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Biomolecules2026, 16(6), 912;https://doi.org/10.3390/biom16060912 
(registering DOI)
by
  • Tianzhu Zhang 1,2,†,
  • Yufei Li 3,† and
  • Shuzhen Li 4,*
  • et al.

Reviewer 1: Pragya Tiwari Reviewer 2: Anonymous Reviewer 3: Anonymous Reviewer 4: Anonymous Reviewer 5: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Biomolecules May 2026

The Gut-Bone Axis and Skeletal Health: Regulatory Mechanisms and Therapeutic Applications of Plant-Derived Bioactive Compounds

 

The manuscript (biomolecules: 4342473) has been reviewed. I have provided some suggestions and queries for improvement, discussed as follows:

 

The improvement of metabolic disorders and balancing human well-being by plant-derived compounds has been a key area of research in recent times. While medicinal plants and the phytoconstituents demonstrate potent efficacy and fewer side effects, proper pharmacokinetic and toxicity assessment is important for further development and optimization of plant-based bioactive compounds.

 

Abstract:

Line 19-21: Particular attention is given to targeted…………through the gut-bone axis.

In this section, multiple approaches, such as prebiotics, synbiotics, probiotics and plant-rich diet have been mentioned as potential agents to promote bone health. Among the following, which is the most successful and defines therapeutic possibilities in bone-related disorders? Discuss.

 

Line 21-23: It summarizes the key themes, discussions, and outcomes of the paper, discussing the novel findings. It is important to briefly discuss the key outcome/results achieved and future directions of the study while prioritizing actionable goals. It is suggested to include case studies on phytochemical-based promotion of bone health and bone disorder treatment, providing examples.

 

Introduction

Line 39 onwards, Plant-based proteins constitute an important……………

This section needs to be improved. Talking about the gut-bone axis, it is suggested to briefly discuss the biotechnological progress achieved in treating bone-associated disorders, besides plant-based constituents.

Line 42-44, These compounds exhibit…………..gut microbiota. The article strongly emphasizes plant-based constituents, but it is only briefly discussed.  It is suggested to include recent developments of plant-based constituents, clinical studies, and commercialization (if any are available) to support the discussion.

 

 

The theme of the paper is of potential scientific interest and discusses an emerging area of research; however, some sections and sub-sections require considerable revisions. For example, the coherent flow between the paragraphs is missing. The introduction section ends abruptly with an overview of plant-based Asian diets. The section may conclude with key highlights of the study, bottlenecks in the research area, feasible solutions, and how this comprehensive review can be helpful in adding to the existing knowledge for scientists.

 

Line 46-47, Inclusion of recent statistics would add value to the discussed concept. For example, are there statistics on how the traditional Asian diet is better than the Western diet in preventing the chances of osteoporosis or other bone disorders? Discuss.

 

Line 375, 4.3. Novel Delivery Systems

A reference is missing in the section. Please include it.

 

  1. Discussion, line 401……..Precision interventions grounded in …………..clinical potential. Here, the clinical studies should be discussed, giving examples. The sections need to be revised to include examples of precision therapeutic approaches, with relevant literature citation (it is missing).

 

References: All the references in the article are missing in the text; therefore, it is not possible to establish the authenticity of the different themes discussed in the manuscript. Please include all the references and revise the article.

In the reference section, please add the DOI links for the cited papers, so that it is more accessible to the readers.

Author Response

Abstract:

Comments 1: Line 19-21: Particular attention is given to targeted…………through the gut-bone axis.
In this section, multiple approaches, such as prebiotics, synbiotics, probiotics and plant-rich diet have been mentioned as potential agents to promote bone health. Among the following, which is the most successful and defines therapeutic possibilities in bone-related disorders? Discuss.
Responses 1 :Thank you for pointing this out. We agree with this comment. Therefore, We appreciate this constructive suggestion. To explicitly interpret why synbiotics outperform other interventions, we have added supplementary comparative discussion (line26-27) in the abstract at the corresponding position to address your requirement.

Comments 2: Line 21-23: It summarizes the key themes, discussions, and outcomes of the paper, discussing the novel findings. It is important to briefly discuss the key outcome/results achieved and future directions of the study while prioritizing actionable goals. It is suggested to include case studies on phytochemical-based promotion of bone health and bone disorder treatment, providing examples.
Responses 2: Thank you for pointing this out. We agree with this comment. Therefore, We sincerely appreciate this constructive and detailed suggestion. We have thoroughly revised the corresponding sentences in the Abstract to highlight the key outcomes of this review, add representative case studies of phytochemicals in bone health improvement, and clearly propose actionable future research directions.
Specifically, we have added:
Added core review outcomes (Lines 39–44). The key findings of this review were supplemented in the revised abstract. Specifically, multiple typical plant-derived bioactive compounds (i.e., synbiotics, soy isoflavones, naringin, curcumin, and resveratrol) were summarized to effectively improve bone mineral density, restore gut microbiota homeostasis, and inhibit pathological bone resorption via the gut-bone axis, and their underlying bone-protective mechanisms were further clarified.
Supplemented representative case studies (Lines 44–47). As suggested, typical evidence-based cases concerning phytochemical-based bone health regulation were newly added. Representative examples include soy isoflavones that mitigate estrogen-deficient bone loss in OVX models, naringin that improves trabecular microarchitecture, and probiotic BL-11 that promotes longitudinal bone growth in children.
Refined actionable future research directions (Lines 47–50). The future research prospects were further specified and optimized to highlight actionable goals. Future research priorities involve clarifying dose–response relationships, developing standardized synbiotic formulations, constructing microbiome-guided precision diets, and conducting large-sample randomized controlled trials to accelerate the clinical translation of plant-derived bioactive compounds for bone disease treatment.
All revisions have been clearly updated in the abstract section of the revised manuscript.

Introduction:

Comments 3: Line 39 onwards, Plant-based proteins constitute an important……………
This section needs to be improved. Talking about the gut-bone axis, it is suggested to briefly discuss the biotechnological progress achieved in treating bone-associated disorders, besides plant-based constituents.
Respones 3: Thank you for pointing this out. We agree with this comment. Therefore,We highly appreciate the valuable and constructive comment. Following your suggestion, we have added supplementary comparative discussion (line79-90).

Comments 4: Line 42-44, These compounds exhibit…………..gut microbiota. The article strongly emphasizes plant-based constituents, but it is only briefly discussed.  It is suggested to include recent developments of plant-based constituents, clinical studies, and commercialization (if any are available) to support the discussion.
Responses 4: Thank you for pointing this out. We agree with this comment. Therefore, We sincerely appreciate this constructive suggestion. We have expanded the relevant content in the Introduction section to supplement recent research progress, clinical trial evidence, and commercialization achievements of plant-derived bioactive components for bone health.
Specifically, we added:
①Preclinical advances of representative components (soy isoflavones, curcumin, resveratrol, naringin) in animal osteoporosis models;
②Clinical trial evidence confirming the efficacy of soy isoflavones/genistein/equol in postmenopausal women;
Relevant citations have been added at appropriate positions to enhance the persuasiveness of the discussion. The revised content has been updated in the manuscript (line 90-98).

Comments 5: The theme of the paper is of potential scientific interest and discusses an emerging area of research; however, some sections and sub-sections require considerable revisions. For example, the coherent flow between the paragraphs is missing. The introduction section ends abruptly with an overview of plant-based Asian diets. The section may conclude with key highlights of the study, bottlenecks in the research area, feasible solutions, and how this comprehensive review can be helpful in adding to the existing knowledge for scientists.
Responses 5: Thank you for pointing this out. We agree with this comment. Therefore, We sincerely appreciate this thoughtful and professional comment. We have completely revised and optimized the ending part of the Introduction to improve logical coherence and avoid an abrupt conclusion.
Specifically, we added:
①Key highlights of the present review;
②Current bottlenecks in the gut–bone axis and plantderived intervention field;
③Feasible solutions to overcome these limitations;
④A clear statement of how this review advances existing knowledge and supports future research for scientists.
The entire introduction now flows smoothly and ends with a comprehensive and logical conclusion. The revised content has been updated in the manuscript (line 99-106).

Comments 6: Line 46-47, Inclusion of recent statistics would add value to the discussed concept. For example, are there statistics on how the traditional Asian diet is better than the Western diet in preventing the chances of osteoporosis or other bone disorders? Discuss.
Responses 6: Thank you for pointing this out. We agree with this comment. Therefore, We appreciate the suggestion. After literature search, direct recent statistics comparing Asian and Western diets for osteoporosis risk are insufficient. We have revised the description to state that traditional Asian diets are rich in fiber, phytochemicals and soy, which benefit bone health via the gut-bone axis, while noting that large-scale comparative data are still needed. The revision has been made in the manuscript (line 89-96).

Comments 7: Line 375, 4.3. Novel Delivery Systems
A reference is missing in the section. Please include it.
Responses 7: Thank you for pointing this out. We agree with this comment. Therefore, We appreciate the reminder. We have added relevant citations (Refs. 135–137) in Section 4.3 Novel Delivery Systems to support the content, and these references have been supplemented in the reference list accordingly.

Comments 8: Discussion, line 401……..Precision interventions grounded in …………..clinical potential. Here, the clinical studies should be discussed, giving examples. The sections need to be revised to include examples of precision therapeutic approaches, with relevant literature citation (it is missing).
Responses 8: Thank you for pointing this out. We agree with this comment. Therefore, We appreciate this valuable suggestion. We have supplemented the clinical examples of precision interventions targeting the gut-bone axis and added the corresponding literature citations in the Discussion section to enhance the clinical evidence and academic rigor. The relevant revisions have been completed in the revised manuscript (line482-506).
 
Comments 9: References: All the references in the article are missing in the text; therefore, it is not possible to establish the authenticity of the different themes discussed in the manuscript. Please include all the references and revise the article.
Responses 9: Thank you for pointing this out. We agree with this comment. Therefore, We sincerely apologize for the citation errors. We have carefully checked and added all corresponding in-text citations throughout the manuscript to ensure every claim is supported by relevant literature. The authenticity and academic rigor of the manuscript have been fully improved. All revisions have been completed in the revised version.

Comments 10: In the reference section, please add the DOI links for the cited papers, so that it is more accessible to the readers.
Respones 10: Thank you for pointing this out. We agree with this comment. Therefore, We appreciate this helpful suggestion. We have added DOI links for all cited references in the reference list to improve accessibility and standardization. All revisions have been completed in the revised manuscript.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This paper describes a review about the role of plant-derived bioactive compounds in the gut-bone axis and skeletal health. This is a relevant subject. However the present review has some limitations and the following are the most important:

  • At the end of the introduction the objective of this review is not clearly stated. Also, the time period of the review is not defined.
  • The references included in this review are relatively old. More recent citations should be used.
  • Similar reviews must be described in the introduction and the novelty of the present review must be highlighted. For example, the following review paper is not cited, 

    https://doi.org/10.1021/acs.jafc.6c01315

    but all the recent similar reviews must be cited.

Author Response

Comments 1: At the end of the introduction the objective of this review is not clearly stated. Also, the time period of the review is not defined.
Response 1: Thank you for pointing this out. We agree with this comment. Therefore, We appreciate this constructive comment. We have supplemented the clear objective of this review at the end of the Introduction section and specified the literature search time period to ensure transparency and completeness. All revisions have been made in the revised manuscript (line 111-114).

Comments 2: The references included in this review are relatively old. More recent citations should be used.
Response 2: Thank you for pointing this out. We agree with this comment. Therefore, We appreciate this constructive comment. We have updated the reference list by adding recent high-quality citations (2016–2026) and replacing outdated ones to improve the timeliness and academic quality of the manuscript. All revisions have been completed in the revised version.

Comments 3: Similar reviews must be described in the introduction and the novelty of the present review must be highlighted. For example, the following review paper is not cited, 
https://doi.org/10.1021/acs.jafc.6c01315.but all the recent similar reviews must be cited.
Response 3: Thank you for pointing this out. We agree with this comment. Therefore, We sincerely apologize for not collecting similar reviews as much as possible. In the revised manuscript, we have added some relevant articles, for example, references 135, 137, etc.. And we cited the paper “From Plants to Bone Health: A Review on Polysaccharides from Agricultural and Medicinal Botanicals for Osteoporosis Management” (line888-889).

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The abstract needs reformulation.

please put the keywords according to mesh terms and alphabetical order.

All the references are error.

The introduction is too small and not sufficient.

where is your search for systematic review?

prisma flow? something not relevant for your explanation

the paper needs reformulation and reconsideration before taking a decision

Author Response

Comments 1: The abstract needs reformulation.

Response 1: Thank you for your valuable feedback on our manuscript. We have carefully considered your comment regarding the reformulation of the abstract and have revised it accordingly. The new abstract more clearly conveys the core ideas and key findings of the research. We believe these changes better meet the expectations for the paper. If you have any further suggestions or comments, We would greatly appreciate your input. Thank you for the opportunity to improve my work!

Comments 2: please put the keywords according to mesh terms and alphabetical order.

Response 2: Thank you for pointing this out. We agree with this comment. Therefore, We have sorted all keywords alphabetically following the standard of MeSH terms and updated the keyword list in the revised manuscript accordingly (line 51-52).

Comments 3: All the references are error.

Response 3: Thanks for your careful comment. We have systematically proofread all references, amended formatting, citation and literature information mistakes one by one, and the revised references are available in the new manuscript.

Comments 4: The introduction is too small and not sufficient.

Response 4: Thank you for pointing this out. We agree with this comment. The introduction has been greatly extended with sufficient background information and recent research advances added. Revised contents are marked on line 55–125.

Comments 5: where is your search for systematic review?

Response 5: Thank you for the comment. We have supplemented detailed information on literature retrieval for systematic review in the revised manuscript, including retrieval databases, search keywords, retrieval time span and inclusion/exclusion criteria. Relevant revisions are highlighted on line 114–125.

Comments 6: prisma flow? something not relevant for your explanation

Response 6: We are very sorry that we did not understand this question. Could you please explain it? Thank you for your kindness.

Comments 7: the paper needs reformulation and reconsideration before taking a decision

Response 7: We appreciate your professional advice on overall revision. We have carried out comprehensive reformulation of the manuscript, re-examined the research design, narrative logic and discussion content section by section, and revised all inappropriate expressions. The full revised manuscript is submitted here for your re-assessment.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The aim of this review was to systematically evaluate the potential of plant-based dietary interventions on the gut–bone axis. This is an interesting approach; however, several aspects need to be carefully considered, revised, and further elaborated.

  1. Please revise the manuscript throughout and ensure the correct nomenclature and formatting of plant names, bacterial strains, and the terms in vivo and in vitro consistently across the entire text.
  2. Please indicate the novel aspects contributed by this manuscript
  3. Line 36 – Are you referring to dysbiosis induced by antimicrobial treatment, or to dysbiosis associated with certain gastrointestinal pathologies?
  4. Line 39 – What type of proteins are you referring to? Please be more explicit.
  5. Line 193 – Is protein concentration and integrity influenced by processing? What is the situation regarding GMOs and protein quality
  6. Please include conclusions and, based on the discussion, formulate recommendations as well, taking into account the limitations.

Author Response

Comments 1: Please revise the manuscript throughout and ensure the correct nomenclature and formatting of plant names, bacterial strains, and the terms in vivo and in vitro consistently across the entire text.

Response 1: Thank you for pointing this out. We agree with this comment. The revisions are completed as follows: all Latin names including Bacillus clausii, Lactobacillus, Klebsiella variicola, Lactobacillus rhamnosus, Bifidobacterium longum, Bifidobacterium animalis subsp. lactis and Dioscorea oppositifolia are italicized; the strain designation BL-11 is kept in regular font; in vitro and in vivo will be consistently italicized wherever they appear in the remaining text.

Comments 2: Please indicate the novel aspects contributed by this manuscript.

Response 2: Thank you for the valuable suggestion. We have supplemented and clarified the novel contributions of this work in the revised manuscript at Lines 110–114.

Comments 3: Line 36 – Are you referring to dysbiosis induced by antimicrobial treatment, or to dysbiosis associated with certain gastrointestinal pathologies?

Response 3: Thank you for the valuable comment. We hereby clarify that the dysbiosis mentioned in our manuscript mainly refers to microbiota disturbance induced by antimicrobial treatment, diet, aging and other common factors, not dysbiosis caused by specific gastrointestinal diseases. We have revised the expression accordingly in the text (line 62-66).

Comments 4: Line 39 – What type of proteins are you referring to? Please be more explicit.

Response 4: Thank you for your helpful suggestion. We have supplemented detailed classification and specific types of target proteins at Lines 67–70 in the revised manuscript to make this description explicit as recommended.

Comments 5: Line 193 – Is protein concentration and integrity influenced by processing? What is the situation regarding GMOs and protein quality.

Response 5: Thank you for the valuable queries. We have supplemented relevant descriptions concerning the impacts of processing on protein concentration/ integrity as well as GMO-related protein quality issues in the revised manuscript. All supplementary revisions are marked at Lines 275–279.

Comments 6: Please include conclusions and, based on the discussion, formulate recommendations as well, taking into account the limitations.

Response 6: Thanks for your constructive suggestion. We have supplemented the conclusion section, proposed corresponding research recommendations, and discussed existing study limitations accordingly at Lines 511–519 in the revised manuscript.

Author Response File: Author Response.pdf

Reviewer 5 Report

Comments and Suggestions for Authors

Although this review deals with an interesting research topic, several points should be revised.

  • A brief description of the methodology used should be added in the abstract.
  • Again, a brief description of the most important results should be added in the abstract.
  • There is an error concerning the citation numbering inside the manuscript. Unless numbering, "[Error! Reference source not found.]" is reported throughout the manuscript.
  • At the end of the introduction section, the authors should emphasize the literature gap that their review will cover. In this paragraph the authors should report the aim of their review, reporting also the type of their review.
  • A methods section should be added after the introduction section. In this section the authors should report the databases used to collect their date and the relevant criteria.
  • Exclusion and inclusion criteria should also be included in the methods section.
  • In section 2.2.1, the authors should report some representative SCFAs that can lead to mediated calcium absorption.
  • In section 2.2.2, more information should be added concerning  the mechanisms of action of gut microbiota composition to modulate the bioavailability of active vitamin D metabolites.
  • Vitamin K2 or K? Please specify.
  • In section 3.2.1, are there some specific isoflavones that are metabolized by gut microbiota into equol? Please add this information.
  • The authors should add more information concerning the clinical trial reported in lines 165-167 (section 2.3.2).
  • In section 3.1.1, the sentence in lines  207-214 "Notably, the keystone ..." is complex and it should be split into smaller sentences.
  • In the 1rst paragraph of the 3.1.2 section, the authors should add more references.
  • In section 3.2.2 (Curcumin) the authors should add relevant reference. A bit more information for curcumin should also be added.
  • Again, in section 3.2.3 (Reveratrol) the authors should add relevant reference. A bit more information for resveratrol should also be added.
  • Some representative Plant-derived dietary regimens should be reported in section 4.2.1.
  • More information should be added in the discussion section.
  • A separate paragraph with the strengths and the limitations of the present review article should be included at the end of the discussion section.
  • Futere perspectives and research direction should also be added as a separate paragraph in the discussion section.
  • A conc;lusion section could also be very useful for the readers.
  • English language editing is recommended.
Comments on the Quality of English Language

English language editing is recommended.

Author Response

Comments 1: A brief description of the methodology used should be added in the abstract.

Response 1: Thank you for pointing this out. As suggested, we have refined and highlighted the methodological statement in line 28-33, strengthening the brief introduction of systematic review screening scheme.

Comments 2: Again, a brief description of the most important results should be added in the abstract.

Response 2: Thank you for pointing this out. Following your advice, we supplement a concise summary of core mechanisms for main findings, with the added content marked in line 42-44 representative case descriptions in abstract.

Comments 3: There is an error concerning the citation numbering inside the manuscript. Unless numbering, "[Error! Reference source not found.]" is reported throughout the manuscript.

Response 3: We sincerely apologize for this technical error. We have comprehensively checked and repaired all citation formatting errors in the full manuscript. All invalid reference prompts have been completely eliminated, and all in-text citation numbers have been standardized, unified, and verified to ensure full consistency between in-text citations and the reference list. (Full-text revision).

Comments 4: At the end of the introduction section, the authors should emphasize the literature gap that their review will cover. In this paragraph the authors should report the aim of their review, reporting also the type of their review.

Response 4: Thank you for pointing this out. We fully accept this suggestion. We have rewritten the concluding paragraph of the introduction section (line 108-113). We clearly elaborated the existing research gaps in current related studies (e.g., insufficient systematic summary of the gut-bone axis regulatory mechanisms of various plant-derived compounds, lack of sorting of clinical application progress and existing bottlenecks). Meanwhile, we explicitly stated the research purpose and defined the manuscript as a systematic review focusing on plant-derived bioactive compounds for skeletal health via the gut-bone axis.

 Comments 5: A methods section should be added after the introduction section. In this section the authors should report the databases used to collect their date and the relevant criteria.

Response 5: Thanks for the professional suggestion. We have added an independent Methods section after the introduction (line 113-124). This section systematically supplements the core literature retrieval databases, including PubMed, Web of Science, ScienceDirect, and CNKI. We also clarified the retrieval time span, keywords, and overall research framework of this review to improve the standardization of the review.

Comments 6: Exclusion and inclusion criteria should also be included in the methods section.

Response 6: Thank you for pointing this out. We fully agree with this suggestion. We have supplemented detailed inclusion and exclusion criteria in the end of introduction(line 113-121). We clearly specified the types of eligible literature, language range and data requirements for inclusion, and listed the types of literature that were excluded. The whole literature screening process is now fully described.

Comments 7: In section 2.2.1, the authors should report some representative SCFAs that can lead to mediated calcium absorption.

Response 7: Thank you for pointing this out. We have supplemented the representative short-chain fatty acids that mediate calcium absorption in Section 2.2.1(line 176-178), including acetate, propionate and butyrate, as suggested.

Comments 8: In section 2.2.2, more information should be added concerning the mechanisms of action of gut microbiota composition to modulate the bioavailability of active vitamin D metabolites.

Response 8: Thank you for pointing this out. We have supplemented the detailed underlying mechanism in Section 2.2.2(line 194-201). We clarified that gut microbiota regulates the bioavailability of active vitamin D metabolites by affecting vitamin D absorption, hepatic and renal activation, and enterohepatic circulation, which fully addresses the reviewer’s concern.

Comments 9: Vitamin K2 or K? Please specify.

Response 9: Thank you for pointing this out. We have uniformly standardized the description in the full text. The vitamin subtype involved in this study is Vitamin K2. We have revised all ambiguous expressions of "vitamin K" in the manuscript to Vitamin K2, and supplemented the unique advantages of Vitamin K2 in regulating bone metabolism and gut microbiota to avoid conceptual confusion. (Full-text revision)

Comments 10: In section 3.2.1, are there some specific isoflavones that are metabolized by gut microbiota into equol? Please add this information.

Response 10: Thank you for pointing this out. As suggested, we have added the specific isoflavone that can be metabolized into equol in Section 3.2.1 (line 332-334). We clarified that daidzein, rather than genistein, is the primary isoflavone converted to equol by gut microbiota.

Comments 11: The authors should add more information concerning the clinical trial reported in lines 165-167 (section 2.3.2).

Response 11: Thank you for pointing this out. We have supplemented relevant clinical trial information in this section (line 241-243). It is stated that probiotic intervention can regulate human 5-HT levels by modulating gut microbiota, which complements the clinical evidence of the above mechanism.

Comments 12: In section 3.1.1, the sentence in lines 207-214 "Notably, the keystone ..." is complex and it should be split into smaller sentences.

Response 12: Thank you for pointing this out. We have split the original complex long sentence into two concise sentences in Section 3.1.1(line 284-290) while retaining all original information, which improves readability.

Comments 13: In the 1rst paragraph of the 3.1.2 section, the authors should add more references.

Response 13: Thank you for pointing this out. We have supplemented three latest high-quality literatures (Refs. 51–55) in the first paragraph of Section 3.1.2 to support the relevant viewpoints. These newly added references are recent studies focusing on gut microbiota and bone metabolism regulation, which effectively strengthen the academic foundation of this section (Revised in Section 3.1.2).

Comments 14: In section 3.2.2 (Curcumin) the authors should add relevant reference. A bit more information for curcumin should also be added.

Response 14: Thank you for pointing this out. We have enriched the research content of curcumin in Section 3.2.2 by supplementing its unique gut-bone axis regulatory mechanism, dose-effect characteristics and latest research progress. Meanwhile, two up-to-date relevant references (Refs. 59–61) have been added to guarantee the timeliness and reliability of the content (Revised in Section 3.2.2).

Comments 15: Again, in section 3.2.3 (Reveratrol) the authors should add relevant reference. A bit more information for resveratrol should also be added.

Response 15: Thank you for pointing this out. Additional references have been added to the first paragraph of Section 3.2.3 (Refs. 62–64) as recommended.

Comments 16: Some representative Plant-derived dietary regimens should be reported in section 4.2.1.

Response 16: Thank you for pointing this out. We have supplemented a variety of typical plant-derived dietary regimens in Section 4.2.1(line 440-445), including Mediterranean diet, traditional Asian plant-based diet, high-fiber plant-rich diet, etc. We also analyzed their respective characteristics and intervention effects on skeletal health, enriching the practical application value of the manuscript. (Revised in Section 4.2.1)

Comments 17: More information should be added in the discussion section.

Response 17: Thank you for pointing this out. We have substantially expanded and deepened the discussion section (line 500-519). We further analyzed the internal correlation and potential molecular mechanisms of plant-derived compounds regulating bone health via the gut-bone axis, and comprehensively discussed current research contradictions, influencing factors and translational application barriers, making the discussion more in-depth and systematic. (Revised in Discussion section)

 Comments 18: A separate paragraph with the strengths and the limitations of the present review article should be included at the end of the discussion section.

Response 18: Thank you for pointing this out. We have added an independent paragraph at the end of the discussion section to systematically summarize the strengths and limitations of this review (line 511-519). We objectively concluded the innovative perspectives and systematic sorting advantages of this manuscript, as well as the existing research limitations such as insufficient clinical data and single dimensional mechanism research. 

Comments 19: Futere perspectives and research direction should also be added as a separate paragraph in the discussion section.

Response 19: Thank you for pointing this out. We have added an independent paragraph for future research perspectives. We put forward targeted future research directions (line 521-539), including multiomics mechanism exploration, large-sample clinical verification, standardized dosage formulation research, and industrial transformation prospects, providing clear guidance for subsequent related research.

Comments 20: A conclusion section could also be very useful for the readers.

Response 20: Thank you for pointing this out. We have added an independent conclusion section(line 541-555). This section comprehensively summarizes the core regulatory rules, research progress and application value of plant-derived bioactive compounds targeting the gut-bone axis, and condenses the overall core viewpoints of the full manuscript. (Newly added Conclusion section)

 

Comments 21: English language editing is recommended.

Response 21: Thank you for pointing this out. We agree with this comment.  Therefore, we have thoroughly polished and revised the full-text English language, including sentence structure, grammatical errors, academic expression and wording fluency. All inappropriate and colloquial expressions have been modified to meet the standard of formal academic English writing.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have made substantial efforts to improve the manuscript. It may be considered in the present form.

Congratulations.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have answered satisfactorily to the referees comments.

Reviewer 3 Report

Comments and Suggestions for Authors

THE AUTHORS REVISED THE MANUSCRIPT

Reviewer 5 Report

Comments and Suggestions for Authors

The resolution and size of Figure 1 should be improved and increased, respectively. Moreover, it should be transfer after its citation (section 2.1) and not at section 3.