Topical Probiotics in Dermatology: Microbiological Mechanisms, Delivery Platforms, and Therapeutic Perspectives

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

General comment

The review is clearly written and provides a nice structured overview of topical probiotics and delivery systems. The topic is timely and relevant given growing interest in microbiome‑based dermatology and advanced topical platforms. However, the manuscript is largely descriptive; the Discussion could better synthesize gaps, controversies and priorities for future research. The search strategy is only briefly described as “targeted”; more detail on inclusion criteria and study selection would strengthen transparency. Overall, the paper is suitable for publication after moderate revisions focused on deepening critical analysis and clarifying methods.

Specific comments

1. Abstract you may shorten the methods description and use the space to emphasize what is novel compared with previous reviews. The list of mechanisms is long; consider grouping them into two or three broader themes to improve readability. 2. Introduction history section is clear but could be shortened to make room for more recent dermatology‑focused advances. Please state the explicit knowledge gaps this review addresses relative to existing probiotic dermatology reviews. 3. The search is called a “narrative review” but PRISMA‑like terms are used; clarify whether this is narrative or systematic and be consistent. Specify exact date of last search, language restrictions and any exclusion of non‑human or non‑topical studies. 4. Section 3 This section nicely summarizes the skin microbiome but partly repeats well‑known concepts; consider trimming or adding a schematic figure instead. When discussing dysbiosis in acne and atopic dermatitis, a short comparison table of key microbial shifts would help readers. 5. Section 4.1 The anti‑inflammatory mechanism is well supported; you could add a short sentence on potential risks of over‑suppressing immune responses. 6. Section 4.2 It would be useful to distinguish clearly between data showing reduced pathogen load and those documenting actual microbiome re‑balancing. 7. Section 4.3 The S. epidermidis ceramide example is strong; perhaps add one contrasting case where commensals may also become pathobionts. 8. Section 4.4 The evidence for sebum regulation is limited; you may want to explicitly acknowledge that clinical data are still preliminary. 9. Section 4.5 Wound‑healing mechanisms are described in detail; a concise mechanistic model (figure or box) could unify inflammation, angiogenesis and ECM effects. 10. Section 4.6 The antioxidant and metabolic effects are promising, but please discuss whether they are specific to certain strains or likely to be general. 11. Section 5.1 Conventional formulations are well covered; a short sentence on preservative use and its compatibility with live probiotics would be valuable. 12. Section 5.2-5.3 advanced systems (hydrogels, microgels, microneedles) are nicely described, but more comparison of advantages and limitations between them would help. 13. Section 7 Regulatory discussion is quite general; consider mentioning at least one concrete example of how classification differs between regions. 14. Conclusions nicely balanced, but you may want to include one or two very concrete recommendations for future clinical trial design. 15. The Introduction and Discussion would benefit from citing recent work on probiotic‑based detoxification and fermentation, for example, Murtaza et al. (Appl Microbiol Biotechnol 2022;106:4353–4365, https://doi.org/10.1007/s00253-022-12009-7), Murtaza et al. (Front Microbiol 2025, https://doi.org/10.3389/fmicb.2025.1533515), and Murtaza et al. (LWT 2023;186:115265, https://doi.org/10.1016/j.lwt.2023.115265), which illustrate strain‑specific mechanisms and practical formulation challenges relevant to topical probiotic applications.

Author Response

Reviewer 1

General comment. We thank the reviewer for the positive overall assessment and for the constructive suggestions regarding critical synthesis and methodological transparency. The Discussion and the Literature Search section have been revised accordingly, as detailed below.

 

Comment 1 — Abstract.

We thank the reviewer for this suggestion. The Abstract has been revised: the methods description was shortened, and the mechanisms previously listed individually have now been grouped into three broader thematic categories — (i) modulation of host responses (inflammation, immune signaling, oxidative stress); (ii) microbial ecology and pathogen control; and (iii) support of barrier and tissue repair. A sentence was added highlighting the novelty of this review relative to previous syntheses, namely its integrated focus on microbiological mechanisms, advanced delivery platforms, and translational/regulatory barriers within a single framework.

 

Comment 2 — Introduction.

The historical section has been shortened, and additional sentences were added to explicitly state the knowledge gaps addressed by this review. Specifically, we now clarify that, while previous reviews have addressed either microbiome biology or probiotic applications in dermatology separately, our work integrates microbiological mechanisms with formulation and delivery technologies, and critically discusses translational and regulatory bottlenecks that remain insufficiently covered in the existing literature.

 

Comment 3 — Search strategy.

We agree that the previous wording was ambiguous. The text has been revised to clearly state that this is a narrative review (not systematic), and PRISMA-like terminology has been removed. We have additionally specified:

- Databases searched (PubMed and ScienceDirect);

- Exact date of the last search (updated in the revised version);

- Time window (2009–2025);

- Language restriction (English only);

- Inclusion criteria (original studies on topical probiotic interventions in human or experimental dermatological models, including in vitro reconstructed skin, ex vivo, animal, and clinical studies);

- Exclusion criteria (non-topical administration routes, purely gastrointestinal probiotic studies without dermatological endpoints, and conference abstracts without peer-reviewed full text).

 

Comment 4 — Section 3.

Following the reviewer's suggestion, well-established background content has been trimmed. A new comparative table summarizing the key microbial shifts in acne and atopic dermatitis (predominant taxa, diversity changes, and main ecological features) has been added to facilitate reader comparison.

 

Comment 5 — Section 4.1.

A sentence has been added acknowledging that excessive or non-selective suppression of cutaneous inflammatory responses could potentially compromise antimicrobial defense and immune surveillance, reinforcing the need for strain- and context-specific characterization.

 

Comment 6 — Section 4.2.

The text has been revised to clearly distinguish between (i) studies that document a reduction in pathogen load (e.g., decreased *C. acnes or S. aureus counts) and (ii) studies that demonstrate actual ecological rebalancing of the cutaneous microbiota (e.g., shifts in community composition or diversity). This distinction is now made explicit in the corresponding paragraphs.

 

Comment 7 — Section 4.3.

We thank the reviewer for this excellent suggestion. A contrasting example has been added: although S. epidermidis generally acts as a beneficial commensal, certain strains can behave as pathobionts under conditions of barrier disruption or immune dysregulation, contributing to biofilm formation and opportunistic infection. This nuance is now explicitly discussed.

 

Comment 8 — Section 4.4.

We agree. A sentence has been added explicitly acknowledging that clinical evidence supporting sebum regulation by topical probiotics remains preliminary, derived mostly from small or exploratory studies, and that larger controlled trials are needed.

 

Comment 9 — Section 4.5.

A concise mechanistic summary box has been added integrating the three main axes of probiotic action in wound healing — modulation of inflammation, promotion of angiogenesis, and effects on extracellular matrix remodeling — to provide a unified mechanistic view.

 

Comment 10 — Section 4.6.

The text has been clarified to indicate that antioxidant and metabolic effects appear to be strain-specific rather than generalizable to topical probiotics as a class, with cited examples illustrating this strain-level variability.

 

Comment 11 — Section 5.1.

A sentence has been added discussing the issue of preservatives in conventional topical formulations and their potential incompatibility with live probiotics, since most antimicrobial preservatives may compromise microbial viability. The need for preservative-free or alternative stabilization approaches is now explicitly mentioned.

 

Comment 12 — Sections 5.2–5.3.

A comparative paragraph has been added contrasting hydrogels, microgels, microparticles, and microneedle-based systems regarding their main advantages (e.g., moisture retention, sustained release, deep delivery) and limitations (e.g., scalability, manufacturing complexity, regulatory considerations).

 

Comment 13 — Section 7.

The regulatory discussion has been expanded with a concrete example illustrating differences in classification between regions — namely, the divergent regulatory framing of topical probiotic products as cosmetics in the European Union versus their potential classification as live biotherapeutic products (LBPs) under the FDA framework in the United States, with corresponding differences in evidentiary and manufacturing requirements.

 

Comment 14 — Conclusions.

Two concrete recommendations for future clinical trial design have been added:

- The need for randomized, placebo-controlled trials with standardized strain characterization, viability quantification at the time of application, and predefined dermatological endpoints (e.g., lesion counts, TEWL, hydration, validated scoring scales);

- The importance of including longitudinal microbiome profiling to assess durability of ecological effects beyond the active treatment phase.

 

Comment 15 — Suggested references (Murtaza et al.).

We thank the reviewer for these suggestions. We carefully assessed the three references proposed (Murtaza et al., Appl Microbiol Biotechnol 2022; Front Microbiol 2025; LWT 2023). After review, we concluded that these works focus primarily on food fermentation, detoxification of mycotoxins, and food-matrix applications, which fall outside the scope of the present review on topical probiotics in dermatology. Their inclusion would not, in our view, strengthen the dermatological focus of the manuscript, and we have therefore respectfully opted not to cite them.

Reviewer 2 Report

Comments and Suggestions for Authors

This review provides a timely and comprehensive overview of topical probiotics in dermatology, covering microbiological mechanisms, formulation strategies, and therapeutic applications. The manuscript is generally well organized, clearly written, and supported by relevant and up-to-date references. However, several points should be addressed to further strengthen the manuscript.

1. Page 3, Lines 90–101 (Section 2: Literature Search Strategy and Scope of the Review)

The literature search methodology is described only briefly. Please provide additional details regarding the search period, inclusion and exclusion criteria, language restrictions, and study selection process. Although this is a narrative review, greater transparency would improve reproducibility and allow readers to better evaluate the scope of the literature included.

2. Table 1 (Pages 9–11)

Several typographical, formatting, and nomenclature inconsistencies were identified in Table 1. For example, apparent spelling errors such as "benefist", "wherease", "hidration", "L. planatarum", and "L. fermetum" should be corrected. In addition, bacterial nomenclature and strain designations should be reviewed carefully to ensure consistent formatting (e.g., spacing between species names and strain identifiers). A thorough proofreading of Table 1 is recommended to improve accuracy and readability.

3. Page 12, Lines 396–401 (Regulatory Challenges)

The discussion on regulatory issues is relevant but relatively brief. The manuscript would benefit from additional comments regarding the distinction between probiotics, postbiotics, bacterial lysates, and live biotherapeutic products, as these categories are increasingly important for future dermatological applications.

Overall, this is a well-written and informative review. After minor revision, the manuscript will provide a valuable overview of this emerging area of microbiome-based dermatological therapy.

Author Response

Reviewer 2

 

We thank the reviewer for the positive evaluation and for the helpful suggestions.

 

Comment 1 — Literature search methodology (Section 2).

As also raised by Reviewer 1, the search strategy has been expanded with full details on databases, time window, last search date, language restrictions, inclusion/exclusion criteria, and study selection process. The narrative nature of the review is now clearly stated, and PRISMA-like terminology has been removed for consistency.

 

Comment 2 — Table 1 (typographical and nomenclature issues).

We sincerely thank the reviewer for the careful reading. Table 1 has been thoroughly proofread and corrected. Specifically:

- "benefist" → "benefit";

- "wherease" → "whereas";

- "hidration" → "hydration";

- "L. planatarum" → "L. plantarum";

- "L. fermetum" → "*L. fermentum";

- "reconstructed human skin t" → "reconstructed human skin";

- Bacterial nomenclature and strain designations have been standardized (italics for genus/species; consistent spacing between species and strain identifiers; abbreviated genus names after first mention).

 

A complete revision of the table for consistency in formatting and nomenclature has been performed.

 

Comment 3 — Regulatory discussion (page 12).

The regulatory section has been expanded to include a clearer distinction between probiotics, postbiotics, bacterial lysates, and live biotherapeutic products (LBPs), highlighting that these categories differ in regulatory framing, evidentiary requirements, and manufacturing standards. The implications of these distinctions for future dermatological applications are now explicitly discussed.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors,

It is an important to shed a light on such complicated issue as using of topical probiotics in dermatology. The review presented at least attracts an attention to the problem, also it creates one more 'starting point' for further investigations. Overall, despite the progress especially in last decade in skin microbiome studies, the real word application of these achievements seems for the future. To my opinion, cosmetic advantadge of a therapy and aging treatment success should be carefully done coupled together all therapy possibilities, and the restoration of normal skin microbiome is one of such opportunities. This manuscript present selected  approaches for topical skin probiotic treatment, aimed to restore normal skin microbiome balance under dermatological conditions and wound healing. The manuscript frankly present current limitations, regulatory challenges, and translational barriers that should be overcomed before introduction of the topical probiotics in dermatological practise. The only remark is the lack of data on bacteriophage application treatment in dermatology, but it is more about virology not microbiology, and should not influence on the acceptance of this maniuscript for publication.

Author Response

Reviewer 3

 

We sincerely thank the reviewer for the positive and supportive evaluation of our manuscript, and for the thoughtful contextualization of the relevance of topical probiotics within broader dermatological and cosmetic strategies.

 

We agree with the reviewer's observation regarding **bacteriophage-based approaches**. As correctly noted, this topic lies more within the field of virology than microbiology and therefore falls outside the intended scope of the present review

 

Reviewer 4 Report

Comments and Suggestions for Authors

 

This manuscript provides a comprehensive review of the current research progress on topical probiotics in dermatology. The review covers three major aspects: the microbiological mechanisms of action of topical probiotics, the delivery systems used for their administration, and their therapeutic and cosmetic applications in dermatology.

 

 

The following suggestions are offered for revision.

 

Line 370 (Table 1)

Reference 28:

“reconstructed human skin t”

It should be revised.

 

Reference 29:

The full names of SLEB and TEWL should be presented.

It should be Hydration.

 

Reference 23:

It should be Micrococcus luteus.

 

Reference 17:

“Topical probiotics demonstrated strain specific effects on in a rat excisional wound model.”

It should be revised.

 

Reference 24:

The full names of SD-Ag should be presented.

 

Reference 30:

The reference cited is not correct. Please check the correctness.

 

Author Response

Reviewer 4

 

We thank the reviewer for the careful reading and for highlighting several inconsistencies in Table 1. All points have been addressed:

 

Reference 28 — "reconstructed human skin t" has been corrected to "reconstructed human skin".

 

Reference 29 — The full names of the abbreviations have been added SLEB (sub-epidermal low-echogenic band) and EWL (transepidermal water loss). The misspelling "hidration" has been corrected to "hydration".

 

Reference 23 — Corrected to "*Micrococcus luteus*" (proper italics and full genus name; the previous "M.s luteus" typo has been removed).

 

Reference 17 — The sentence "Topical probiotics demonstrated strain specific effects on in a rat excisional wound model." has been revised to: "Topical probiotics demonstrated strain-specific effects in a rat excisional wound model."

 

Reference 24 — The meaning of SD-Ag (silver sulfadiazine) has been added.

 

Reference 30 — We thank the reviewer for noticing this. The reference has been re-checked. The citation in Table 1 for the Bacillus subtilis PVA microparticles study should correspond to Ben David et al., ACS Omega 2021 (reference 22 in the reference list), not to Kober & Bowe 2015. This has been corrected, and the reference numbering in the table and across the manuscript has been verified for consistency.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author has revised all comments carefully and this version is now acceptable in principle. However i believe some parts may have been generated with AI so i suggest requesting one more minor revision to remove any AI like phrasing (—) and improve the manuscript originality and readability

Author Response

Dear reviewer,

Thank you for your comments. We fully agree and, therefore, we revised the texts.