Post-COVID Gut Dysbiosis and Its Role in Persistent Skin Disorders: A Gut–Skin Axis Perspective

Round 1

Reviewer 1 Report

Consider adding a sentence explicitly outlining the review's objectives (e.g., to explore mechanisms, clinical implications, and potential interventions).

Explain why post-COVID gut dysbiosis is particularly relevant to dermatologic conditions, referencing the most recent studies (2023–2024) if possible.

Revise statements that suggest causality between gut dysbiosis and skin disorders—many cited studies are observational.

Add a limitations section acknowledging gaps in research, such as: lack of large-scale, longitudinal studies on post-COVID gut microbiome changes, and insufficient clinical trials testing microbiome-targeted interventions for skin disorders, etc.

Suggest future research directions, such as randomized controlled trials on probiotic treatments for post-COVID dermatologic conditions.

Consider also including studies that do not support a strong gut-skin connection to provide a balanced perspective.

Discuss alternative explanations for post-COVID skin manifestations (e.g., systemic inflammation, autoimmune dysregulation) rather than solely focusing on gut microbiome changes.

Provide a detailed discussion on gut-skin axis pathways, including: the role of short-chain fatty acids (SCFAs) in modulating skin inflammation; how gut permeability ("leaky gut") might influence systemic immune responses, and the interaction between gut microbiota and cytokine release (IL-17, IL-22) in inflammatory skin diseases.

Ensure all mechanistic claims are supported by primary research articles rather than review papers.

Revise figure captions to provide more detail on the mechanistic pathways illustrated (e.g., clearly label SCFA effects, cytokine interactions).

Include references for intervention tables to ensure dietary and probiotic recommendations are evidence-based.

Ensure figures are high-resolution and easily readable.

Discuss how dermatologists can integrate microbiome-targeted interventions into clinical practice.

Provide screening recommendations for long COVID patients with persistent skin disorders (e.g., should gut microbiome testing be considered?).

Summarize potential treatment options (probiotics, prebiotics, dietary changes) and their current level of clinical evidence.

Ensure that older references (pre-2019) are replaced with more recent meta-analyses or cohort studies where possible.

Revise long, complex sentences for better readability.

Ensure consistent terminology usage (e.g., standardize "gut microbiota" vs. "gut microbiome").

Conduct a final proofreading.

See above.

Author Response

1. Consider adding a sentence explicitly outlining the review's objectives (e.g., to explore mechanisms, clinical implications, and potential interventions).

We thank the reviewer for this valuable suggestion. In response, we have added the following sentence to the end of the introduction:

“This review aims to explore the mechanisms by which SARS-CoV-2-induced gut dysbiosis may contribute to persistent skin disorders, examine the clinical implications of the gut-skin axis in long COVID, and evaluate potential microbiome-targeted interventions for managing post-COVID dermatologic conditions.”

2. Explain why post-COVID gut dysbiosis is particularly relevant to dermatologic conditions, referencing the most recent studies (2023–2024) if possible.

We thank the reviewer comment. The added sentence in section 2.4 now reads:

“Emerging evidence supports this link, with studies showing that gut dysbiosis in long COVID patients is associated with elevated levels of circulating inflammatory markers, such as IL-6 and TNF-α, which are known to exacerbate skin conditions.”

3. Revise statements that suggest causality between gut dysbiosis and skin disorders—many cited studies are observational.

We thank the reviewer for their comments. Please see below for the changes made, which are also highlighted in red in the Tracked Version of the new manuscript:

Introduction

Original:
"Given that COVID-19-induced gut dysbiosis triggers systemic inflammation, it is plausible that these changes contribute to persistent - or even worsening - dermatologic conditions such as eczema, acne, and rosacea in long COVID patients."

Revised:
"Given that COVID-19-induced gut dysbiosis is linked to systemic inflammation, these changes may be associated with persistent - or even worsening - dermatologic conditions such as eczema, acne, and rosacea in long COVID patients."

Section 2.4 - Clinical Evidence of Gut Dysbiosis in COVID-19 Survivors

Original:
"This connection suggests that the systemic inflammation driven by gut dysbiosis may contribute to dermatologic manifestations such as eczema, acne, and psoriasis."

Revised:
"This connection suggests that systemic inflammation associated with gut dysbiosis may play a role in dermatologic manifestations such as eczema, acne, and psoriasis."

Section 3.1 - Mechanisms Linking Gut Dysbiosis to Skin Inflammation

Original:
"The gut microbiome plays a crucial role in regulating systemic immune responses, and disruptions in microbial balance can contribute to chronic inflammation that manifests in various organs, including the skin."

Revised:
"The gut microbiome plays a crucial role in regulating systemic immune responses, and disruptions in microbial balance have been linked to chronic inflammation that may affect various organs, including the skin."

Section 3.2 - Post-COVID Dermatologic Conditions Associated with Gut Dysbiosis

Original:
"Acne and rosacea have also been reported in long COVID patients. Firstly, gut dysbiosis can contribute to acne by increasing systemic inflammation and altering hormonal regulation."

Revised:
"Acne and rosacea have also been reported in long COVID patients. Some evidence suggests that gut dysbiosis may be linked to acne by increasing systemic inflammation and altering hormonal regulation."

Conclusion

Original:
"Disruptions in the gut microbiome contribute to systemic inflammation, increased intestinal permeability, and immune dysregulation, all of which can exacerbate skin conditions such as eczema, acne, rosacea, and psoriasis."

Revised:
"Disruptions in the gut microbiome have been associated with systemic inflammation, increased intestinal permeability, and immune dysregulation, which may influence skin conditions such as eczema, acne, rosacea, and psoriasis."

4. Add a limitations section acknowledging gaps in research, such as: lack of large-scale, longitudinal studies on post-COVID gut microbiome changes, and insufficient clinical trials testing microbiome-targeted interventions for skin disorders, etc.

We thank the reviewer for this important suggestion. In response, we have added a section titled "Limitations and Future Research Directions" in section 5.1, where we discuss the gaps in current research, including the lack of large-scale, longitudinal studies on post-COVID gut microbiome changes and the insufficient clinical trials testing microbiome-targeted interventions for skin disorders.

5. Suggest future research directions, such as randomized controlled trials on probiotic treatments for post-COVID dermatologic conditions.

We appreciate the reviewer’s helpful suggestion. In response, we have included a discussion of potential future research directions in section 5.1, where we propose the conduct of randomized controlled trials on probiotic treatments for post-COVID dermatologic conditions.

6. Consider also including studies that do not support a strong gut-skin connection to provide a balanced perspective.

We thank the reviewer for this important suggestion. Paragraph added to section 3.3 now reads: “However, not all studies support a strong gut-skin connection in long COVID. Some research has found that while gut dysbiosis is common in long COVID patients, the correlation with skin conditions is less clear. One 2024 found no significant association between gut microbiome alterations and the severity of skin conditions in long COVID patients, suggesting that other factors, such as direct viral effects or immune dysregulation, may play a more prominent role in dermatologic manifestations  Similarly, a meta-analysis concluded that while gut dysbiosis is prevalent in long COVID, its impact on skin health may be overstated, with only weak correlations observed between gut microbiome changes and specific skin conditions like eczema and psoriasis.”

7. Discuss alternative explanations for post-COVID skin manifestations (e.g., systemic inflammation, autoimmune dysregulation) rather than solely focusing on gut microbiome changes.

We thank the reviewer for this insightful suggestion. In response, we have expanded the final two paragraphs of section 3.3 to include additional explanations for post-COVID skin manifestations, such as systemic inflammation and autoimmune dysregulation, alongside the discussion of gut microbiome changes.

8. Provide a detailed discussion on gut-skin axis pathways, including: the role of short-chain fatty acids (SCFAs) in modulating skin inflammation; how gut permeability ("leaky gut") might influence systemic immune responses, and the interaction between “ and cytokine release (IL-17, IL-22) in inflammatory skin diseases.

We thank the reviewer for this valuable suggestion. In response, we have expanded section 3.1 to include a detailed discussion of the gut-skin axis pathways. This includes the role of short-chain fatty acids (SCFAs) in modulating skin inflammation, the potential influence of gut permeability ("leaky gut") on systemic immune responses, and the interaction between gut microbiota and cytokine release in inflammatory skin diseases.

9. Ensure all mechanistic claims are supported by primary research articles rather than review papers.

Thank you for your comment. We have made every effort to replace review papers with primary research articles to support all mechanistic claims. Where appropriate, we have cited the most relevant studies to ensure a strong foundation for the claims presented.

10. Revise figure captions to provide more detail on the mechanistic pathways illustrated (e.g., clearly label SCFA effects, cytokine interactions).

Thank you for your comment. While we appreciate the suggestion to add more details, we aimed to keep the figure as simple and clear as possible. Adding additional details, such as labeling SCFA effects and cytokine interactions, may potentially overwhelm the reader or detract from the overall clarity of the figure. We believe the current version maintains the balance between simplicity and informativeness.

11. Include references for intervention tables to ensure dietary and probiotic recommendations are evidence-based.

Thank you for your suggestion. References have been added to Table 2 to support the listed claims and provide clearer insight. Please see the updated table for these additions.

12. Ensure figures are high-resolution and easily readable.

Thank you for your comment. We have ensured that all figures are high-resolution and easily readable to meet the review's requirements.

13. Discuss how dermatologists can integrate microbiome-targeted interventions into clinical practice.

Thank you for your comment. The following was added to section 5, “Discussion”:

“Dermatologists can integrate microbiome-targeted interventions into clinical practice by evaluating patients’ gut health as part of a comprehensive approach to managing dermatologic conditions. This could involve recommending probiotic and prebiotic supplements, dietary adjustments, and, where appropriate, referrals for further microbiome-based therapies like FMT. As the evidence base grows, dermatologists may also incorporate microbiome sequencing to personalize treatments, targeting specific microbial imbalances contributing to skin conditions.”

14. Provide screening recommendations for long COVID patients with persistent skin disorders (e.g., should gut microbiome testing be considered?).

Thank you for your comment. The following was added to section 5, “Discussion”:

For long COVID patients with persistent skin disorders, it may be beneficial to consider gut microbiome testing as part of a diagnostic workup, especially when traditional treatments fail. This could help identify underlying dysbiosis contributing to skin symptoms and guide targeted microbiome-based therapies.

15. Summarize potential treatment options (probiotics, prebiotics, dietary changes) and their current level of clinical evidence.

Thank you for your comment. We have done so in Tables 1 and 2.

16. Ensure that older references (pre-2019) are replaced with more recent meta-analyses or cohort studies where possible.

Thank you for your comment. We have updated the citations, ensuring that all references are from 2019 or more recent, prioritizing meta-analyses and cohort studies where applicable.

17. Revise long, complex sentences for better readability.

Thank you for your comment. We have revised several sections to simplify long, complex sentences and improve overall readability.

18. Ensure consistent terminology usage (e.g., standardize "gut microbiota" vs. "gut microbiome").

Thank you for your helpful comment. We have reviewed the manuscript and ensured that the the terminology for "gut microbiota" and "gut microbiome" are correct throughout the text. In cases where the focus is on the microorganisms themselves, We have used "gut microbiota", and where the genetic material or functional aspects of these microorganisms are discussed, we have used "gut microbiome". This distinction has been clarified to ensure consistency and accuracy in terminology. Paragraph 1 of section 2, “COVID-19 and Gut Dysbiosis” now reads as follows:

“COVID-19 affects the GI tract through multiple mechanisms and leads to significant alterations in gut microbiota composition, a condition known as "gut dysbiosis" (the imbalance in the microbial community). This is not to be confused with the gut micro-biome, which refers to the collective genetic material of these microorganisms, and also plays a crucial role in maintaining gut health.”

19. Conduct a final proofreading.

Thank you for your suggestion. A final proofreading has been completed to ensure clarity, accuracy, and consistency throughout the manuscript.

Reviewer 2 Report

Review paper "Post-COVID Gut Dysbiosis and Its Role in Persistent Skin Dis- 2
orders: A Gut-Skin Axis Perspective" by Dorra Guermazi provides a comprehensive insight of the long-term COVID-19 consequences that were not explored enough. The contribution to the field is significant as the manuscript not only summarizes the knowledge about post-covid microbiota dysbiosis and related consequences to systemic and local, skin immune reactivity, but it also proposes the treatment. At some points, the narrative is too vague. Manuscript could be improved by using more detailed language regarding conclusions of in vitro, in vivo, clinical trials etc.  In addition, author should avoid repetition and redundancy of information in the manuscript. 

Line 74 - The statement is too vague. Please explain if the study  was done on animal model and if there were supporting studies involving human participants. Which part of the immune system was affected and where (lungs, GIT, blood...)?

Line 76 - Please provide references for this statement. 

Lines 103 - 109 Please provide the source for these statements.

Line 130 - Please avoid repetition of the phrases such as leaky gut. It was mentioned earlier in the text and again, later in the manuscript.

Here, it would be useful to add relevant information about the type of immune cells and their effector molecules that are involved and affected by leaky gut as well as how this exactly affects skin (based on data obtained from animal models and from human studies). 

Lines 230-235 - please provide the references.

Section 290-313 should be written in more details, outlining findings from animal models and then main conclusions and limitations of clinical trials. 

The whole Discussion section seems to repeat a majority of ideas outlined earlier in the text. Please provide new information here or just a short summary.

Table 1 - please add references that support listed claims, for more clear insight.

Table 1 and Table 2 seem to be redundant. I suggest that author make one table and include information from both present tables , for more clarity.

Author Response

We thank the reviewer for their comments. Please see below for our responses. 

Response to Reviewer 2 Comments

1. The Discussion section repeats information provided earlier in the text. Please see the comments.

Thank you for your helpful comment. The Discussion section has been significantly condensed to reduce repetition and enhance clarity. Please see the revised Section 5, "Discussion," for the updated version.

2. Line 74 - The statement is too vague. Please explain if the study  was done on animal model and if there were supporting studies involving human participants. Which part of the immune system was affected and where (lungs, GIT, blood...)?

Thank you for your helpful comment. Statement now reads: Evidence from both human and animal studies suggests that gut dysbiosis can worsen pulmonary inflammation, and vice versa, creating a cycle of persistent immune activation that prolongs recovery. In humans, long COVID patients with gut dysbiosis show in-creased systemic inflammation, particularly in the lungs and gastrointestinal tract. Animal studies further support this by demonstrating that gut dysbiosis leads to immune dysregulation, affecting immune cells like Th17 cells and macrophages, which contribute to inflammation in both the gut and lungs

3. Line 76 - Please provide references for this statement. 

Thank you for your comment. We have added the appropriate references to support this statement.

4. Lines 103 - 109 Please provide the source for these statements.

Thank you for your comment. We have added the appropriate references to support this statement.

5. Line 130 - Please avoid repetition of the phrases such as leaky gut. It was mentioned earlier in the text and again, later in the manuscript.

Thank you for your feedback. All mentions of "leaky gut" have been removed to avoid repetition while maintaining clarity.

6. Here, it would be useful to add relevant information about the type of immune cells and their effector molecules that are involved and affected by leaky gut as well as how this exactly affects skin (based on data obtained from animal models and from human studies). 

Repetition of “leaky gut” has been removed and information on LPS, TLR4, Th17 and 22, and Tregs has been added.

7. Lines 230-235 - please provide the references.

Thank you for your comment. We have added the appropriate references to support this statement.

8. Section 290-313 should be written in more details, outlining findings from animal models and then main conclusions and limitations of clinical trials. 

Thank you for your feedback.We  have expanded Section 4.3 to include animal model findings, detailing how FMT reduces inflammation and improves skin health. We have also clarified clinical trial conclusions, highlighting its efficacy in IBD and IBS while noting the limited dermatologic data. Additionally, we have outlined key limitations, including donor variability, safety concerns, and the need for standardized protocols. Lastly, we have addressed gaps in emerging therapies, such as rifaximin and butyrate, in the context of long COVID skin conditions. Please see Section 4.3 for the revisions.

9. The whole Discussion section seems to repeat a majority of ideas outlined earlier in the text. Please provide new information here or just a short summary.

The discussion has been heavily condensed. Please see updated section 5, “Discussion”

10. Table 1 - please add references that support listed claims, for more clear insight.

Thank you for your suggestion. References have been added to Table 1 to support the listed claims and provide clearer insight. Please see the updated table for these additions.

11. Table 1 and Table 2 seem to be redundant. I suggest that author make one table and include information from both present tables, for more clarity.

Thank you for your suggestion. To maintain clarity and logical flow, we have kept Tables 1 and 2 separate—Table 1 focuses on dermatologic conditions, while Table 2 highlights microbiome-based interventions. This separation improves readability and ensures each table serves a distinct purpose. We appreciate your feedback.

Round 2

Reviewer 1 Report

Add further discussion on endothelial dysfunction and its role in dermatologic changes in Section 3.3, and cite additional recent literature if available.

Consider adding a supplementary figure legend to clarify the suggested mechanistic pathways.

See above.

Author Response

Dear Reviewer,

We sincerely appreciate your time and effort in reviewing our manuscript. Your insightful comments and suggestions have been invaluable in refining our work. We have carefully considered your feedback and made the necessary revisions, and we hope that our edits effectively address your concerns. Thank you again for your thoughtful review and for helping us improve our manuscript. We truly appreciate your expertise and guidance.

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Responses to reviewer comments:

1. Add further discussion on endothelial dysfunction and its role in dermatologic changes in Section 3.3, and cite additional recent literature if available.

We thank the reviewer for their comment. The following has been added to Section 3.3 and is highlighted in Red in the Tracked version of the manuscript submitted:

“Endothelial dysfunction may further contribute to these dermatologic manifestations, as SARS-CoV-2 has been shown to directly infect endothelial cells, leading to vascular damage, impaired microcirculation, and increased vascular permeability. These effects can manifest in the skin as rashes, chilblains, and livedo reticularis, which have been frequently reported in long COVID patients. Endothelial injury also promotes a pro-thrombotic state, potentially contributing to vasculopathy-related skin conditions such as purpura and necrosis.”

“Furthermore, endothelial dysfunction exacerbates systemic inflammation by increasing the release of pro-inflammatory cytokines and reactive oxygen species, creating a cycle of immune activation that worsens skin conditions. A recent study found that long COVID patients with persistent skin symptoms exhibited elevated markers of endothelial activation, including von Willebrand factor and soluble thrombomodulin, highlighting the potential role of vascular pathology in post-COVID dermatologic changes”

“These vascular changes, combined with systemic inflammation and immune dysregulation, provide additional mechanisms linking endothelial dysfunction to post-COVID skin conditions.”

Below are the new Sources added, which have been cited in the manuscript text:

1. Canale MP, Menghini R, Martelli E, Federici M. COVID-19-Associated Endothelial Dysfunction and Microvascular Injury: From Pathophysiology to Clinical Manifestations. Card Electrophysiol Clin. 2022 Mar;14(1):21-28. doi: 10.1016/j.ccep.2021.10.003. Epub 2021 Oct 30. PMID: 35221082; PMCID: PMC8556628.
2. Gu, S.X., Tyagi, T., Jain, K. et al.Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol18, 194–209 (2021). https://doi.org/10.1038/s41569-020-00469-1
3. Genovese G, Moltrasio C, Berti E, Marzano AV. Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives. Dermatology. 2021;237(1):1-12. doi: 10.1159/000512932. Epub 2020 Nov 24. PMID: 33232965; PMCID: PMC7801998.
4. Sadeghzadeh-Bazargan A, Rezai M, Najar Nobari N, Mozafarpoor S, Goodarzi A. Skin manifestations as potential symptoms of diffuse vascular injury in critical COVID-19 patients. J Cutan Pathol. 2021 Oct;48(10):1266-1276. doi: 10.1111/cup.14059. Epub 2021 Jun 15. PMID: 33978234; PMCID: PMC8239514.
5. Valencia, I., Lumpuy-Castillo, J., Magalhaes, G. et al.Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus. Cardiovasc Diabetol23, 75 (2024). https://doi.org/10.1186/s12933-023-02097-8
6. Yanai H, Adachi H, Hakoshima M, Katsuyama H, Sako A. The Significance of Endothelial Dysfunction in Long COVID-19 for the Possible Future Pandemic of Chronic Kidney Disease and Cardiovascular Disease. Biomolecules. 2024; 14(8):965. https://doi.org/10.3390/biom14080965

2. Consider adding a supplementary figure legend to clarify the suggested mechanistic pathways.

We thank the reviewer for their comment. The caption of Figure 1 now reads:

“Figure 1. The Gut-Skin Axis in Long COVID. COVID-19 can disrupt gut microbiota, leading to gut dysbiosis, which causes increased intestinal permeability and systemic inflammation. This inflammatory response contributes to skin conditions such as eczema, acne, psoriasis, and rosacea, with persistent symptoms in long COVID. Potential interventions, including probiotics, an anti-inflammatory diet, fecal microbiota trans-plantation (FMT), and SCFA supplementation, may help restore gut balance and reduce skin-related symptoms.”