Targeting the Gut Vascular Axis in Atherosclerosis: Probiotic and Phytoantioxidant Crosstalk as a Hypothesis-Generating Framework for Residual Cardiovascular Risk
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe central idea of synergy between probiotics and phytoantioxidants remains largely hypothetical: the authors mainly bring together findings from separate probiotic and antioxidant studies, while direct evidence from combination trials is lacking.
The clinical literature itself is still small and highly variable in terms of strains, compounds, doses, study duration, and outcomes, so the therapeutic conclusions should be substantially toned down.
I am also concerned by the close overlap with an earlier review from the same authors and by several internal inconsistencies, which should be examined carefully by the editor.
Author Response
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Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsOverall, this is a well-written and well-organized narrative review on a timely topic. The manuscript clearly provides a balanced overview of the current literature. However, several scientific and conceptual issues should be addressed to further strengthen the manuscript.
1. The manuscript proposes that combining probiotics with phytoantioxidants may provide synergistic benefits in atherosclerosis. However, there is little direct evidence demonstrating that the combination is more effective than either intervention alone. If no original studies have investigated or demonstrated such a synergistic effect, the title should be revised to better reflect the current level of evidence and avoid overstating the conclusions.
2. The Materials and Methods section is somewhat confusing. It is unclear why the reference verification process of a previous manuscript draft is described as part of the review methodology. In addition, Figure 1 presents the curation of only 64 references, making it difficult to understand how the studies included in the current review were identified and selected. The literature search and study selection process for the current review should be described more clearly and distinguished from the revision history of the previous manuscript draft.
3. Sex differences are increasingly recognized in gut microbiota composition, atherosclerosis progression, and treatment response. In animal models of atherosclerosis, the beneficial effects of certain phytochemical interventions have been observed predominantly in males, which may be partly explained by baseline differences in gut microbiota. Moreover, the effects of these interventions on gut microbiota composition may also differ between sexes. A brief discussion of sex-specific responses and their potential implications should be included.
4. The review mainly summarizes the mechanisms of probiotics and phytoantioxidants independently and only briefly mentions that probiotics may improve polyphenol bioavailability while polyphenols may exert prebiotic-like effects. The manuscript would be strengthened by the inclusion of a dedicated section or schematic figure illustrating the potential molecular crosstalk and mechanistic interactions between these two interventions.
5. Different probiotic species, and even different strains within the same species, can exert distinct effects on gut barrier integrity, SCFA production, bile acid metabolism, and TMAO reduction. A discussion of the probiotic strains with the strongest evidence for atherosclerosis, together with any available consensus regarding effective strains, doses, and treatment duration, should be included. If sufficient evidence is not currently available, this limitation should be explicitly acknowledged and highlighted as an important direction for future research.
Comments for author File: Comments.pdf
Author Response
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Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThis is a review of the effects of probiotics and phytoantioxidants on atherosclerotic cardiovascular disease as an indication of microbiome influence on the cardiovascular system.
Table 1 presents only one clinical study and four animal studies, indicating that evidence supporting the authors' hypothesis is limited and the review is premature.
Clinical trials and animal studies are not well-delineated in Table 2, with even less evidence than in Table 1.
The proscriptions for future studies is not a good enough reason to publish such a review.
Author Response
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Author Response File: Author Response.pdf
Reviewer 4 Report
Comments and Suggestions for AuthorsMajor Revisions
1. The literature search process is non-reproducible; a formal PRISMA flowchart and complete retrieval strategy must be supplemented, and invalid citations need to be deleted.
2. Direct experimental evidence for the synergistic effect of probiotics and phytoantioxidants is insufficient; relevant combined-treatment studies should be added.
3. Clinical trial bias evaluation is only placed in attachments; the main text needs to restrict conclusions according to evidence quality.
4. The gut-vascular axis signaling chain is fragmented; a complete graphical abstract is required to sort out the whole mechanism.
Minor Revisions
1. Tables and figures lack unified labeling of evidence levels; abbreviations should be annotated at first occurrence.
2. Duplicated descriptions exist in abstract, introduction and conclusion; redundant contents need to be trimmed.
3. Delivery system and precision nutrition prospects are superficially discussed; supporting references should be supplemented.
English needs to be polished by professionals.
Author Response
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Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsSeveral statements do not appear to accurately reflect the cited literature. For example, the manuscript mischaracterizes the MESA findings, reports a change in TNF-α where the probiotic study actually measured IL-12, and attributes a statin–bile-salt-hydrolase–coprostanol mechanism to a JACC review that does not support this claim. The review methods also need substantial clarification. The search strategy and study-selection process are not described in enough detail to be reproduced, so it is difficult to determine whether the evidence presented is complete and reasonably balanced.
Author Response
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Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsWith the author revisions and clarifications, this review does serve to elucidate the inadequacies of previous studies of probiotics and antioxidants for amelioration of atherosclerosis. The supplemental files provide a level of transparency that reveals the rigor of the analysis. Thus, the authors' contention that the review provides specific direction to remedying the field's shortcomings and putting it on more solid scientific footing is supported. Although the clinical studies added to Table 1 are problematic, as detailed in supplemental file #2, they suggest specific benefits of certain probiotics for inhibiting atheroprogression.
Author Response
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Author Response File: Author Response.pdf
Reviewer 4 Report
Comments and Suggestions for AuthorsThe author has responded to the comments and made revisions to the manuscript, meeting the publication standards.
Author Response
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Author Response File: Author Response.pdf
