Unraveling the Gut–Skin Axis: The Role of Microbiota in Skin Health and Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review focuses on the connection between the gut microbiota and the skin, namely its health and the way dysbiosis contributes to certain inflammatory conditions. The gut microbiota remains a highly relevant topic with a plethora of novelty to unfold.

The introduction is quite vast, detailing several of the skin’s components and how it functions. The authors begin by giving a brief introduction on the skin as an immune system and how it contributes to regulating health. It then transitions to the gut microbiota, albeit it does not go into as much detail as the skin’s section. As this has been vastly reported, it would go beyond the scope of this review to detail it further. However, throughout the manuscript, authors lack some perspective, sometimes going into redundant details or repeating information unnecessarily. Only on line 297 do we get a first glimpse of the topic of this review.

This review would benefit from restructuring, with the authors being more focused on the theme throughout the entirety of the sections. It would avoid repeating already mentioned information. Additionally, the review does not dwell on what should be its main topic: how the gut-skin axis is connected and how this pertains to the improvement (or not) of several skin conditions. The authors place rosacea, atopic dermatitis, acne and psoriasis all in the same “bag”, even though these are extremely different conditions with different immune alterations and mechanisms.

The scope of this review is well written and the methodology well established.

Major:

Line 76: How do advanced glycation end-products contribute to impaired skin structure and function?

Line 86: I suggest removing the “In conclusion” to better establish the connection with the following section.

The first paragraph of section 2.1 seems repetitive as the authors say pretty much the same thing on the first paragraph of section 1.2. As it appears before, consider adding the necessary information there, and removing it from section 2.1. The authors may consider rewriting the first sentence of the second paragraph to connect with section 1.2. E.g. As previously mentioned, the gut microbiota contains several etc etc. All these microbial communities…

Line 227: This has been mentioned before (line 184). Please rewrite. E.g.: As mentioned, medications also play a role in gut microbiota composition.

Line 416: Placing all of these conditions and mentioning how a healthier diet can “reduce” these conditions seems a bit of a stretch. All the conditions mentioned have underlying extremely complex immune responses that are different among them. Simply saying a diet can “reduce” them (and not the associated symptoms) is wrong. Also, not exploring it further leaves a gap in the review.

Line 580: Is it a delicate balance or is the microbiota resilient, as mentioned in line 179?

Are there in vivo studies pertaining to the topic of this review?

How altered is the skin microbiome in psoriatic (and in other non-psoriatic) patients? Could the dysbiosis of the skin’s microbiota be associated with the dysbiosis of the gut microbiota? Why is this not explored further?

Figure 2: “By strengthening the intestinal barrier, these SCFAs lessen systemic inflammation, which exacerbates skin disorders”. A better way to phrase it could be replacing the final part of the sentence with “which in turn, could help ameliorate skin disorders”.

Minor:

Line 53: Candida albicans should be written in italics.

Line 57: Please write MHC in full before using it as an abbreviation.

Line 74: Please write TCA in full before using it as an abbreviation.

Line 76: Please write AGE in full before using it as an abbreviation.

Line 136: Consider replacing “like” with “including” and rephrasing accordingly.

Line 184: Rewriting proposal: “Thus, the composition of the gut microbiota is mainly influenced by early life exposure, genetics diet and medications.” Also, consider not doing paragraph and joining this sentence with the paragraph beforehand.

Line 204: Again, consider joining this sentence with the following paragraph, as it works as a small introduction.

Author Response

R1

We thank you for your suggestions and comments, dear reviewer. We give our response to the queries in red, and the reviewers’ are in black.

Comments:

This review focuses on the connection between the gut microbiota and the skin, namely its health and the way dysbiosis contributes to certain inflammatory conditions. The gut microbiota remains a highly relevant topic with a plethora of novelty to unfold.

The introduction is quite vast, detailing several of the skin’s components and how it functions. The authors begin by giving a brief introduction on the skin as an immune system and how it contributes to regulating health. It then transitions to the gut microbiota, albeit it does not go into as much detail as the skin’s section. As this has been vastly reported, it would go beyond the scope of this review to detail it further. However, throughout the manuscript, authors lack some perspective, sometimes going into redundant details or repeating information unnecessarily. Only on line 297 do we get a first glimpse of the topic of this review.

You are right, according to your suggestions, we appreciate that our manuscript has been significantly improved.

This review would benefit from restructuring, with the authors being more focused on the theme throughout the entirety of the sections. It would avoid repeating already mentioned information. Additionally, the review does not dwell on what should be its main topic: how the gut-skin axis is connected and how this pertains to the improvement (or not) of several skin conditions. The authors place rosacea, atopic dermatitis, acne and psoriasis all in the same “bag”, even though these are extremely different conditions with different immune alterations and mechanisms.

You're right, thank you for the suggestion. We've made clarifications on this.

The scope of this review is well written and the methodology well established.

Major:

Line 76: How do advanced glycation end-products contribute to impaired skin structure and function?

Thank you for the question! We explained this with the following paragraph:

The dangerous substances known as Advanced Glycation End-products (AGEs) are created when proteins and carbs interact. They cause wrinkles, sagging, and a lack of elasticity by harming important proteins like collagen and elastin, which accelerates the aging process of the skin [10]. Because they adversely affect multiple tissues by producing reactive oxygen species (ROS), aberrant proteins or growth factors, changing the structure of the extracellular matrix (ECM), and secreting pro-inflammatory cytokines, AGEs are potentially harmful molecules that pose a threat to human health [11, 12]. They damage the skin's protective barrier, leading to dryness, and can impact skin cells, causing structural changes, hyperpigmentation, and the breakdown of collagen and elastin [13]. 

Line 86: I suggest removing the “In conclusion” to better establish the connection with the following section.

Thank you, we corrected according to your suggestion.

The first paragraph of section 2.1 seems repetitive as the authors say pretty much the same thing on the first paragraph of section 1.2. As it appears before, consider adding the necessary information there, and removing it from section 2.1. The authors may consider rewriting the first sentence of the second paragraph to connect with section 1.2. E.g. As previously mentioned, the gut microbiota contains several etc etc. All these microbial communities…

We made the changes according to your observations. Thank you!

Line 227: This has been mentioned before (line 184). Please rewrite. E.g.: As mentioned, medications also play a role in gut microbiota composition.

As you recommended, we deleted the text.

Line 416: Placing all of these conditions and mentioning how a healthier diet can “reduce” these conditions seems a bit of a stretch. All the conditions mentioned have underlying extremely complex immune responses that are different among them. Simply saying a diet can “reduce” them (and not the associated symptoms) is wrong. Also, not exploring it further leaves a gap in the review.

You are right. Thank you very much for the suggestion. As you recommended, we have made the changes.

Line 580: Is it a delicate balance or is the microbiota resilient, as mentioned in line 179?

Thank you for this question! The relationship between the gut microbiota and its stability is best understood as a dynamic equilibrium, possessing both resilience and a delicate balance. These two concepts are not mutually exclusive, instead, they describe different aspects of how the microbial community responds to various factors.

Are there in vivo studies pertaining to the topic of this review?

Yes, they are presented more efficiently after this question. Thank you!

How altered is the skin microbiome in psoriatic (and in other non-psoriatic) patients? Could the dysbiosis of the skin’s microbiota be associated with the dysbiosis of the gut microbiota? Why is this not explored further?

Thank you for the questions. The answers to these questions make our article much better.

Figure 2: “By strengthening the intestinal barrier, these SCFAs lessen systemic inflammation, which exacerbates skin disorders”. A better way to phrase it could be replacing the final part of the sentence with “which in turn, could help ameliorate skin disorders”.

Thank you for the observation. We made the changes according to it.

Minor:

Line 53: Candida albicans should be written in italics.

You are right. We wrote in italics.

Line 57: Please write MHC in full before using it as an abbreviation.

We wrote the full definition.

Line 74: Please write TCA in full before using it as an abbreviation.

You are right. We added the full text.

Line 76: Please write AGE in full before using it as an abbreviation.

You are right. We added the full text.

Line 136: Consider replacing “like” with “including” and rephrasing accordingly.

Thank you. We corrected.

Line 184: Rewriting proposal: “Thus, the composition of the gut microbiota is mainly influenced by early life exposure, genetics diet and medications.” Also, consider not doing paragraph and joining this sentence with the paragraph beforehand.

Good idea! Thank you very much!

Line 204: Again, consider joining this sentence with the following paragraph, as it works as a small introduction.

Good idea! Thank you very much!

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

The paper is well done and enclosed by right figure and sufficient references.Nowever the english language has to be reviewed as well as the Introduction is to be ameliorated

Comments on the Quality of English Language

In my opinion the english language has to be ameliorated as well as the Introduction remarks.However the paper is sufficiently clear,also if ,in my opinion,could be written more simply.Conclusion and references as well as the reported figures are ok.

Author Response

R 2

We thank you for your suggestions and comments, dear reviewer. We give our response to the queries in red, and the reviewers’ are in black.

The paper is well done and enclosed by right figure and sufficient references.Nowever the english language has to be reviewed as well as the Introduction is to be ameliorated

We kindly thank you for reading our manuscript thoroughly and with such detail. The English language was reviewed, and the Introduction was enhanced.

In my opinion the english language has to be ameliorated as well as the Introduction remarks.However the paper is sufficiently clear,also if ,in my opinion,could be written more simply.Conclusion and references as well as the reported figures are ok.

We sincerely thank you for your appreciation. We have improved our manuscript according to your suggestions

Reviewer 3 Report

Comments and Suggestions for Authors

Authors' review covers an interesting and very current topic. However, I have some concerns about this review that may improve its quality.

1. Figure 1 is too simple. Authors should represent in more details the gut-skin axis as described in the figure legends.
2. Citation 18 is poorly reliable and does not add any useful information to the reader. I suggest to remove it and focus on more recent literature.
3. In chapter 2.1 the literature cited is scarse. Authors should check other papers published and use also that information to reinforce their concepts.
4. Figure 2 is not clear. I suggest authors to recreate maybe using Biorender.
5. The skin-gut axis is superficially described and requires a deeper description.

In general, the review is interesting but requires an extensive revision of the language, that has several errors throughout the text and some revisions of the manuscript as I suggested. 

Author Response

R 3

We thank you for your suggestions and comments, dear reviewer. We give our response to the queries in red, and the reviewers’ are in black.

1. Figure 1 is too simple. Authors should represent in more details the gut-skin axis as described in the figure legends.

Thank you for your suggestion. Figure 1 now represents in more detail the gut-skin axis.

2. Citation 18 is poorly reliable and does not add any useful information to the reader. I suggest to remove it and focus on more recent literature.

According to your suggestion, citation 18 was removed, and now the beginning of the paragraph has been improved.

3. In chapter 2.1 the literature cited is scarse. Authors should check other papers published and use also that information to reinforce their concepts.

We appreciate your attention to detail, and Chapter 2.1 has been enhanced with other papers and information.

4. Figure 2 is not clear. I suggest authors to recreate maybe using Biorender.

Thank you for your observation! We improved the quality of Figure 2.

5. The skin-gut axis is superficially described and requires a deeper description.

We are grateful for your opinion. The skin-gut axis is now better described in Chapter 1.3.

 

Reviewer 4 Report

Comments and Suggestions for Authors

 

• Specify whether the review focuses on clinical evidence, mechanistic pathways, or therapeutic interventions. For instance, rephrase to: “This review critically examines the mechanistic pathways and therapeutic potential of targeting the gut microbiota in dermatological diseases.”
• Add a sentence briefly summarizing key mechanisms (e.g., role of short-chain fatty acids, Th17/IL-17 pathway) to strengthen the scientific depth
• Clarify with an example or reference how skin diseases might impact gut microbiota (e.g., via systemic inflammation or altered neuroendocrine signaling)
  • Acknowledge challenges such as variability in individual responses, regulatory issues, or limited clinical trial data supporting probiotics for skin health.

   

  • Mention if the Manuscript includes recent clinical trials, novel microbial targets, or integrates multidisciplinary insights (e.g., microbiology + dermatology + immunology).

   

 

Comments on the Quality of English Language

Language editing could enhance overall readability;

e.g.:

Phrases like “crucial field of study” and “exciting possibilities” are somewhat vague and subjective. May  use more academic and precise language, e.g., “emerging area of research” instead of “crucial field of study”, and “promising therapeutic avenues” instead of “exciting possibilities.”

• • “…has become a crucial field of study for comprehending…” → “…has emerged as a critical area of study for understanding…”

 

 

Author Response

R 4

We thank you for your suggestions and comments, dear reviewer. We give our response to the queries in red, and the reviewers’ are in black.

Comments:

 

Specify whether the review focuses on clinical evidence, mechanistic pathways, or therapeutic interventions. For instance, rephrase to: “This review critically examines the mechanistic pathways and therapeutic potential of targeting the gut microbiota in dermatological diseases.”

 

Thank you very much for the observation! We rephrased.

 

Add a sentence briefly summarizing key mechanisms (e.g., role of short-chain fatty acids, Th17/IL-17 pathway) to strengthen the scientific depth

Good idea! We added key mechanisms. Thank you!

Clarify with an example or reference how skin diseases might impact gut microbiota (e.g., via systemic inflammation or altered neuroendocrine signaling)

 

Thank you for the suggestion. We clarified.

 

Acknowledge challenges such as variability in individual responses, regulatory issues, or limited clinical trial data supporting probiotics for skin health.

Thank you so much! We added information according to your requirements.

Mention if the Manuscript includes recent clinical trials, novel microbial targets, or integrates multidisciplinary insights (e.g., microbiology + dermatology + immunology).

Thank you! We mentioned all these in our manuscript.

 

Language editing could enhance overall readability;

 

e.g.:

 

Phrases like “crucial field of study” and “exciting possibilities” are somewhat vague and subjective. May  use more academic and precise language, e.g., “emerging area of research” instead of “crucial field of study”, and “promising therapeutic avenues” instead of “exciting possibilities.”

 

“…has become a crucial field of study for comprehending…” → “…has emerged as a critical area of study for understanding…”

You are right! Thank you so much. We used more academic and precise language.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been greatly improved and seems appropriate for publication.

Author Response

The manuscript has been greatly improved and seems appropriate for publication.

Thank you, we appreciate your feedback.

Reviewer 3 Report

Comments and Suggestions for Authors

Authors addressed most of my comments, but I still have a concern about Figure 1. The figure legend describes very well the skin-gut axis that does not correlate with the picture. I suggest to authors to represent exactly the figure legend in Figure 1 to allow the reader to immediately understand the skin-gut axis that could be not so easy to understand. 

Author Response

Authors addressed most of my comments, but I still have a concern about Figure 1. The figure legend describes very well the skin-gut axis that does not correlate with the picture. I suggest to authors to represent exactly the figure legend in Figure 1 to allow the reader to immediately understand the skin-gut axis that could be not so easy to understand. 

Thank you for your valuable suggestions and feedback.
We have revised Figure 1 according to your comments to better represent the figure legend and clarify the skin-gut axis for the reader. The revised figure has been added to the manuscript.