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

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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

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Dear Dr. Liu,

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Kind regards,

Zohreh Sajadi Hezaveh

Academic Editor

PLOS ONE

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