The Gut Microbiota in Parkinson’s Disease: Mechanistic Insights into Microbial–Host Interactions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review, entitled "The gut microbiota in Parkinson’s disease: mechanistic insights into microbial–host interactions", focuses on the association between Parkinson's disease (PD) and gut microbiota, systematically expounds the characteristics of PD related gut microbiota Dysbiosis (such as the reduction of short chain fatty acid producing bacteria, the enrichment of proinflammatory bacteria, the change of microbial alpha diversity, etc.), analyzes the core mechanisms of Dysbiosis in triggering chronic low-grade systemic inflammation by destroying the intestinal barrier, promoting the abnormal aggregation of α - synuclein in the enteric nervous system and its transmission to the central nervous system via the vagus nerve, damaging the blood-brain barrier and activating microglia to trigger neuroinflammation, and also proposed PD The regulatory framework of "gut immune brain" and the models of gut priority, brain priority and dual origin of the disease, as well as the factors driving the Dysbiosis of intestinal flora, such as host genetics, age, diet, antibiotics, etc. The significance of this study is to break through the traditional cognition that PD is only a degenerative disease of the central nervous system, clarify that the intestinal flora is one of the upstream drivers of PD, reveal the key role of the flora gut brain axis in the pathogenesis and progression of PD, provide a new perspective for understanding the multisystem pathogenesis of PD, also open up a new direction for the prevention and treatment of PD to target the intestinal flora, and provide a theoretical basis for the research and development of new disease modification strategies such as probiotics, prebiotics, dietary intervention, etc. Nevertheless, there are still the following problems worthy of improvement in the manuscript:

1. The author is suggested to introduce the current treatment of Parkinson's disease in the introduction;
2. The introduction part describes the clinical characteristics of PD too long. It is suggested to simplify the basic clinical knowledge and highlight the research entry point;
3. There are too many long sentences in the article. It is suggested to split the broken sentences appropriately to improve readability;
4. The conclusion is better to put forward the limitations of current research and future research directions, rather than simply summarize the current situation.

Author Response

We thank the Editor and Reviewers for their constructive and insightful comments on our manuscript. We have carefully revised the manuscript to address all of the points raised, improving the focus, structure, and readability while preserving the scope and message of the review.

Below we provide a point‑by‑point response, indicating how each comment has been implemented in the revised version of the manuscript.

Comment 1. “The author is suggested to introduce the current treatment of Parkinson's disease in the introduction.”

Response 1. We agree that a brief overview of current therapeutic options is important to frame the clinical context of Parkinson’s disease. In the Introduction, we have added a concise paragraph summarizing the main pharmacological treatments and non‑pharmacological/advanced interventions, emphasizing that available approaches remain largely symptomatic and that no disease‑modifying therapy is currently established. This revision clarifies the unmet therapeutic need and provides a natural rationale for exploring gut microbiota-related mechanisms and interventions.

Comment 2. “The introduction part describes the clinical characteristics of PD too long. It is suggested to simplify the basic clinical knowledge and highlight the research entry point.”

Response 2. We appreciate this observation and have streamlined the description of the clinical characteristics of Parkinson’s disease in the Introduction. Redundant or highly basic clinical information has been removed or condensed, with greater emphasis now placed on non‑motor manifestations-particularly gastrointestinal dysfunction. These changes shorten the section and more clearly guide the reader toward the main focus on gut microbiota and dysbiosis.

Comment 3. “There are too many long sentences in the article. It is suggested to split the broken sentences appropriately to improve readability.”

Response 3. We thank the reviewer for pointing out this stylistic issue. The manuscript has been carefully edited to shorten overly long sentences, simplify syntax, and improve paragraph structure. We have also revised transitions between sections to enhance clarity and make the text more accessible to a broad readership, while preserving the scientific content.

Comment 4. “The conclusion is better to put forward the limitations of current research and future research directions, rather than simply summarize the current situation.”

Response 4. We fully agree with this suggestion. The Conclusion section has been rewritten to go beyond a descriptive summary and now explicitly discusses key limitations of the current literature on gut microbiota and Parkinson’s disease. In addition, we have introduced a new subsection titled “Future Directions” near the end of the manuscript. In this section, we summarize the main knowledge gaps and outline priority areas for future research.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “The Gut Microbiota in Parkinson’s Disease: Mechanistic Insights into Microbial–Host Interactions” represents a well-written, relevant, and timely review addressing an increasingly important topic in the field of neurodegenerative diseases and microbiome research. The authors provide a useful overview of current knowledge regarding the potential mechanistic links between gut microbiota and the pathophysiology of Parkinson’s disease, which will be of interest to a broad scientific audience.

However, several minor refinements are recommended before the manuscript can be considered for publication:

1. Typing and numbering issues: The manuscript would benefit from careful proofreading, as there are several minor typing errors and inconsistencies in section or reference numeration that should be corrected.

2. Compliance with the Instructions for Authors: The formatting and structure of the manuscript should be revised to ensure full compliance with the journal’s Instructions for Authors (e.g., formatting of headings, references, abbreviations, and general structure).

3. Future directions: A dedicated section discussing future research directions would strengthen the review and provide readers with perspectives on the most promising areas for further investigation.

4. Therapeutic possibilities: The manuscript would benefit from a section addressing potential therapeutic strategies related to the gut microbiota, such as microbiota modulation, probiotics, diet-based approaches, or other emerging interventions relevant to Parkinson’s disease.

5. Summary table: It is strongly recommended to include a table summarizing the key points of the manuscript, such as major microbial mechanisms, pathways involved in microbial–host interactions, and their potential implications for Parkinson’s disease. This would improve clarity and enhance the overall readability of the review.

Overall, the manuscript is a nice contribution to the field, and with these revisions it will be further strengthened and more informative for readers.

Comments on the Quality of English Language

English language and style needs some minor refinements

Author Response

We thank the Editor and Reviewers for their constructive and insightful comments on our manuscript. We have carefully revised the manuscript to address all of the points raised, improving the focus, structure, and readability while preserving the scope and message of the review.

Below we provide a point‑by‑point response, indicating how each comment has been implemented in the revised version of the manuscript.

Comment 1. “Typing and numbering issues: The manuscript would benefit from careful proofreading, as there are several minor typing errors and inconsistencies in section or reference numeration that should be corrected.”

Response 1. We appreciate this comment. The manuscript has undergone thorough proofreading to correct typographical errors, spelling inconsistencies, and issues in section, figure, and reference numbering. We have also harmonized the style of abbreviations and terminology throughout the text.

Comment 2. “Compliance with the Instructions for Authors: The formatting and structure of the manuscript should be revised to ensure full compliance with the journal’s Instructions for Authors (e.g., formatting of headings, references, abbreviations, and general structure).”

Response 2. We thank the reviewer for this practical suggestion. The manuscript has been reformatted according to the journal’s Instructions for Authors, including the hierarchy and wording of headings, reference style, abbreviation use, figure legends, and overall structure of the review. We have verified that all sections required by the journal are present and formatted as requested.

Comment 3. “Future directions: A dedicated section discussing future research directions would strengthen the review and provide readers with perspectives on the most promising areas for further investigation.”

Response 3. We agree that a dedicated discussion of future directions adds important value, and we have introduced a new subsection titled “Future Directions” near the end of the manuscript. In this section, we summarize the main knowledge gaps and outline priority areas for future research, including longitudinal cohorts integrating metagenomics, metabolomics, and immune profiling; experimental work dissecting causal pathways linking specific microbial functions to α‑synuclein pathology and neuroinflammation; and well‑controlled interventional studies exploring microbiota‑targeted strategies in Parkinson’s disease.

Comment 4. “Therapeutic possibilities: The manuscript would benefit from a section addressing potential therapeutic strategies related to the gut microbiota, such as microbiota modulation, probiotics, diet-based approaches, or other emerging interventions relevant to Parkinson’s disease.”

Response 4. We appreciate this important recommendation. We have added a new subsection entitled “Therapeutic Implications and Microbiota‑Targeted Interventions,” in which we briefly discuss potential strategies aimed at modulating the gut microbiota and its metabolites in Parkinson’s disease. This section covers general concepts related to microbiota modulation (e.g., diet‑based approaches, probiotics, prebiotics, and other emerging interventions) and links them to the mechanistic pathways described in the review.

Comment 5. “Summary table: It is strongly recommended to include a table summarizing the key points of the manuscript, such as major microbial mechanisms, pathways involved in microbial–host interactions, and their potential implications for Parkinson’s disease. This would improve clarity and enhance the overall readability of the review.”

Response 5. We thank the reviewer for this excellent suggestion. We have incorporated a new summary table (Table 1) that synthesizes the main elements discussed in the review, including: (i) major microbial alterations associated with Parkinson’s disease, (ii) Representative taxa or signals, (iii) key host–microbe interaction pathways (e.g., barrier integrity, immune activation, metabolic signaling), and (iv) their proposed implications in Parkinson’s disease. The content of this table is derived from and consistent with the information already presented in the text, and we believe it will greatly improve readability and provide readers with a concise overview of the mechanistic framework.

Comment on English language. “English language and style needs some minor refinements.”

Response 6. We acknowledge this comment and have carefully revised the English language and style throughout the manuscript. Sentences have been simplified where appropriate, awkward phrasing has been corrected, and terminology has been standardized. We trust that these edits have improved the clarity and overall readability of the manuscript.