Gut Microbiota, Microbial Metabolites, and Inflammation in Cardiac Surgery: Implications for Clinical Outcomes—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This narrative review addresses an important and emerging topic at the intersection of microbiome science and cardiac surgery. The manuscript synthesizes findings from a small number of studies exploring perioperative gut microbiota changes and their association with inflammation and complications such as POAF and infection. With moderate revisions focused on clarifying the review methodology, improving the integration of mechanistic insights, and ensuring consistency and clarity throughout, the manuscript has the potential to make a valuable contribution to the field.

1. While the authors outline a search strategy and screening process, the final selection of only six studies (five human, one animal) suggests a narrow evidence base. The authors should clarify the rationale for excluding other relevant studies that might have met inclusion criteria or broaden the scope to include emerging or less strictly defined studies to enrich the review.

2. Although the manuscript is framed as a narrative review, it incorporates elements of a systematic approach. The authors should clarify the intended review type and consider including a formal assessment of study quality or risk of bias to improve methodological transparency and scientific rigor.

3. The summaries of individual studies are informative but could be strengthened by a more integrated discussion connecting microbial shifts and metabolite alterations to known inflammatory and cardiac pathophysiology mechanisms (e.g., how SCFA depletion promotes leaky gut and SIRS, or how TMAO and bile acids contribute to arrhythmogenesis). This would enhance the mechanistic understanding and clinical relevance.

4. Terminology related to microbial diversity and dysbiosis should be used consistently throughout the manuscript to avoid confusion

5. The manuscript would benefit from additional editorial review to correct minor typographical and formatting issues.

Author Response

Reviewer 1

1. While the authors outline a search strategy and screening process, the final selection of only six studies (five human, one animal) suggests a narrow evidence base. The authors should clarify the rationale for excluding other relevant studies that might have met inclusion criteria or broaden the scope to include emerging or less strictly defined studies to enrich the review.

We appreciate this thoughtful comment regarding our study selection process. While we acknowledge that our strict inclusion criteria resulted in a focused set of six high-quality studies, this approach was deliberately chosen to address a specific gap in the literature. Several existing reviews have indeed taken broader approaches to gut microbiota in cardiac surgery (e.g., Manita Paneri​ and Prashant Sevta, 2022; Joseph Mc Loughlin and J Hinchion, 2022; Zhang et al. 2025), often including observational studies without control groups. Our review specifically targeted studies that met three key criteria not simultaneously addressed in previous work: (1) longitudinal microbiota analysis before and after cardiac surgery, (2) measurement of both microbial composition and inflammatory biomarkers, and (3) clinical outcome correlation. This stringent methodology allowed us to perform direct comparisons across studies and draw more definitive conclusions about causal relationships between dysbiosis patterns and postoperative outcomes. The trade-off between breadth and depth is particularly important in this emerging field. While larger, less restrictive reviews provide valuable exploratory insights, our focused analysis offers clinicians and researchers:

• Higher-grade evidence for specific microbiota-outcome associations
• Clearer mechanistic pathways supported by multi-omics data
• More actionable targets for intervention studies

That said, we agree that complementary approaches are valuable, and we have added a new paragraph in the discussion (Section 8) explicitly comparing our findings with those from broader reviews. Lines 570-601.

2. Although the manuscript is framed as a narrative review, it incorporates elements of a systematic approach. The authors should clarify the intended review type and consider including a formal assessment of study quality or risk of bias to improve methodological transparency and scientific rigor.

Thank you for your valuable comment. We acknowledge the reviewer’s insightful observation regarding the hybrid nature of our review methodology. Our manuscript was conceived as a narrative review with systematic elements, a design choice that warrants clarification. This hybrid design was selected because the field lacks standardized microbiota methodologies (sequencing platforms, sampling timepoints), making direct study comparisons challenging. Besides, our primary goal was to map mechanistic pathways rather than aggregate clinical effect sizes. Unlike purely systematic reviews focused on clinical endpoints, our synthesis prioritized mechanistic plausibility: How microbiota changes biologically drive inflammation (e.g., SCFA depletion → barrier failure → endotoxemia), and translational insights: Identifying testable hypotheses for interventions (e.g., perioperative TMAO-lowering therapies).

To clarify our approach, we labeled the review as a "systematically informed narrative" in the Methods section. Line 104-105.

3. The summaries of individual studies are informative but could be strengthened by a more integrated discussion connecting microbial shifts and metabolite alterations to known inflammatory and cardiac pathophysiology mechanisms (e.g., how SCFA depletion promotes leaky gut and SIRS, or how TMAO and bile acids contribute to arrhythmogenesis). This would enhance the mechanistic understanding and clinical relevance.

Thank you for your comment. Discussion revised. Lines 450-477.

4. Terminology related to microbial diversity and dysbiosis should be used consistently throughout the manuscript to avoid confusion

Corrected.

5. The manuscript would benefit from additional editorial review to correct minor typographical and formatting issues.

Corrected.

 

Reviewer 2 Report

Comments and Suggestions for Authors

An interesting article has been submitted for my review. The authors have addressed the topic of the heart-gut axis, which has recently become a very fashionable approach. However, as the authors have proven, there is a lack of clinical trials in this area.

However, I have a few comments.

1. Abstract: The authors used the phrase: "This review investigates" - this is incorrect - because a review article only presents, summarizes, and shows different opinions, comments, but certainly does not investigate, because it is not a research article.

2. I propose that the aim that guided the authors should be specified. The phrase "In this review, we aim to examine the available literature on this emerging topic systematically" is incorrect.

3. Although the authors have carried the discussion correctly, it is tedious, full of facts, and lacks summaries and comments; it is "written in one breath" - difficult to follow.

4. I think the article should be much more in-depth.

I suggest you at least look at the article from 2025 - doi: 10.1038/s41522-025-00646-5
In the article above, the researchers approach the subject in a more in-depth way; here, instead of cardiac surgery, there is cardiometabolic syndrome.
The current article lacks metabolic pathways, due to the journal's profile, Microorganisms, there should be much more information about microbiota content in the article itself. I want to note that in Table 1, gut microbiota results are presented in a difficult format. And this is the most important thing here, maybe it should be sorted out somehow - in the current version, it is not even fully known which article this description concerns.

5. It would be good if the researchers compared several disease entities and checked whether significant differences exist.
After all, most cardiovascular diseases have cardiometabolic syndrome at their root. Such a comparison would undoubtedly make this article more attractive. Otherwise, it is hard to say whether it is characterized by novelty and will interest readers.

6. In addition, I would like to ask whether and how drugs affected the microbiota in the presented topic?

7. The graphical abstract should be " more complicated" a bit - in the current version, it shows most of what people familiar with the topic certainly already know. It should be deepened.

8. The article is correct, but requires adding something to make it more cognitive and enjoyable for the potential reader. The authors should work on the message; the article should be more attractive in graphics. More summaries and opinions of researchers would be helpful - this is what is expected from review articles today.

9. The conclusions should be more coherent; the current ones are general and contain many obvious things.

Author Response

Reviewer 2

1. Abstract: The authors used the phrase: "This review investigates" - this is incorrect - because a review article only presents, summarizes, and shows different opinions, comments, but certainly does not investigate, because it is not a research article.

Thank you for your comment. The phrase was corrected (line 15).

2. I propose that the aim that guided the authors should be specified. The phrase "In this review, we aim to examine the available literature on this emerging topic systematically" is incorrect.

The phrase has been removed. The revised text can be found in lines 103-109.

3. Although the authors have carried the discussion correctly, it is tedious, full of facts, and lacks summaries and comments; it is "written in one breath" - difficult to follow.

Thank you for your comment. We revised the Discussion. Lines 451-477, 499-513, 524-601.

4. I think the article should be much more in-depth.

I suggest you at least look at the article from 2025 - doi: 10.1038/s41522-025-00646-5

In the article above, the researchers approach the subject in a more in-depth way; here, instead of cardiac surgery, there is cardiometabolic syndrome. The current article lacks metabolic pathways, due to the journal's profile, Microorganisms, there should be much more information about microbiota content in the article itself. I want to note that in Table 1, gut microbiota results are presented in a difficult format. And this is the most important thing here, maybe it should be sorted out somehow - in the current version, it is not even fully known which article this description concerns.

Thank you for your comment. Table 1 was rewritten more clearly and enriched accordingly with your advice.

A new section was written with the title: Microbial Metabolites in Cardiac Surgery: Mechanisms of Inflammation Modulation. Lines 269-313.

 

5. It would be good if the researchers compared several disease entities and checked whether significant differences exist.

After all, most cardiovascular diseases have cardiometabolic syndrome at their root. Such a comparison would undoubtedly make this article more attractive. Otherwise, it is hard to say whether it is characterized by novelty and will interest readers.

Thank you for your valuable comment. Revisions done in lines 524-570.

6. In addition, I would like to ask whether and how drugs affected the microbiota in the presented topic?

Thank you for your valuable comment. Revised text in Lines 499-516.

7. The graphical abstract should be " more complicated" a bit - in the current version, it shows most of what people familiar with the topic certainly already know. It should be deepened.

Thank you for your valuable comment. Done.

8. The article is correct, but requires adding something to make it more cognitive and enjoyable for the potential reader. The authors should work on the message; the article should be more attractive in graphics. More summaries and opinions of researchers would be helpful - this is what is expected from review articles today.

Thank you for your valuable comment. A new table was added (Table 2: Therapeutic Strategies Targeting Gut-Heart Axis in Cardiac Surgery Patients) in the Discussion section.

9. The conclusions should be more coherent; the current ones are general and contain many obvious things.

Thank you for your valuable comment. The conclusion was revised. Lines 626-641.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The article has been very well revised. Thank you for preparing an interesting graphic abstract. In the revised version, the authors have taken into account all my suggestions and responded to them appropriately. I have no further comments, and I believe the article can be accepted in its current form.

Author Response

We thank the reviewer for his/her valuable insight and its critical contribution to the final manuscript.