Review Reports - Rethinking Acne Vulgaris: The Gut–Skin Axis as a Central Mechanism and Therapeutic Target

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor,

I have reviewed the manuscript entitled “The Therapeutic Potential of Probiotics, Prebiotics, and Synbiotics in the Treatment of Acne Vulgaris.” The topic is relevant and timely; however, several revisions are necessary to improve clarity, scientific rigor, and overall structure.

Major Comments

Title
The title is somewhat generic and does not fully reflect the scientific scope of the manuscript. I recommend revising it to be more precise and informative, potentially incorporating the microbiome or gut–skin axis perspective and clarifying the nature of the review.
Abstract
The abstract is well-written but overly positive in tone. It should present a more balanced and critical perspective by acknowledging the limitations of current evidence. The authors should avoid generalized claims and better reflect the level of evidence available.
Introduction
The introduction requires reorganization for better scientific flow. I recommend the following order:

Definition of acne vulgaris
Epidemiology/prevalence
Etiology and pathophysiology

Currently, prevalence is presented too early, which disrupts the logical progression of ideas.

Section Organization (Axes 3 and 4)
There is noticeable redundancy between sections 3 and 4. The content should be streamlined to avoid repetition.

In Section 3 (“Probiotics, prebiotics, synbiotics – definitions and potential impact on acne”), the authors should add a clear definition of postbiotics, as this is an important and emerging concept in microbiome-based therapies.
Section 4 should focus strictly on clinical evidence, without repeating background or mechanistic details already discussed in Section 3.

Redundancy in Section 4 (Clinical Evidence)
The authors repeatedly conclude each study description with statements meaning “further research is needed.” This is redundant and reduces the impact of the discussion. Instead, such statements should be synthesized and presented once at the end of the section in a concise and cohesive manner.
Limitations Section
The limitations should be rewritten to provide a clearer and more structured critical appraisal of the evidence. The authors are encouraged to:

Figures and Visual Support
The manuscript lacks illustrative material to support key concepts. In particular, a figure illustrating the gut–skin axis and its role in acne pathogenesis and treatment would significantly enhance clarity and reader engagement. The authors are encouraged to include a schematic diagram summarizing:

Interactions between gut microbiota and skin
Immune and inflammatory pathways
Points of action of probiotics, prebiotics, synbiotics (and postbiotics)

Minor Comments

Correct formatting and typographical errors throughout the manuscript.
Improve conciseness by reducing overly long sentences and repetitive phrasing.

The manuscript addresses an important topic but requires moderate to substantial revision to enhance its scientific quality and readability.
Reviewer

Author Response

Dear Reviewer,

Thank you for studying the topics undertaken in our article and for your detailed review. In correcting our review, we followed all your recommendations, for which we are very thankful. Our corrections are presented below:

Major Comments

Title

The title is somewhat generic and does not fully reflect the scientific scope of the manuscript. I recommend revising it to be more precise and informative, potentially incorporating the microbiome or gut–skin axis perspective and clarifying the nature of the review.

Response: We appreciate this helpful comment. Following the Reviewer’s advice, we have revised the title to better reflect the scientific scope of the manuscript.

Abstract

The abstract is well-written but overly positive in tone. It should present a more balanced and critical perspective by acknowledging the limitations of current evidence. The authors should avoid generalized claims and better reflect the level of evidence available.

Response:

We would like to thank the reviewer for this comment. We have revised the Abstract. We have rewritten it in a more balanced style and added a critical discussion of the limitations. It now reads as follows:

“Acne vulgaris is a chronic inflammatory disease of the pilosabaceous unit with a multifactorial pathogenesis involving sebaceous gland activity, follicular hyperkeratinization, microbial dysbiosis, and immune dysregulation. Increasing attention has been given to the role of the skin and gut microbiome, as well as the gut-skin axis, although their clinical significance has not yet been fully explained. This review critically evaluates the current evidence regarding the use of probiotics, prebiotics, and synbiotics in the treatment of acne. Available studies suggest that microbiome-targeted interventions may influence inflammatory pathways, microbial composition, and metabolic regulators such as IGF-1 and mTORC1. Some clinical trials indicate improvements in acne severity and skin parameters following oral or local interventions. However, the evidence is heterogeneous and limited by small sample numbers, short study durations, and variability in formulations and outcomes. Therefore, although microbiome-based strategies may have potential as adjunctive therapy, their clinical efficacy remains uncertain. Further, well-designed, large-scale studies are needed to determine their role in dermatological practice.”

We hope that the reviewer will find it satisfactory in its current form.

Introduction

The introduction requires reorganization for better scientific flow. I recommend the following order: Definition of acne vulgaris Epidemiology/prevalence Etiology and pathophysiology Currently, prevalence is presented too early, which disrupts the logical progression of ideas.

Response: We thank the Reviewer for this suggestion. We have reorganized Introduction to follow a more systematic progression.

1. Section Organization (Axes 3 and 4) There is noticeable redundancy between sections 3 and 4. The content should be streamlined to avoid repetition.

Response:

We thank the Reviewer for this comment. Sections 3 and 4 have been revised to remove redundancy and improve clarity. Section 3 focuses on mechanistic aspects, while Section 4 has been streamlined to clinical evidence, with removal of overlapping background and mechanistic content.

In Section 3 (“Probiotics, prebiotics, synbiotics – definitions and potential impact on acne”), the authors should add a clear definition of postbiotics, as this is an important and emerging concept in microbiome- based therapies.

Response:

We thank the Reviewer for this valuable comment. A definition of postbiotics has been included in Section 4.2, where this topic is discussed in greater detail. We chose to introduce the definition in this section to maintain a clear logical flow, linking the concept of postbiotics directly with the subsequent discussion of studies on topical postbiotics. This approach allows for a more coherent presentation of the definition in the appropriate context.

Section 4 should focus strictly on clinical evidence, without repeating background or mechanistic details already discussed in Section 3.

Response:
We thank the Reviewer for this important comment. In response, Section 4 has been revised to focus strictly on clinical evidence. We have added more precise information regarding the design of the described clinical studies (e.g., open-label, placebo-controlled, randomized clinical trials) to improve clarity and scientific rigor. Notably, the section is now predominantly centered on clinical data, as 7 out of the 9 studies discussed involve human participants.
In addition, mechanistic content and background information previously overlapping with Section 3 have been removed wherever possible, while preserving the coherence and interpretability of the text.

Redundancy in Section 4 (Clinical Evidence) The authors repeatedly conclude each study description with statements meaning “further research is needed.” This is redundant and reduces the impact of the discussion. Instead, such statements should be synthesized and presented once at the end of the section in a concise and cohesive manner.

Response:
We thank the Reviewer for this valuable comment. In response, we have revised Section 4 by removing repetitive concluding statements after individual study descriptions. Instead, we added three concluding paragraphs at the end of Section 4.3, which provide a structured and coherent synthesis of the evidence presented in Sections 4.1, 4.2, and 4.3, in accordance with the Reviewer’s suggestion to present these statements once in a concise and cohesive manner.

Limitations Section

The limitations should be rewritten to provide a clearer and more structured critical appraisal of the evidence.

Response:

We would like to thank the reviewer for this comment. We have rewritten the “Limitations” section to make it more organized, resulting in a clearer presentation. In its current form, it reads as follows:

“Despite a growing body to evidence pointing to the role of microbiome modulation in the treatment of acne, the findings summarized in this review have several significant limitations that may affect the reliability of the current conclusions. Therefore, it should be interpreted with great caution.

A significant portion of the available studies are based on relatively small groups, often with less than 50 participants. Such a limited sample size reduces statistical power and increases the risk of error. Furthermore, many studies have a short duration (typically 4-12 weeks), which is insufficient to assess the long-term efficacy and durability of treatment effects in the case of a chronic and recurrent condition such as acne vulgaris.

Furthermore, the available literature is highly heterogeneous. There is significant variability in the probiotic strains, prebiotic substances, synbiotic formulations, doses, and routes of administration used. This heterogeneity significantly limits comparability between studies and makes it difficult to identify consistent therapeutic effects or develop standard treatment protocols. Importantly, microbiome-related effects are often strain-specific and therefore cannot be generalized across different interventions.

It is also important to note the methodological limitations that further weaken the strength of the evidence. Many studies lack proper randomization, placebo control, or double-blind design. Furthermore, the assessment of outcomes is not always standardized, and some studies rely on subjective or invalidated acne severity scales. These issues carry a risk of bias and may lead to an overestimation of treatment efficacy.

Finally, data on the long-term safety and potential adverse effects of microbiome-targeted interventions remain limited. This is particularly relevant for oral supplementation, which may induce permanent changes in the composition of the gut microbiota. Furthermore, potential interactions between microbiome-based therapies and conventional acne treatments – such as retinoids, antibiotics, or hormonal therapies – have not been adequately studied.

In summary, based on available literature, definitive conclusions regarding the efficacy and safety of microbiome modulation in the treatment of acne cannot be made. Therefore, these limitations underscore the need for more rigorous, standardized and long-term clinical trials.”

We hope the reviewer will find the revised version satisfactory.

The authors are encouraged to:

Figures and Visual Support

The manuscript lacks illustrative material to support key concepts. In particular, a figure illustrating the gut–skin axis and its role in acne pathogenesis and treatment would significantly enhance clarity and reader engagement. The authors are encouraged to include a schematic diagram summarizing:

Interactions between gut microbiota and skin

Immune and inflammatory pathways

Points of action of probiotics, prebiotics, synbiotics (and postbiotics)
Response: We thank the Reviewer for this comment. We have added a new figure (Figure 2) to the revised manuscript.

Minor Comments

Correct formatting and typographical errors throughout the manuscript.
Response: We thank the Reviewer for this important comment. The manuscript has been revised to correct typographical errors and formatting inconsistencies.

Improve conciseness by reducing overly long sentences and repetitive phrasing.
Response: We appreciate this helpful comment. We have revised the manuscript to improve clarity and conciseness. Long, complex sentences have been broken down into shorter, more direct statements, and redundant phrasing has been removed.

We have made every effort to prepare this revised version of the manuscript. We hope that the revisions we have made will meet with the reviewer’s approval and satisfaction. We kindly invite the reviewer to review the latest version of the article.

Kind regards

Anna Duda-Madej

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review discusses the potential applications of microecological agents (probiotics, prebiotics, and synbiotics) in the treatment of acne vulgaris. The topic is clinically relevant and the manuscript has a relatively complete structure. However, the writing logic of the review is not sufficiently concise, and there is considerable repetition of content across multiple sections.
1. It is recommended to merge sections "2.2 Skin microbiome" and "2.3 Gut Microbiome" into a single section entitled: "The Gut-Skin Axis: Integrated Role of Skin and Gut Microbiomes in Acne Pathogenesis". This section should be organized around the following sub-topics: “Overview of common mechanisms, Specifics of the skin microbiome, Specifics of the gut microbiome, The gut-skin axis”.
2. It is recommended to logically restructure the content of sections "3. Probiotics, prebiotics, synbiotics – definitions and potential impact on the acne" and "4. Clinical evidence for probiotics, prebiotics and synbiotics in acne management" into the following two sections:
Section 1: "3. Mechanisms of Action of Microbiome-Based Interventions in Acne". This section should comprehensively discuss the common mechanistic pathways of probiotics, prebiotics, and synbiotics, rather than addressing them separately in a piecemeal fashion.
Section 2: "4. Applications of Probiotics, Prebiotics, and Synbiotics in the Treatment of Acne". This section should provide a detailed discussion from three levels: in vitro studies, animal experiments, and clinical trials. Furthermore, the reported findings from in vitro and animal studies should be compiled into a single table.

Author Response

Dear Reviewer,

It is recommended to merge sections “2.2 Skin microbiome” and “2.3 Gut Microbiome” into a single section entitled: “The Gut-Skin Axis: Integrated Role of Skin and Gut Microbiomes in Acne Pathogenesis”;. This section should be organized around the following sub-topics: “Overview of common mechanisms, Specifics of the skin microbiome, Specifics of the gut microbiome, The gut-skin axis”.

Response:We thank the Reviewer for this insightful and constructive comment. Following this recommendation, we have carefully restructured the manuscript to improve clarity and logical flow. Specifically, the sections “2.2 Skin Microbiome” and “2.3 Gut Microbiome” have been merged into a single, integrated section entitled: “The Gut-Skin Axis: Integrated Role of Skin and Gut Microbiomes in Acne Pathogenesis.” This section has been reorganized to include the following subtopics: overview of common mechanisms, specifics of the skin microbiome, specifics of the gut microbiome, and the gut–skin axis, as suggested.

It is recommended to logically restructure the content of sections “ Probiotics, prebiotics, synbiotics – definitions and potential impact on the acne” and “ Clinical evidence for probiotics, prebiotics and synbiotics in acne management” into the following two sections:

Section 1: “ Mechanisms of Action of Microbiome-Based Interventions in Acne”. This section should comprehensively discuss the common mechanistic pathways of probiotics, prebiotics, and synbiotics, rather than addressing them separately in a piecemeal fashion.
Response:
We appreciate this constructive comment. In response, the title of section 3 has been changed to: “Mechanisms of Action of Microbiome-Based Interventions in Acne”. In the revised section, we presented the mechanisms of action of probiotics, prebiotics, and synbiotics in an integrated manner, wherever supporting evidence was available (particularly for synbiotics interventions): in section 3.1 “Microbiota and metabolome modulation” we discussed potential alterations in both gut and skin microbiota, associated metabolomic changes, as well as antimicrobial effects; in section 3.2 “Cytokine modulation and inflammation control” we provide a comprehensive overview of immunomodulatory mechanisms; in section 3.3 “Insulin sensitivity and lipogenesis” we addressed the impact of these interventions on systemic metabolism, including hormonal regulation and sebogenesis.

Section 2: “ Applications of Probiotics, Prebiotics, and Synbiotics in the Treatment of Acne”. This section should provide a detailed discussion from three levels: in vitro studies, animal experiments, and clinical trials. Furthermore, the reported findings in vitro and animal studies should be compiled into a single table.

Response:
We thank the Reviewer for this valuable suggestion. The title of Section 4 has been changed to: “Applications of Probiotics, Prebiotics, Postbiotics and Synbiotics in the Treatment of Acne”. The manuscript has also been appropriately revised to improve the organization of Section 4 by distinguishing, where possible, between in vitro, animal, and clinical studies. In the case of clinical studies, more precise descriptions of study designs (e.g., randomized, open-label, placebo-controlled trials) have been added to highlight the clinical relevance and methodological quality of this section.

However, as the majority of the included studies (7 out of 9) are clinical in nature and several reports combine different experimental approaches, a strict separation into three fully independent subsections was not feasible. Therefore, an integrated structure was maintained to preserve coherence and accurately reflect the available evidence. Additionally, the required summary table (Table 1. Experimental interventions and assessed outcomes.) has been added to improve clarity and facilitate comparison of the included studies.

Kind regards

Anna Duda-Madej

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

authors have made the necessary revisions

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have carefully answered my questions and made improvements to the manuscript.