Psychobiotics and CNS-Targeting Pharmacotherapies for Binge-Eating Disorder: Dual Systematic Reviews and Meta-Analyses

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents two systematic reviews in one; these concern the effectiveness and safety of CNS-targeting pharmacological interventions
and psychobiotic-based treatments for BED respectively. Although these treatments are not directly compared within any of the included studies, their relative efficacy for reducing binge eating frequency is compared across studies, along with associated adverse events. I have only minor comments for the authors as outlined below.

Title: This should reflect the dual focus of the review.

Abstract: Please indicate SMD as 'standardized mean differences'.

Introduction: The Introduction presents a reasonable case for the neurobiological connection between the gut and psychiatric disorders (specifically Binge Eating Disorder). The focus for the review/s novel, capturing the status of research in an emerging topic area: psychobiotics and eating disorders. 

Line 69: Please simply the following text for improved readability/meaning "allows microbial metabolites and inflammatory mediators to translocate into systemic circulation".

Lines 81 to 99: It would be helpful to more explicitly link the evidence in this paragraph to consequences for mood, appetite regulation and inflammatory responses respectively. Please use leading sentences or separate paragraphs to delineate the benefits of psychobiotics for these different outcomes. 

Method: The systematic reviews are conducted in accordance with PRISMA guidelines, documented in checklists presented at the end of the article. Analytic methods appear to be appropriate.

Line 123: Please clarify inclusion criterion (1) - Were participants required to have a DSM 5 diagnosis of Binge Eating Disorder? (DSM 5 is cited later - line 136).

In section 2.4, the risk of bias assessment appears to be duplicated. If using the same method for both reviews, then please specify rather than duplicating this information in full.

Results: This section is clearly written and well supported by tables and figures. I would like to see a more detailed description for the risk of bias assessment.

Discussion: This section of the review lacks detail/specifics and I found myself having to refer to the tables (which should be supplementary) to extract the key findings from the review. Line 376 - Please address - in the text - the drug classes included (which predominated?) and which pharmacological interventions specifically (line 398) are supported as treatment effective by the review.

Line 412 - See above comment - please address which psychobiotics specifically are supported in the review.

Minor edits:

Line 33: Typo (corrections in CAPS) - POSES a significant public health challenge.

Line 34: Typo - ITS prevalence.

Lines 48 and 49: Other central nervous system targeting (WORD MISSING?) to manage different BED SYMPTOMS.

Line 56: THEREFORE should be connected to the previous sentence.

Line 337 - 'I' squared should be R squared.

 

Author Response

Dear Editor and Reviewers,
We sincerely thank you for the careful evaluation of our manuscript (obesities-4218027) and for the constructive comments and suggestions. We have revised the manuscript extensively in response to all comments. In particular,we expanded the theoretical framework linking binge-cating disorder (BED), gut dysbiosis, and the gut-brain axis;clarified the distinction between conventional CNS-targeting pharmaco therapies and psychobiotic interventions;strengthened the Abstract, Introduction, Results, and Discussion; improved the risk-of-bias description; corrected terminology, formatting, and table/figure inconsistencies; and added the recent references recommended by the Academic Editor.
Below, we provide a detailed point-by-point response. Reviewer comments are reproduced in bold, followed by our responses.

Comment: Title: This should reflect the dual focus of the review.

Response: We agree and revised the title to: “Psychobiotics and CNS-Targeting Pharmacotherapies for Binge-Eating Disorder: Two Dual Systematic Reviews and Meta-Analyses.” This revised title more accurately reflects the manuscript’s dual focus while avoiding the impression that the two intervention types were directly compared within the same clinical trials.

Comment: Abstract: Please indicate SMD as “standardized mean differences”.

Response: Thank you. We now define SMD at first mention in the Abstract as “standardized mean difference,” and we also define the other statistical abbreviations at first use.

Comment: Line 69: Please simplify the following text for improved readability/meaning: “allows microbial metabolites and inflammatory mediators to translocate into systemic circulation.”

Response: We revised this sentence for clarity and readability. The revised text now explains that dysbiosis can impair intestinal barrier integrity, increase intestinal permeability (“leaky gut”), and allow microbial metabolites and inflammatory mediators to enter the systemic circulation, thereby contributing to systemic inflammation.

Comment: Lines 81 to 99: It would be helpful to more explicitly link the evidence in this paragraph to consequences for mood, appetite regulation and inflammatory responses respectively. Please use leading sentences or separate paragraphs to delineate the benefits of psychobiotics for these different outcomes.

Response: We agree and expanded this section substantially. In the revised Introduction, we reorganized the discussion to more clearly separate the consequences of dysbiosis for mood regulation, appetite control, and inflammatory responses. We also added clearer transitions and explanatory sentences to show how specific psychobiotic strains may influence these domains through gut–brain, immune, and neurochemical pathways.

Comment: Line 123: Please clarify inclusion criterion (1) — Were participants required to have a DSM-5 diagnosis of Binge-Eating Disorder?

Response: We clarified this criterion in the Methods section. The revised manuscript now states that eligible studies included participants meeting diagnostic criteria for BED based on self-reported symptoms or validated assessment tools, with or without a formal clinical diagnosis. We also clarified that binge-eating frequency was selected as the primary outcome because it aligns with the DSM-5 definition of BED.

Comment: In Section 2.4, the risk-of-bias assessment appears to be duplicated. If using the same method for both reviews, then please specify rather than duplicating this information in full.

Response: Thank you. We revised Section 2.4 to avoid duplication. The manuscript now states clearly that the same Cochrane RoB-2 methodology was applied across both systematic reviews and meta-analyses, rather than repeating the full description separately.

Comment: Results: I would like to see a more detailed description for the risk of bias assessment.

Response: We expanded the Results section to provide a more informative description of the risk-of-bias findings. Specifically, we now explain the most common reasons for high-risk or “some concerns” judgments, including attrition, limitations in blinding procedures, and selective reporting concerns when study protocols were unavailable or incompletely reported.

Comment: Discussion: Please address in the text which drug classes predominated and which pharmacological interventions specifically are supported as treatment effective by the review. Please also address which psychobiotics specifically are supported in the review.

Response: We revised the Discussion to include specific findings rather than referring readers only to tables and figures. For pharmacological interventions, we now identify the drug classes represented in the review and discuss which agents showed significant benefit, including the stronger signal seen with certain antidepressant-related interventions such as sibutramine in the included dataset. For psychobiotics, we now specify the strains and formulations supported by the included trials, including Lactobacillus acidophilus NCFM plus Bifidobacterium lactis Bi-07, Lactobacillus rhamnosus HA-114, Lactobacillus rhamnosus CGMCC1.3724, and the multi-strain formulation containing Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium lactis, Bifidobacterium longum, Lactobacillus reuteri, and Lactobacillus rhamnosus.

Comment: Minor edits, including typographical and wording corrections.

Response: All minor edits were addressed throughout the manuscript. We corrected the noted typographical issues, improved sentence flow and grammar, and revised wording for clarity. Regarding the suggestion to change I² to R², we respectfully retained I² in the heterogeneity section because I² is the appropriate statistic for describing between-study heterogeneity in the meta-analysis, whereas R² was used only in the meta-regression analyses.

We are grateful for the reviewers’ and Academic Editor’s insightful comments, which have significantly improved the quality, clarity, and rigor of our manuscript. We hope that the revised version is now suitable for publication in Obesities.

Sincerely,
Ahmed El-Shamy (Corresponding Author), on behalf of all co-authors

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The systematic review and meta-analysis address a novel and clinically significant topic: the use of psychobiotics for Binge-Eating Disorder (BED). However, the manuscript currently lacks the necessary depth in its theoretical framework and consistency in its presentation. The connection between gut dysbiosis and BED pathophysiology is not sufficiently detailed, and there are several formal errors regarding citations and data presentation. In its current form, the manuscript is not suitable for publication and requires a major revision.

Major Comments

1. The authors must provide a more robust contextualization of BED. For a reader not specialized in the field, it is difficult to interpret the results without a clear comparison between standard pharmacological treatments and emerging biotherapies (probiotics and psychobiotics).
2. The manuscript needs to delve deeper into the specific mechanisms by which psychobiotics may modulate the symptoms of BED, contrasting this with current conventional drug therapies

 

Minor Comments

Affiliations

Please check the authors' affiliations; the country of residence has been omitted.

Abstract

Binge-eating disorder (BED) should be formally defined in this section.

The assertion that “gut microbiota dysbiosis contributes to BED pathophysiology” requires more precision. The authors should specify the mechanisms or pathways through which this dysbiosis contributes to the disorder.

Please define all statistical abbreviations at their first mention (e.g., SMD, CI, $I^2$).

The conclusion stating that psychobiotics appear to be a “safe and potentially effective adjunctive approach” is not sufficiently supported by the data provided in the abstract text.

Introduction

The introduction should be broadened regarding the relationship between gut microbiota and BED, as well as the use of probiotics and psychobiotics.

A proper contextualization of current drug therapies for BED should be provided for readers not specialized in the topic.

Lines 60-63: This sentence is critical as it introduces the concept of gut microbiota in BED patients; however, bibliographic references are missing. Furthermore, the authors should clearly state how the Firmicutes/Bacteroidetes (F/B) ratio is altered.

The subsequent paragraphs regarding dysbiosis in BED patients should be expanded.

Line 66: Names of bacterial genera must be written in italics.

Line 74: Please clarify the term “eating ED.”

Lines 88-98: Please specify the particular bacterial strains used.

Results

In Table 2 and Figure 1, please verify that references are written correctly and consistently (e.g., Grant 2020 vs. Grant et al., 2020).

There are two tables identified as “Table 2.” Please correct the numbering.

Please unify the font size across all tables and figures and ensure all references follow a single format.

Author Response

Dear Editor and Reviewers,
We sincerely thank you for the careful evaluation of our manuscript (obesities-4218027) and for the constructive comments and suggestions. We have revised the manuscript extensively in response to all comments. In particular,we expanded the theoretical framework linking binge-cating disorder (BED), gut dysbiosis, and the gut-brain axis;clarified the distinction between conventional CNS-targeting pharmaco therapies and psychobiotic interventions;strengthened the Abstract, Introduction, Results, and Discussion; improved the risk-of-bias description; corrected terminology, formatting, and table/figure inconsistencies; and added the recent references recommended by the Academic Editor.
Below, we provide a detailed point-by-point response. Reviewer comments are reproduced in bold, followed by our responses.

Comment:
The manuscript needs more robust contextualization of BED. For a reader not specialized in the field, it is difficult to interpret the results without a clear comparison between standard pharmacological treatments and emerging biotherapies. The manuscript also needs to delve deeper into the specific mechanisms by which psychobiotics may modulate BED symptoms, contrasting this with current conventional drug therapies.

Response:
We appreciate this important comment and revised the Introduction extensively. We added a broader clinical and mechanistic overview of BED for non-specialist readers, including discussion of conventional CNS-targeting pharmacotherapies, their rationale, and their limitations. We also expanded the gut–brain-axis framework and described in greater depth how psychobiotics may affect BED-relevant processes such as satiety, reward-related behavior, mood regulation, inflammation, intestinal permeability, and neurochemical signaling. The revised Introduction now provides a clearer conceptual contrast between conventional pharmacotherapy and microbiome-based approaches.

Comment:
Affiliations: Please check the authors’ affiliations; the country of residence has been omitted.

Response:
Thank you. We corrected the affiliations so that they now consistently include city, state, and country.

Comment:
Abstract: BED should be formally defined. The statement that gut microbiota dysbiosis contributes to BED pathophysiology requires more precision. Please define all statistical abbreviations at first mention. The conclusion stating that psychobiotics appear to be a safe and potentially effective adjunctive approach is not sufficiently supported by the data provided in the abstract text.

Response:
We revised the Abstract accordingly. BED is now formally defined at first mention. We also clarified, in a concise manner appropriate for the Abstract, that dysbiosis may contribute to BED through gut–brain-axis mechanisms involving intestinal permeability, inflammatory signaling, and neurochemical regulation. In addition, we now define SMD, CI, and I² at first use. Finally, we softened the concluding language by stating that psychobiotics “may” represent a safe and potentially effective adjunctive approach, which better reflects the evidence and the limitations of the available studies.

Comment:
Introduction: The introduction should be broadened regarding the relationship between gut microbiota and BED, as well as the use of probiotics and psychobiotics. A proper contextualization of current drug therapies for BED should be provided. Lines 60–63 require bibliographic references and clarification regarding the Firmicutes/Bacteroidetes ratio. The subsequent paragraphs regarding dysbiosis in BED patients should be expanded. Names of bacterial genera must be written in italics. Please clarify the term “eating ED.” Please specify the particular bacterial strains used.

Response:
We addressed all of these points in the revised Introduction. We broadened the discussion of gut microbiota, BED, probiotics, and psychobiotics, and added a clearer overview of currently used drug therapies for BED. We inserted additional supporting references where needed, including references for dysbiosis-related concepts and the altered Firmicutes/Bacteroidetes ratio reported in BED-related literature. We expanded the discussion of dysbiosis in BED patients and corrected bacterial genus formatting to italics throughout. The unclear term “eating ED” was corrected. We also now specify the psychobiotic strains and formulations discussed in the manuscript, including Lactobacillus, Bifidobacterium, and Ligilactobacillus-related examples where relevant.

Comment:
Results: In Table 2 and Figure 1, please verify that references are written correctly and consistently. There are two tables identified as “Table 2.” Please correct the numbering. Please unify the font size across all tables and figures and ensure all references follow a single format.

Response:
Thank you. We reviewed and corrected the formatting throughout the Results section and supplementary materials. Reference formatting in figures and tables has been standardized to a consistent author–year style where applicable. The duplicate table numbering was corrected so that only one main Table 2 and one supplementary Table S2 remain. We also reviewed font size and formatting across tables and figures and standardized these elements as much as possible within the constraints of the figure-export software.

Comment:
Minor comments for the abstract and introduction.

Response:
All minor comments were addressed. In particular, we refined wording, corrected terminology, improved grammatical consistency, defined abbreviations at first mention, clarified mechanistic statements, and revised several passages in the Abstract and Introduction for readability and precision.

We are grateful for the reviewers’ and Academic Editor’s insightful comments, which have significantly improved the quality, clarity, and rigor of our manuscript. We hope that the revised version is now suitable for publication in Obesities.

Sincerely,
Ahmed El-Shamy (Corresponding Author), on behalf of all co-authors

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors have addressed all the comments made by this referee. The manuscript seems to be suitable for publication.