-analysis

Miaomiao Ma ^1,², Bo Li ^1,², Zhi Qu ^1,², Shejuan Liu ^1,^2,^*, Sisi Li ^1,²

Editor: Zohreh Sajadi Hezaveh³

PMCID: PMC12047807 PMID: 40315198

Abstract

Objective

To conduct an in-depth exploration of the specific impacts of probiotics and prebiotic supplements on cognitive impairment, it is imperative to also investigate pertinent factors, including the optimal dosage of probiotics for enhancing cognitive function. This investigation is essential for optimizing probiotic interventions to prevent and treat cognitive decline, aimed at preventing and aiding in the treatment of cognitive decline among patients with cognitive impairment.

Methods

A comprehensive computerized search was conducted across the Embase, PubMed, Web of Science, Cochrane Library, SinoMed, CNKI, Wanfang and WeiPu Data. Studies targeting randomized controlled trials (RCTs) were included. This search covered a timeframe extending from the inception of each database to September 2024. Following an independent process of literature screening, data extraction, and rigorous quality assessment conducted by two investigators, a meta-analysis was performed using Stata 15.0 software.

Results

A total of ten studies, involving 778 patients, were included in the analysis. The meta-analysis revealed that probiotics were effective in enhancing cognitive function among patients with cognitive impairment, with a standardized mean difference (SMD) of 0.52 (95% CI: 0.07, 0.98; P < 0.001). Subgroup analysis further demonstrated that the largest effect size was observed for studies utilizing the Mini-Mental State Examination (MMSE) scale as the outcome measure (SMD = 0.88). Additionally, the greatest efficacy was associated with single-strain probiotics (SMD = 0.81), and interventions lasting ≤12 weeks exhibited the most pronounced effect (SMD = 0.61).

Conclusion

Probiotics have been shown to enhance cognitive function, with a probiotic intervention program featuring a single probiotic strain and a duration of ≤12 weeks demonstrating particularly robust efficacy in improving cognitive function, as assessed by the MMSE scale.

Introduction

Cognitive impairment is a condition characterized by diminished brain function, resulting from a variety of etiologies. It is typically manifested by declines or deficits in cognitive abilities, including memory loss, language impairment, visuospatial dysfunction, reduced executive functioning, and impaired comprehension. It primarily encompasses mild cognitive impairment (MCI) and dementia [1]. As the global population ages, the incidence of cognitive impairment among the elderly is progressively rising [2]. According to WHO statistics from 2021, the number of individuals worldwide suffering from cognitive disorders has surpassed 55 million. Some studies predict that this figure will climb to 78 million by 2030 and reach 152.8 million by 2050 [3,4]. In China, cognitive impairment has emerged as a pivotal public health concern [5]. Estimates indicate that the proportion of individuals aged 60 and above with cognitive impairment in China increased from 13.26% in 2010 to 18.70% in 2020 [6]. By 2030, the number of dementia patients in China is projected to exceed 16 million. Dementia ranks as the fourth most significant health threat to the elderly, following cardiovascular, cerebrovascular, and neoplastic diseases [7]. As dementia patients often experience disability and dependence, it imposes substantial economic burdens on families and society [8]. In 2018, it was reported to have caused approximately $1 trillion in global economic losses [9]. If unaddressed, dementia poses a substantial obstacle to social and economic development.

Given the gradual progression of cognitive impairment, identifying and developing interventions targeted at early stages of cognitive decline is of utmost importance [10]. Over the past decade, numerous randomized controlled trials (RCTs) have highlighted the potential beneficial effects of dietary interventions in AD, particularly emphasizing the role of probiotic and prebiotic supplements in slowing the progression of AD [11,12]. Modulating the gut-brain axis has emerged as a novel therapeutic strategy for neurodegenerative disorders, including AD [13]. As our understanding of gut microbiota alterations in AD patients deepens, research is increasingly directed towards more precise “gut microbiota-directed” interventions aimed at managing the progression of AD.

According to the consensus definition established by the International Society for the International Scientific Association for Probiotics and Prebiotics (ISAPP), probiotics are defined as “live microorganisms that, when taken in sufficient amounts, provide health benefits to the host.” [14], whereas prebiotics are described as “substrates that are selectively utilized by host microorganisms in the gut to confer a health benefit” [15]. In addition, synbiotics are defined as a mixture of live microorganisms and substrates that selectively stimulate the growth and/or activity of one or a limited number of microorganisms in the gut. They primarily affect the production of neurotransmitters and promote brain health by regulating the gut microbiota and its metabolites [16]. Given their capacity to modulate the structure and composition of the intestinal microbiota and elicit health benefits, probiotics and prebiotic supplements present novel approaches for the prevention or treatment of certain diseases. Indeed, several representative studies have provided compelling evidence supporting the neuroprotective effects of probiotics and prebiotics in neurological disorders [17–19].

With a surge in research interest, numerous reviews have delved into the therapeutic impacts of probiotic supplementation on neurological disorders, including AD. Notably, these include one systematic review [20] and four meta-analyses [21–24]. While these reviews offer a comprehensive overview of the early literature and provide valuable insights for guiding clinical trials, they are not devoid of limitations. For instance, discrepancies exist among the meta-analysis findings: one study reported no enhancement in cognitive function with probiotics [22], whereas the other three demonstrated improvements in cognitive function post-probiotic treatment [21,23,24]. Unassessed publication bias and high between-group heterogeneity may lead to discrepancies with the results of other studies. Importantly, these meta-analyses solely encompassed studies on the benefits of probiotics and prebiotics published prior to 2021. To update the evidence base, we incorporated data from recently published studies [25–28]. Publication bias was also assessed, and sensitivity analyses were performed to improve the reliability of the results. Furthermore, two of the four meta-analyses [21,23] included only a single study and combined MCI and AD as a singular outcome in their quantitative analyses, potentially leading to biased results. The meta-analysis by Krüger J et al. [22], which encompassed only three studies, did not assess for publication bias, which could be a contributing factor to inter-study heterogeneity. González C et al. [23] did not conduct subgroup analyses despite observing high intergroup heterogeneity in their meta-analysis. Additionally, Lv et al. [29] found that probiotics may be more efficacious in enhancing cognitive function in cognitively impaired individuals compared to healthy individuals, but the study did not explore the potential influence of other pertinent factors, such as dosage.

To address these limitations, we conducted a systematic evaluation and meta-analysis of recently published clinical trials, aiming to provide a deeper understanding of the specific effects of probiotics versus prebiotic supplements on cognitive impairment. We also explored other pertinent factors, such as the optimal dosage of probiotics for improving cognitive function, to better develop a suitable probiotic intervention program for clinical use in the prevention and adjunctive treatment of cognitive impairment in patients.

Materials and methods

Study design

This systematic evaluation and meta-analysis adhered to the rigorous guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Inclusion and exclusion criteria

The inclusion criteria for this systematic review were established according to the PICOS framework (Population, Intervention, Comparison, Outcomes, Study design), as detailed in Table 1. Specifically, the inclusion criteria encompassed:①Study Design: Randomized controlled trials (RCTs) were considered;②Population: Participants had to exhibit cognitive impairment;③Intervention: The intervention group received probiotics, whereas the control group underwent a placebo intervention;④Outcome Measures: Primary focus was on cognitive function. The exclusion criteria were as follows:①Duplicate Literature: Articles that were identical to others in the review were excluded;②Language Restriction: Only Chinese and English language publications were included;③Data Accessibility and Quality: Studies that were unavailable in full text, had ambiguous, incomplete, or unconvertible data, or those that could not be merged with other studies were excluded;④Quality Assessment: Studies rated as grade C in the quality evaluation were not included.

Table 1. Inclusion criteria for PICOS studies.

Parameter	Inclusion criteria
Participants	Human studies
Interventions	Probiotics (MeSH+free terms)
Comparisons	Consistent with an experimental group without any probiotic supplementation (including free-text words)
Outcomes	cognitive function
Study design	Randomized controlled trial

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Notes: MeSH, Medical Subject Headings.

Search strategy

A comprehensive computerized literature search was conducted across Web of Science, Embase, Pubmed, the Cochrane Library, CNKI, WeiPu Database, Wanfang Database, and SinoMed. The search strategy employed a combination of subject headings (Mesh terms) and free-text terms, covering a timeframe from inception to September 2024. For instance, in Web of Science, the search query was structured as follows: Cognitive Dysfunction (Topic) OR Cognitive Dysfunctions (Topic) OR Dysfunction, Cognitive (Topic) OR Dysfunctions, Cognitive (Topic) OR Cognitive Impairments (Topic) OR Cognitive Impairment (Topic) OR Impairment, Cognitive (Topic) OR Impairments, Cognitive (Topic) OR Cognitive Disorder (Topic) OR Cognitive Disorders (Topic) OR Disorder, Cognitive (Topic) OR Disorders, Cognitive (Topic) OR Mild Cognitive Impairment (Topic) OR Cognitive Impairment, Mild (Topic) OR Cognitive Impairments, Mild (Topic) OR Impairment, Mild Cognitive (Topic) OR Impairments, Mild Cognitive (Topic) OR Mild Cognitive Impairments (Topic) OR Cognitive Decline (Topic) OR Cognitive Declines (Topic) OR Decline, Cognitive (Topic) OR Declines, Cognitive (Topic) OR Mental Deterioration (Topic) OR Deterioration, Mental (Topic) OR Deteriorations, Mental (Topic) OR Mental Deteriorations (Topic) and Probiotics (Topic) OR Probiotic (Topic) and ((((TS=(randomized controlled trial)) OR TS=(randomized)) OR TS=(placebo)) OR TS=(randomised)) OR TS=(random).

Literature screening and data extraction

Two independent researchers meticulously screened the literature based on predefined inclusion and exclusion criteria, utilizing EndNote software to eliminate duplicates efficiently. In instances where disagreement arose during the screening process, a third researcher was consulted to engage in a collaborative discussion, ultimately determining the consensus on the final screening outcomes. When necessary, authors were reached out to procure crucial data that was integral to the analysis. The extracted literature encompassed the following data points:①Basic Bibliographic Information: This included details such as the authors’ names and the publication dates.②Study Population Characteristics: Information pertaining to the age of participants, duration of their illness, and the sample size was recorded.③Intervention Details: For both the control and intervention groups, specifics on the interventions employed, as well as their timing, were documented.④Outcome Metrics and Measurement Data: The outcome indicators and the corresponding measurement data were meticulously noted.

Literature quality assessment

The quality of the literature was evaluated by two investigators utilizing the assessment tool outlined in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 [30], specifically tailored for randomized controlled trials. The assessments focused on several key domains: the adequacy of random sequence generation, allocation concealment, blinding of study participants and personnel, blinding of outcome assessors, completeness of outcome data, selective reporting, and other potential sources of bias. The outcomes of these evaluations were categorized as indicating a “high risk,” “low risk,” or “unclear risk” of bias. Based on the cumulative assessment across these domains, studies were graded as follows: Grade A: Studies that fully met all the assessment criteria, demonstrating a low risk of bias across all evaluated domains; Grade B: Studies that met the criteria to a substantial degree but showed some concerns in one or more areas, indicating a mixed level of risk; Grade C: Studies that did not meet the assessment criteria adequately, highlighting significant concerns or a high risk of bias in multiple domains.

Statistical analysis

A meta-analysis was conducted using Stata version 15.0 software. Heterogeneity across the studies was assessed based on both the P-value and the I² statistic. In cases where P > 0.1 and I² ≤ 50%, indicating the absence of significant heterogeneity, a fixed-effects model was chosen for analysis. Conversely, if P ≤ 0.1 and I² > 50%, suggesting substantial heterogeneity, a random-effects model was employed. Additionally, sensitivity analyses and subgroup analyses were conducted for variables that could potentially contribute to heterogeneity, accompanied by a bias assessment. The outcome measures reported in the included studies were continuous variables, and given the utilization of diverse measurement tools, the standard mean difference (SMD) was adopted as the effect size, with a corresponding 95% confidence interval (CI) calculated. To evaluate the robustness and publication bias of the study, sensitivity analyses and funnel plots were utilized.

Results

Search results and Literature characteristics

The initial search yielded a total of 968 articles. Following the removal of duplicates, 700 articles remained for further consideration. Upon meticulous review of the titles, abstracts, and full texts, ten articles [25–28,31–36] were ultimately selected for inclusion in this study. Among these, five were published in English and five in Chinese, collectively encompassing 778 patients; 389 patients comprised the intervention group, and 389 comprised the control group. The screening process and the basic characteristics of the included articles are illustrated in Fig 1 and summarized in Table 2, respectively.

Table 2. Basic characteristics of the included literature.

Study	Year	Country	Sample size (Intervention group/control group)	Average age (Intervention group/Control group)	Intervention		Duration	Measurement tools for outcome indicators
Study	Year	Country	Sample size (Intervention group/control group)	Average age (Intervention group/Control group)	Intervention group	Control group
Ma Li	2021	China	30/30	71 ± 6/71 ± 6	Galantamine Tablets + Probiotics	Galanthamine tablets + placebo	16w	ADAS-cog
Wu Baifu	2020	China	54/53	60.03 ± 10.29/ 60.42 ± 10.16	Low frequency repetitive transcranial magnetic stimulation+ probiotics	Low frequency repetitive transcranial magnetic stimulation	4w	MMSE
Wang Xiaodong	2015	China	14/14	67.33 ± 13.08/ 68.32 ± 12.36	Shimotang Oral Liquid + Jin Shuangqi Oral Treatment	Shimotang Oral Liquid	12m	MMSE
He Xianyan	2022	China	40/40	70.85 ± 4.47/ 71.02 ± 4.31	Donepezil + Probiotics	Donepezil	3m	MMSE+ADAS-Cog
Wang Jing	2022	China	29/30	74.97 ± 6.78/ 72.21 ± 8.74	Donepezil Tablets + Bifidobacterium Triplex Capsules	Donepezil tablets + placebo	12w	MMSE
Xiao, Jinzhong	2020	Japan	39/39	61.3(7.7)/60.9(6.9)	Probiotics	Placebo	16w	RBANS
Daisuke Asaoka	2022	Japan	55/60	77.2/78.9	Probiotics	Placebo	24w	MMSE+ADAS-Jcog
Elmira Akbari	2016	Iran	26/26	77.67 ± 2.62/ 82.00 ± 1.69	Probiotic milk	Milk	12w	MMSE
Y. Kobayashi	2019	Japan	59/58	61.5(6.83)/ 61.6 (6.37)	Probiotics	Placebo	12w	MMSE+ RBANS
Yuzhe Fei	2023	China	20/20	76.40 ± 9.61/ 75.30 ± 9.75	Probiotics	Placebo	12w	MMSE+MoCA

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Notes: w, Week; m, Month; ADAS-cog, Alzheimer disease assessment scale-cog; MMSE, Mini-Mental State Examination; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; MoCA, Montreal Cognitive Assessment.

Evaluation of the quality of literature

Among the ten papers included in the analysis, five were classified as quality A(26, 27, 34–36), with an equal number, five, designated as quality B(25, 28, 31–33). The comprehensive results of the risk of bias assessment conducted on these studies are meticulously outlined in Table 3.

Table 3. Quality evaluation of the literature.

Study	Random sequence generation	Assignment hiding	Blinding	Completeness of outcome data (follow-up shedding with or without instructions)	Selective reporting of research findings	Additional sources of bias	Quality grade (level)
Li Ma [31]	Low risk	Unclear	High risk	Low risk	Low risk	Low risk	B
Baifu Wu [33]	Low risk	Unclear	High risk	Low risk	Low risk	Low risk	B
Xiaodong Wang [32]	Unclear	Unclear	High risk	Low risk	Low risk	Low risk	B
Xianyan He [25]	Low risk	Unclear	High risk	Low risk	Low risk	Low risk	B
Jing Wang [26]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	A
Xiao, Jinzhong [36]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	A
Daisuke Asaoka [27]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	A
Elmira Akbari [34]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	A
Y. Kobayashi [35]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	A
Yuzhe Fei [28]	Low risk	Low risk	High risk	Low risk	Low risk	Low risk	B

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Meta-analysis results

Overall inspection.

Ten studies reported on the effectiveness of probiotics in individuals with cognitive impairment, utilizing the standardized mean difference (SMD) as the metric for the combined effect size. Analysis revealed significant heterogeneity among the findings (I² = 88.5%, P < 0.001), prompting the application of the random-effects model for further analysis. As illustrated in Fig 2, the pooled effect size for probiotics in enhancing cognitive function was SMD = 0.52 (P < 0.001), with a 95% confidence interval (CI) ranging from 0.07 to 0.98. This suggests a beneficial role of probiotics in improving cognitive function.

Subgroup analyses.

Separate subgroup analyses were undertaken, employing the type of cognitive assessment scale (MMSE, ADAS-cog, MoCA, and RBANS), the classification of probiotics (single-species versus multi-species probiotics), and the duration of intervention (≥12 weeks versus <12 weeks) as the respective subgrouping criteria (Table 4).

Table 4. Subgroup analysis results.

Subgroup variable	Categorization	Number of publications (articles)	Effect size and 95% CI	Heterogeneity test
Subgroup variable	Categorization	Number of publications (articles)	Effect size and 95% CI	I²(%)	P-value
Scale	MMSE	6	0.88 [0.67, 1.10]	66.6%	P = 0.01
	ADAS-cog	2	-0.31 [-0.61,-0.001]	90.6%	P ＜ 0.01
	RBANS	2	0.39 [0.10,0.68]	89.6%	P ＜ 0.01
Probiotics types	Probiotic complex	8	0.17 [0.01,0.33]	92.2%	P ＜ 0.01
Probiotics types	Mono-probiotic	2	0.81 [0.37,1.26]	81.9%	P = 0.019
Intervention period	≤12 weeks	6	0.61 [0.42,0.80]	79.5%	P ＜ 0.01
Intervention period	>12 weeks	4	0.17 [-0.07,0.42]	93.2%	P ＜ 0.01

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(1)
Subgroup Analysis by Scale Type: Six studies [25,26,28,32–34] utilized the MMSE as the primary outcome measure, while two studies [27,31] employed the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and another two studies [35,36] used the RBANS. The three subgroups exhibited substantial heterogeneity (I² = 87.9%, p < 0.001), hinting at an influence of the scale type on the association between probiotics and cognitive impairment. Notably, the MMSE scale produced the largest effect size SMD = 0.88 (P = 0.01), 95% CI = (0.67, 1.10) for the outcome of probiotic intervention for cognitive impairment. This was followed by the RBANS scale with an effect size SMD = 0.39 (P = 0.002), 95% CI=(0.10, 0.68). the ADAS-cog scale produced the smallest effect size, SMD = -0.31 (P = 0.001), 95% CI=(-0.61, -0.001).
(2)
Subgroup Analysis by Probiotic Class: Eight studies [25,27,28,31,33–36] involved complex probiotics, whereas two studies [26,32] focused on single-species. High heterogeneity was observed between these subgroups (I² = 91.2%, P < 0.001), indicating that the class of probiotics may influence the efficacy of interventions for cognitive impairment. Single probiotics produced the largest effect size in improving cognitive function SMD = 0.81 (P = 0.019), 95% CI = (0.37, 1.26). Complex probiotics produced a smaller effect size SMD = 0.17 (P < 0.001), 95% CI= (0.01, 0.33).
(3)
Subgroup Analysis by Intervention Duration: The shortest intervention period in the studies was 4 weeks [33], while the longest lasted for 12 months [32]. For the purpose of this subgroup analysis, the extreme values were excluded, and the median duration was adopted as the representative intervention period for inclusion in the analysis. Consequently, six studies [25,26,28,33–35] featured an intervention duration of ≤ 12 weeks, and four studies [27,31,32,36] had an intervention duration exceeding 12 weeks. High heterogeneity was noted in the effect sizes between these two subgroups (I² = 88.2%, P < 0.001), suggesting that the length of the intervention period may have a moderate influence on the effectiveness of probiotic interventions in improving cognitive function. Specifically, intervention period ≤12 weeks produced the largest effect size SMD = 0.61 (P < 0.001), 95% CI = (0.42, 0.80) in improving cognitive function. Conversely, intervention period >12 weeks had a smaller effect size SMD = 0.17 (P < 0.001), 95% CI = (-0.07, 0.42).

Publication bias and sensitivity.

The funnel plot analysis revealed certain asymmetry in the results, potentially suggesting the presence of publication bias within the study. A sensitivity analysis was conducted, involving the sequential exclusion of individual studies to compare changes in the combined outcomes. The analysis indicated that the changes in the results were insignificant, thereby demonstrating the robustness and stability of the study findings (Fig 3 and Fig 4).

Discussion

Among the ten studies included in this research, five were rated as quality A and five as quality B, all considered to be of high quality. Nine of these studies [25–28,31,33–36] detailed specific methods for generating randomized sequences. Six studies [26–28,34–36] explicitly described the method used for allocation concealment in their text, while five studies [26,27,34–36] specified the blinding procedure for study participants or the individuals administering/measuring the intervention. The consistency of our study with previous studies in terms of the positive effects of probiotics compared to theirs further validates the effectiveness of probiotics in promoting health. However, this study included additional literature and study subjects, and assessed publication bias and performed sensitivity analyses to further enhance the reliability of the results. The included literature comprehensively reported both primary and secondary outcome indicators. The potential sources of heterogeneity in this meta-analysis can be attributed to two factors: firstly, the subjective nature of cognitive functioning scales may contribute to increased heterogeneity in responses related to cognitive functioning effects. Secondly, the study participants hailed from diverse countries and utilized locally adapted scales to assess intervention effects.

In our study, we synthesized data from recent randomized controlled trials examining the use of probiotic and prebiotic supplements in patients with cognitive impairment. The results indicated that, compared to placebo or control treatments, probiotic supplementation exhibited statistically significant positive effects on cognitive function among these patients. Additionally, to delve deeper into the substantial heterogeneity observed among the included studies, we conducted a subgroup analysis. This analysis unveiled correlations between the magnitude of cognitive improvement and factors such as the type of probiotic strain (single versus combination), the duration of the intervention, and the specific cognitive assessment scale utilized. Collectively, these novel findings align with prior research documenting the neuroprotective benefits of probiotics and prebiotics in neurological disorders [17–19].

The findings of this meta-analysis indicate that probiotics can enhance cognitive function in individuals with cognitive impairment. Several studies [21,37,38] have demonstrated that ingesting probiotics or prebiotics can modulate cognitive function. This effect is mediated by the gut microbiota, which reduces inflammatory and oxidative biomarkers. These interactions occur through the microbiota-gut-brain axis. The gut-brain axis is a complex communication system between the gut microbiota and the central nervous system, influencing brain function and behavior through neural, immune, and endocrine pathways. Key mechanisms include neurotransmitter regulation (e.g., serotonin, dopamine, and GABA), which can impact mood and cognitive states; inflammation and immune modulation, where gut dysbiosis can trigger systemic inflammation and neuroinflammation; and direct neural signaling via pathways like the vagus nerve. Probiotics and prebiotics can improve cognitive outcomes by reducing inflammation, regulating neurotransmitters, and enhancing neural signaling. Dietary interventions facilitated by the microbiota-gut-brain axis are being considered as a promising therapeutic approach for cognitive impairment [39,40]. Tao Na and colleagues [41] showed that the integration of probiotics into conventional treatment improved cognitive function, along with lipid and blood glucose profiles, in patients with cognitive impairment.

Probiotics also exhibit the capability to ameliorate symptoms such as anxiety and depression, ultimately enhancing cognitive function. Over the past decade, a continuous influx of novel research has highlighted the favorable effects of dietary probiotic interventions on anxiety, depression, and cognitive function in various disease states [42]. For instance, a randomized, double-blind, placebo-controlled clinical trial [43] revealed that a daily probiotic intake for 12 consecutive days significantly elevated MDS-UPDRS (Unified Parkinson’s Disease Rating Scale) scores among patients with Parkinson’s disease. Furthermore, a recent study [18] noted a slight but statistically significant improvement in depression and anxiety symptoms with daily probiotic consumption, whereas no such effect was observed with prebiotic intake. Other studies have provided evidence that similarly supports the positive impact of probiotic therapy on disorders linked to the gut-brain axis. A randomized controlled trial [44] demonstrated that healthy volunteers treated with a probiotic mixture had a significantly reduced response to sadness. This effect was observed compared to a placebo group over a 4-week intervention period. Another study conducted on healthy individuals [45] found that consuming yogurt containing probiotics for 3 consecutive weeks significantly improved mood states. Additionally, an earlier study on irritable bowel syndrome (IBS) [46] revealed beneficial systemic and immunomodulatory effects of probiotics, with a notable normalization of the interleukin-10 to interleukin-12 ratio observed exclusively in IBS patients treated with Bifidobacterium infantis 35624. These findings suggest that the immunologic benefits of probiotics are not only extensive but also exhibit more pronounced strain-specificity than previously recognized [47].

Furthermore, given the variability in the severity of the participants enrolled in this study, the choice of an appropriate scale for assessing cognitive impairment was of paramount importance. The results of our subgroup analysis, which included only the MMSE, ADAS-cog, and RBANS scales, indicated that the MMSE scale yielded the largest effect size in evaluating cognitive improvement, implying its superiority over the other scales in this regard. In a study by D.A. Loewenstein et al. [48] involving older adults with an average age of 75 years or older, it was found that when using a MMSE cut-off value of ≤26 points, the sensitivity for distinguishing MCI from normal aging was 70.8%, with a specificity of 84.6%. The authors concluded that while the MMSE was effective in differentiating cognitive impairment from normal aging, it was less discriminatory between normal aging and MCI. Consequently, future clinical studies should consider the influence of multiple factors when selecting assessment tools, aiming to more precisely evaluate the impact of probiotics on cognitive functioning, thereby accurately assessing the intervention effect of probiotics.

The impact of probiotic species and the duration of the intervention on cognitive enhancement varies. The findings of this study suggest that a single probiotic species exerts the most significant effect on improving cognition in individuals with cognitive dysfunction. This aligns with the observations made by Tingting Lv et al. [29], who demonstrated that supplementation with a single probiotic species exhibited a more pronounced therapeutic effect. This may be attributed to the antagonistic interactions and competition for gut nutrients among composite probiotic species, which could potentially diminish their efficacy [49]. Furthermore, our study results indicate that intervention periods of ≤ 12 weeks yield the greatest improvement in cognitive function. The difference in cognitive enhancement observed with intervention cycles exceeding 12 weeks was not statistically significant, contrasting with the findings of Nanyang Liu et al. [50], who reported that supplementation durations longer than 12 weeks were effective in enhancing cognitive performance. The discrepancy in results may stem from the inclusion of both Chinese and English literature in our analysis. Additional studies are required in the future to further validate these findings.

Research findings indicate that various probiotics can ameliorate cognitive dysfunction, and a consensus statement published by the ISAPP [14] suggests that adequate probiotic supplementation may offer certain health benefits. However, ISAPP does not delineate specific dosages and frequencies for probiotic supplementation. Over the past decade, entities such as ISAPP [14] and the World Gastroenterology Organisation [51] have endeavors to establish recommended probiotic doses. To ensure the safety and effectiveness of probiotic use, the ISAPP advises that the daily count of live probiotic cells in foods and dietary supplements should be at least 1 × 10^9 colony-forming units (CFU). In the literature reviewed for this study, intervention doses could not be standardized in terms of units due to the inclusion of diverse probiotic forms such as capsules, liquids, and others, and some studies [28,35] failed to specify the intervention frequency. Consequently, the available data were insufficient for conducting a subgroup analysis. Future research should endeavor to screen probiotic supplements for optimal dosage and ingestion frequency. Additionally, there is a pressing need for more efficacious probiotic screening methodologies to develop targeted probiotic strategies for cognitive impairment.

The current study is subject to several limitations. Firstly, the literature reviewed in this paper did not exclude the potential interference of other medications or forms of exercise, such as galantamine tablets, donepezil, moderate resistance training, and other factors. These medications and forms of exercise may exert a direct influence on gut microbiota composition and metabolic profiles, which could subsequently impact the gut-brain axis and related disorders. Therefore, it is imperative that future studies account for these variables. Secondly, heterogeneity may arise due to variations in probiotic supplement manufacturers. While probiotics as dietary supplements have been widely deemed safe for use based on prior research, the elderly population is particularly susceptible to serious adverse effects, including gastrointestinal discomfort, systemic infections, and skin issues, owing to their decreased immune function. Furthermore, quality assessment of included studies is based on predetermined criteria, but some subjective judgment may be involved in the process. Synthesizing results is challenging because of the heterogeneity of studies in terms of interventions and outcomes. Finally, this study inevitably faces the challenges of limited sample size and short duration, which undoubtedly limit its applicability. In particular, small sample sizes may weaken the robustness of statistical results and generalizability of conclusions, while short study durations may not provide a comprehensive picture of the long-term trends in the evolution of the study variables or their potential far-reaching implications. In light of this, future studies must improve the reporting of potential adverse effects associated with probiotic supplements [52]. and robiotics can be compared with other interventions to enhance the effectiveness of probiotics as a treatment. By thoroughly considering these factors and addressing the limitations when designing probiotic intervention programs, we can gain a more comprehensive understanding of the potential benefits of probiotics on cognitive impairment. This will facilitate the systematic advancement of research aimed at improving cognitive function with probiotics.

Conclusions

In In summary, the meta-analysis conducted in this study revealed that probiotics can enhance cognitive abilities in patients with cognitive impairment. Furthermore, this study furnishes a robust scientific rationale for the potential application of probiotics in areas encompassing neurodegenerative diseases and mental health concerns. Future research endeavors should concentrate on refining the dosage and administration protocols of probiotics to ensure the maximization of their salutary effects on brain health. Concurrently, we advocate for interdisciplinary synergy, amalgamating the expertise of neuroscience, microbiology, and clinical medicine to propel advancements in probiotics research pertaining to brain health.

Supporting information

S1 Table. PRISMA checklist.

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pone.0321567.s001.docx^{(504.3KB, docx)}

S2 Table. List of raw analysis data.

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pone.0321567.s002.docx^{(504.3KB, docx)}

S3 Table. Study extraction overview table.

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pone.0321567.s003.xlsx^{(12.5KB, xlsx)}

S4 Table. Comprehensive study table with inclusion and exclusion details.

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pone.0321567.s004.xlsx^{(101.4KB, xlsx)}

S1 File. Quality evaluation of the literature.

(DOCX)

pone.0321567.s005.docx^{(26.1KB, docx)}

S2 File. Search strategy.

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pone.0321567.s006.docx^{(20.5KB, docx)}

S3 File. Retrieval process and data extraction.

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pone.0321567.s007.docx^{(120.4KB, docx)}

S4 File. Data analysis and results.

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pone.0321567.s008.docx^{(288.3KB, docx)}

Acknowledgments

The authors would like to thank all the participants of the study.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

Funder: Science and Technology Development of Henan Province in the year 2023 Project number: 232102310136 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

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PLoS One. 2025 May 2;20(5):e0321567. doi: 10.1371/journal.pone.0321567.r001

Author response to Decision Letter 0

6 Nov 2024

PLoS One. doi: 10.1371/journal.pone.0321567.r002

Decision Letter 0

Zohreh Sajadi Hezaveh

24 Feb 2025

PONE-D-24-49949Efficacy of probiotics in patients with cognitive impairment: A systematic review and meta-analysisPLOS ONE

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Reviewer #1: In this systematic review and meta-analysis, the impact of probiotics on patients with cognitive impairment was evaluated. Conclusion: Probiotics have been proven to enhance cognitive function, and a probiotic intervention program containing a single probiotic strain with a duration of<12 weeks has shown particularly strong effects in evaluating cognitive function through Mini Mental State Examination (MMSE). Some possible mechanisms have also been proposed in this regard. After careful evaluation, I found that most of the criteria for the review and meta-analysis of this manuscript have been taken into account. However, recheck the manuscript using the PRISMA checklist and revise or complete it to ensure that all standards have been met.

This paper is very interesting, but the following modifications still need to be made.

1.We noticed that the articles included in this review were from the establishment of the database until September 2024. But we noticed that the articles included by the researchers were mostly from after 2015. Based on your search strategy and search time, have you conducted sufficient searches on various databases, and were there any relevant articles before 2015? For what reason was it not included?

2.In the subgroup analysis, separate analyses were conducted on the scales used, intervention time, and types of probiotics. We noticed that the age range of the researchers included in this study was between 50-85 years old. As aging and aging are themselves high-risk factors for cognitive decline, no age-related subgroup analysis was conducted to determine the reasons for this.

3.The author order in Tables 3 and 4 should be based on alphabetical order or the year of publication of the article.

4.In the discussion, we found that sometimes cognitive impairment is used, but later it is also described in patients with Alzheimer's disease. Please clarify and distinguish the concepts of the two, pay attention to the theme of this article, and maintain consistency before and after.

5. In the discussion, if you can compare your findings with other intervention measures and ultimately determine the efficiency of your findings, it will be more convincing

6. This study found that the underlying theory needs a clearer explanation.

Some sentences are too long to understand and keep up with.

Reviewer #2: General Comment: This manuscript addresses an important topic—the effect of probiotics on cognitive impairment—through a systematic review and meta-analysis. The paper is generally well-structured, but there are several areas that need clarification and improvement. Below are my detailed comments:

Abstract:

1. Line 8-10: The sentence "Such an investigation is crucial for developing a tailored probiotic intervention program..." could be made more concise. Consider revising to: "This investigation is essential for optimizing probiotic interventions to prevent and treat cognitive decline."

2. Study Selection Criteria: It would be helpful to briefly mention the inclusion criteria for the meta-analysis in the abstract (e.g., "Only randomized controlled trials (RCTs) were included.").

3. The full term "Mini-Mental State Examination (MMSE)" is spelled out correctly upon first mention (e.g., in line 29). Please use abbreviations on line 36.

Introduction:

4. Line 24-26: The paper mentions "several studies" providing evidence for the neuroprotective effects of probiotics but only lists a limited number of citations (17-19). Consider adding more references or specifying that these are representative studies.

5. Line 30-32: The introduction of synbiotics is relevant but should include a brief explanation of their role in cognitive function to make the connection clearer for readers unfamiliar with the topic.

6. Contradictory Findings: The introduction briefly touches on inconsistencies in previous meta-analyses but does not explore this in enough detail. It would be helpful to discuss why there are discrepancies among prior findings and how your study addresses these issues.

Methods:

7. Inclusion Criteria: The PICOS framework is described well. However, the exclusion criteria (particularly point ③ regarding data accessibility) could benefit from more detail. For instance, how was data ambiguity determined? Were attempts made to contact study authors for missing data?

8. Search Strategy: The search is comprehensive, but the search terms and databases are listed in an unclear manner. Please provide a sample search string (e.g., for Embase, PubMed, Web of Science,) as supplementary material or in an appendix for transparency and reproducibility.

9. Quality Assessment: The use of Cochrane's risk of bias tool is appropriate, but you mention "subjective judgment" in quality assessment. Could you specify if this was mitigated by having two reviewers assess each study independently? Including details about inter-rater agreement would strengthen the validity of the assessment.

Results:

10. Tables 2 and 4: The table presents a good summary, but it could be enhanced by adding a footnote explaining the abbreviations in the intervention column (e.g., MMSE, ADAS-cog). This will help readers unfamiliar with these terms.

Discussion:

11. Line 140-145: The discussion effectively highlights the key findings. However, the limitations of the included studies (such as small sample sizes or short durations) are not sufficiently addressed. A more thorough discussion of these limitations would strengthen the paper.

12. Interpretation of Results: The positive effect of probiotics is well-established, but the discussion could be improved by directly comparing the results with those from prior meta-analyses. Specifically, how do your results differ from the studies by Den et al. (2020) or Krüger et al. (2021)?

13. Line 167-172: The mention of gut-brain axis mechanisms is important but lacks depth. More specific details on the biological mechanisms (e.g., reduction of inflammation, modulation of neurotransmitters) could enhance the discussion.

Conclusion:

14. Line 190-195: The conclusion could be more concise. Consider reducing the repetition of points already made in the discussion. Also, a clearer statement regarding clinical implications and future research directions (e.g., focusing on probiotic dosage) would be useful.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2025 May 2;20(5):e0321567. doi: 10.1371/journal.pone.0321567.r003

Author response to Decision Letter 1

3 Mar 2025

Revision Report

First of all, I would like to express our sincere gratitude to the reviewers for their comments. These comments are all valuable and helpful for revising and improving our manuscript, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portions are marked in red in the revised version. The responses to the reviewer’s comments are listed below.

Response to editors and reviewers

(original comments by editors and reviewers are in blue color )

Editors:

1.Comment: Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

1.Reply: Thank you for your comments. We have made sure that the manuscript meets PLOS ONE's style requirements, including file naming.

2.Comment: As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:A numbered table of all studies identified in the literature search, including those that were excluded from the analyses�For every excluded study, the table should list the reason(s) for exclusion�If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed�A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study:Name of data extractors and date of data extraction�Confirmation that the study was eligible to be included in the review.�All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group�If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome�An explanation of how missing data were handled.

2.Reply�A numbered table of all studies identified in the literature search, including those excluded from the analyses, is provided in the supplementary information (Comprehensive study table with inclusion and exclusion details). For each excluded study, the table lists the specific reason(s) for exclusion. Additionally, some tables of all data extracted from the primary research sources for the systematic review and/or meta-analysis is included in the supplementary information(S2 Table; S3 Table; S1 File; S3 File). No missing data were identified in this study, and all included studies were published.

3.Comment: We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.

3.Reply�Thank you for your suggestion. We appreciate your attention to the language quality of our manuscript. Before submission, the manuscript was thoroughly reviewed and corrected by faculty members specializing in English from our college. Upon receiving feedback, we meticulously checked the language, spelling, and grammar to ensure that each word was spelled correctly and that terminology was consistent and accurate throughout the document. We have also carefully reviewed the manuscript to ensure that the format is consistent, and the language is logical and fluent. We are confident that this rigorous review process has greatly enhanced the professionalism and quality of our manuscript.

4.Comment: We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4.Reply�Thank you for bringing this discrepancy to our attention. We apologize for the inconsistency between the grant information provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections. We have carefully reviewed the grant details and will ensure that the correct grant numbers for the awards received for our study are accurately listed in the ‘Funding Information’ section upon resubmission.

5.Comment: Thank you for stating the following financial disclosure:“This study was supported by the Science and Technology Development of Henan Province in the year 2023 (232102310136). The funders were not associated with the conceptualization, design, implementation, or approval of this study.”Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.""If this statement is not correct you must amend it as needed.Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

5.Reply�Thank you for your suggestion. We have made the requested modifications and revised the funder role statement as follows: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." This revised statement has been included in the cover letter to ensure clarity and consistency.

6.Comment: We note that your Data Availability Statement is currently as follows: All relevant data are within the manuscript and its Supporting Information files.Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods(https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

6.Reply�The authors have confirmed that the submitted file contains all the raw data needed to replicate the results of the study. All relevant data are within the paper and its Supporting Information files.

7.Comment: Please include a separate caption for each figure in your manuscript.

7.Reply�Thank you for your careful review of the manuscript. During the manuscript preparation stage, we assigned a descriptive title to each image, with the aim of clearly and accurately conveying the content and core message of the figure. Upon receiving your feedback, we have meticulously reviewed and correctly cited each figure title in the manuscript to ensure consistency with the overall style and formatting requirements. We have also verified that all terminology is accurate and consistent throughout the document to enhance the clarity and coherence of the manuscript.

8.Comment: Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly.

8.Reply�In response to your request, we have appended the titles of all supporting information documents at the conclusion of the manuscript. These documents encompass, but are not confined to: S1 Table. PRISMA checklist; S2 Table. List of raw analysis data; S3 Table. Study extraction overview table; S1 File. Quality evaluation of the literature; S2 File.Search strategy; S3 File.Retrieval process and data extraction; S4 File. Data analysis and results. etc. To facilitate readers in locating and citing pertinent supporting information documents, we have thoroughly updated all references to these documents within the main text of the manuscript.

Reviewer #1�

1.Comment: We noticed that the articles included in this review were from the establishment of the database until September 2024. But we noticed that the articles included by the researchers were mostly from after 2015. Based on your search strategy and search time, have you conducted sufficient searches on various databases, and were there any relevant articles before 2015? For what reason was it not included?

1.Reply�In response to your queries, we conducted a comprehensive review. A total of 60 articles published before 2015 were excluded because they did not meet the inclusion criteria. These criteria included: (1) articles reporting animal experiments; (2) studies whose content did not match our research focus; and (3) literature classified as reviews or systematic reviews. The specific reasons for excluding each article are detailed in the supporting information (Comprehensive study table with inclusion and exclusion details). For example, the 2007 article by D. Benton titled “Impact of consuming a milk drink containing a probiotic on mood and cognition” was excluded because it examined the effects of drinking milk containing probiotics on mood and was conducted in healthy adults. Additionally, research on probiotics and cognitive impairment has increased significantly since 2016. Specifically, there were 12 publications in 2014, 10 in 2015, and 27 in 2016. By 2020, the number had reached 75. We hope this response clarifies the rationale behind our article selection process.

2.Comment: In the subgroup analysis, separate analyses were conducted on the scales used, intervention time, and types of probiotics. We noticed that the age range of the researchers included in this study was between 50-85 years old. As aging and aging are themselves high-risk factors for cognitive decline, no age-related subgroup analysis was conducted to determine the reasons for this.

2.Reply�Thank you for your insightful comment. We have conducted an in-depth discussion regarding the questions you raised concerning age-related subgroup analysis. As you aptly noted, the participants in this study spanned an age range from 50 to 85 years, with aging itself being a recognized risk factor for cognitive decline. When performing subgroup analyses, our primary focus was on factors such as the scales employed, the duration of intervention, and the type of probiotics used, and we were unable to perform a more nuanced stratification analysis for age.

To further elaborate and clarify:

Firstly, during the initial design phase of this study, our primary emphasis was on assessing the impact of probiotics on cognitive ability. Based on this focus, we developed a corresponding subgroup analysis plan.

Secondly, the limited number of studies included in our analysis, coupled with variations in age distribution among these studies, may have contributed to non-conclusive findings from the subgroup analyses.

Lastly, the age-related subgroup analysis you proposed is indeed intriguing. In future research endeavors, we will give greater attention to the variable of age and endeavor to collect data from larger sample sizes to facilitate more detailed and in-depth subgroup analyses.

Your feedback is highly valued, and we will take these considerations into account in our future work.

3.Comment: The author order in Tables 3 and 4 should be based on alphabetical order or the year of publication of the article.

3.Reply�We agree with your suggestion and have accordingly arranged the authors listed in Tables 2 and 3 in alphabetical order.(Table 4 represents a subgroup analysis and does not require alphabetical sorting.)

4.Comment: In the discussion, we found that sometimes cognitive impairment is used, but later it is also described in patients with Alzheimer's disease. Please clarify and distinguish the concepts of the two, pay attention to the theme of this article, and maintain consistency before and after.

4.Reply: In response to your review comment, we acknowledge the need for clarification and distinction between the concepts of "cognitive impairment" and "Alzheimer's disease" within our discussion. It is important to maintain consistency with the theme of our paper.To clarify, On the one hand,cognitive impairment refers to a broad range of symptoms that affect mental functioning, including memory, language, and problem-solving abilities. These impairments can be mild, moderate, or severe and may be caused by various factors, including aging, brain injuries, or underlying medical conditions.On the other hand, Alzheimer's disease is a specific type of dementia that is characterized by progressive decline in memory, thinking, and behavioral abilities. It is a chronic neurodegenerative disorder that affects multiple brain regions and eventually leads to severe cognitive and functional impairment.

In our discussion, we may have used the term "cognitive impairment" in a general sense to describe the overall effects of the intervention on cognitive functioning. However, when specifically referring to studies that focused on Alzheimer's disease patients, we have clearly identified them as such.

To ensure consistency with the theme of our paper,We have revised the terminology in the discussion section to maintain consistency of terminology and themes before and after.We will ensure that our terminology is accurate and that our discussion remains focused on the relevant aspects of our research.

Thank you for bringing this to our attention, and we appreciate your constructive feedback.

5.Comment: In the discussion, if you can compare your findings with other intervention measures and ultimately determine the efficiency of your findings, it will be more convincing

5.Reply�We fully understand the significance of such comparisons in enhancing the persuasiveness of our discussion.However, it is important to note that various intervention measures, including probiotics, often have their specific application scopes and are utilized based on the unique characteristics and needs of individual patients. In the case of probiotics, while they have shown promising results as an adjunctive therapy in numerous studies, they are indeed rarely used as a standalone treatment.

Given this context, we acknowledge that a direct comparison of probiotics with other primary intervention measures may not always be straightforward or entirely applicable. Instead, we have focused on discussing the potential benefits and limitations of probiotics as an adjunctive therapy, highlighting their role in supporting the overall treatment regimen.

We will carefully consider these points and add to the discussion accordingly to ensure that our findings are presented in a comprehensive and persuasive manner.

6.Comment: This study found that the underlying theory needs a clearer explanation.Some sentences are too long to understand and keep up with.

6.Reply�I apologize for any difficulty caused by the lengthy sentences in the manuscript. In response to your feedback, Firstly�we have explained the concepts of grounded theory in the manuscript in a more detailed and clearer way, for example, the sentence "Cognitive impairment encompasses the decline in one or more cognitive domains, including memory, language, visuospatial abilities, executive functions, computation, and comprehension and judgment" modified to "Cognitive impairment is a condition characterized by diminished brain function, resulting from a variety of etiologies". Secondly�We have reviewed the entire manuscript and revised the long sentences to improve clarity and readability. For instance�the sentence "Several studies(21, 37, 38) have demonstrated that the ingestion of probiotics or prebiotics enables the gut microbiota to regulate cognitive function by reducing inflammatory and oxidative biomarkers via interactions with the brain through the microbiota-gut-brain axis." modified to "Several studies(21, 37, 38) have demonstrat

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PLoS One. doi: 10.1371/journal.pone.0321567.r004

Decision Letter 1

Zohreh Sajadi Hezaveh

9 Mar 2025

Efficacy of probiotics in patients with cognitive impairment: A systematic review and meta-analysis

PONE-D-24-49949R1

Dear Dr. Liu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Zohreh Sajadi Hezaveh

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0321567.r005

Acceptance letter

Zohreh Sajadi Hezaveh

PONE-D-24-49949R1

PLOS ONE

Dear Dr. Liu,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. PRISMA checklist.

(DOCX)

pone.0321567.s001.docx^{(504.3KB, docx)}

S2 Table. List of raw analysis data.

(XLSX)

pone.0321567.s002.docx^{(504.3KB, docx)}

S3 Table. Study extraction overview table.

(DOCX)

pone.0321567.s003.xlsx^{(12.5KB, xlsx)}

S4 Table. Comprehensive study table with inclusion and exclusion details.

(XLSX)

pone.0321567.s004.xlsx^{(101.4KB, xlsx)}

S1 File. Quality evaluation of the literature.

(DOCX)

pone.0321567.s005.docx^{(26.1KB, docx)}

S2 File. Search strategy.

(DOCX)

pone.0321567.s006.docx^{(20.5KB, docx)}

S3 File. Retrieval process and data extraction.

(DOCX)

pone.0321567.s007.docx^{(120.4KB, docx)}

S4 File. Data analysis and results.

(DOCX)

pone.0321567.s008.docx^{(288.3KB, docx)}

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Efficacy of probiotics in patients with cognitive impairment: A systematic review and meta-analysis

Miaomiao Ma

Bo Li

Zhi Qu

Shejuan Liu

Sisi Li

Roles

Abstract

Objective

Methods

Results

Conclusion

Introduction

Materials and methods

Study design

Inclusion and exclusion criteria

Table 1. Inclusion criteria for PICOS studies.

Search strategy

Literature screening and data extraction

Literature quality assessment

Statistical analysis

Results

Search results and Literature characteristics

Fig 1. PRISMA flow chart for the study selection process.

Table 2. Basic characteristics of the included literature.

Evaluation of the quality of literature

Table 3. Quality evaluation of the literature.

Meta-analysis results

Overall inspection.

Fig 2. Forest plot of the overall effect of probiotics on cognition in a random-effects model.

Subgroup analyses.

Table 4. Subgroup analysis results.

Publication bias and sensitivity.

Fig 3. Funnel plot.

Fig 4. Sensitivity analysis.

Discussion

Conclusions

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Decision Letter 0

Zohreh Sajadi Hezaveh

Roles

Author response to Decision Letter 1

Decision Letter 1

Zohreh Sajadi Hezaveh

Roles

Acceptance letter

Zohreh Sajadi Hezaveh

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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