Akkermansia muciniphila in Cardiometabolic Medicine: Mechanisms, Clinical Studies, and Therapeutic Outlook

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this manuscript, the authors reviewed important preclinical and clinical trials using A. muciniphila. This is an interesting topic for a general audience, as there is an increasing awareness of the benefits of probiotics for overall well-being, as well as their benefits in various diseases.

The following are comments to improve the manuscript:

This is an interesting topic for all kinds of readers, so the authors can replace technical terms with simpler words to improve the readability of this manuscript. The overall quality of the writing can also be enhanced.

The authors could have highlighted the impact of the growth conditions used in Plovier’s study.

The impact of A. muciniphila on MASLD, as discussed in section 3.1, can be moved to section 3.5 for relevance and to prevent repeating information.

Please provide citations for the study mentioned in L107-108 and the ongoing trials mentioned in L698-700. It would be helpful to readers if citations were included wherever appropriate. Whenever you can add citations in the manuscript, please do so.

Section 4.3 on commercialization can be rewritten. Currently, the manufacturers' names are unclear and confusing.

Author Response

1) Simplify technical language & tighten prose (global)
Response: Thank you for emphasizing readability; this was very helpful in guiding global edits. We revised the manuscript to simplify terminology, shorten sentences, and remove redundancies. 

2) Highlight growth-condition impact in Plovier’s study
Response: Thank you for drawing attention to this key translational detail; it sharpened our clinical bridge. We added 2–3 sentences noting cultivation in a synthetic, animal-component–free medium and that pasteurization enhanced efficacy in obese/diabetic mice, which supports testing pasteurized preparations in humans.

3) Move MASLD content to Section 3.5
Response: Thank you for the structural suggestion; it improved flow and eliminated redundancy. We consolidated MASLD material into Section 3.5 and replaced duplicative lines in Section 3.1 with a cross-reference.

4) Add missing citations (L107–108; L698–700)
Response: Thank you for the careful citation check; this strengthened attribution and traceability. We added citations supporting early mouse findings (live cells initially required) and citations for ongoing clinical trials.

5) Rewrite §4.3 “Commercialization” for clarity
Response: Thank you for flagging ambiguity here; the section is now clearer and more useful for readers. We rewrote Section 4.3 to name manufacturers unambiguously and to distinguish live versus pasteurized/postbiotic products, aligning descriptions with evidence and regulatory status.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript submitted for consideration by FakhriRavari and Nguyen titled: "The Role of Akkermansia muciniphila in Human Health: A Clinical Review"  is a review aiming to investigate and discuss the potential of Akkermansia muciniphila.  The review is interesting and is addressing a topic that is seemingly understudied. 

The reviewer would like to offer the following points for consideration by the authors:

1. The title is fairly generic and requires refining and focus. What aspects of Human Health are examined? This needs to be reflected in the title. Also the term "clinical review" is somewhat confusing and inaccurate. If only clinical studies are considered as part of this review then this should be expressed in the titled differently. Also it appears that this is not quite the case however since there is a table in the manuscript where in vivo and in vitro studies are described and presented.
2. The review seems to be covering a lot of breadth and ground yet superficially. 
3. Consider including a PRISMA diagram.
4. Consider adding more information in terms of the inclusion and exclusion criteria used for the selection of articles considered for this review. 
5. When it comes to human trials the data are lean and the studies few with potentially confounding factors in terms of their comparability. This is something that needs to be noted by the authors so that the results are not presented in a manner that may generate potentially biased and misleading conclusions.
6. Also conditions such as obesity, type 2 diabetes mellitus and metabolic syndrome are very complex and present variations in intensity of symptoms to various individuals. Thus it is important to consider this dimension in the discussion section.

Comments on the Quality of English Language

The manuscript would benefit from being read through by a native English speaker. 

Author Response

1) Retitle for accuracy and focus
Response: Thank you for the helpful title guidance; it improved the paper’s framing. We retitled the manuscript: “Akkermansia muciniphila in Cardiometabolic Medicine: Mechanisms, Clinical Studies, and Therapeutic Outlook.”

2) “Breadth but superficiality”
Response: Thank you for encouraging added depth; this led to substantive improvements without sacrificing readability. We expanded more details, and enhanced Table 1 with a new Limitations column and tighter synthesis paragraphs.

3) PRISMA diagram
Response: Thank you for the suggestion; it helped us clarify our methodological stance. Because this is a narrative (not systematic) review, we did not include a PRISMA diagram; we explicitly state our narrative scope in Methods now.

4) Inclusion/exclusion criteria
Response: Thank you for requesting greater transparency; this improved methodological clarity. We revised Methods to specify inclusion and exclusion criteria suitable for a narrative synthesis (prioritizing human interventional evidence while using preclinical work to clarify mechanisms).

5) Temper conclusions; note heterogeneity and confounding
Response: Thank you for prompting a more cautious interpretation; this sharpened our take-home message. We revised §4.2 and §4.4 to emphasize small samples, short durations, formulation heterogeneity, and potential confounding (e.g., standard care, diet), and we updated the Conclusions accordingly.

6) Complexity of obesity/T2D/metabolic syndrome
Response: Thank you for underscoring disease heterogeneity; this addition improves clinical relevance. We added a paragraph in §4.4 addressing phenotype/severity variation and recommending prospective stratification by baseline features to avoid averaging away meaningful subgroup effects.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript by Alireza FakhriRavari and Minh Hien Chau Nguyen presents a well-written and informative review that explores the role of Akkermansia muciniphila in maintaining and improving human health. The work provides a comprehensive overview, covering a wide range of aspects. The topic is highly relevant to the scope of Gastrointestinal Disorders and will be of great interest to both researchers and clinicians working in the field of microbiome and gastrointestinal health.

The authors demonstrate a solid understanding of the subject and present a comprehensive and balanced perspective on the medical relevance of A. muciniphila, supported by appropriate and up-to-date literature. The manuscript is logically structured, clearly written, and scientifically sound.

Nevertheless, I would suggest minor revisions before acceptance:

1. The current title, “A Clinical Review,” is not entirely accurate, since the manuscript is neither a purely clinical review, nor a systematic review, nor a meta-analysis. I recommend revising the title to better reflect the nature of the work, e.g., “A Comprehensive Review” or “An Updated Overview”.
2. The manuscript discusses postbiotics in several sections; however, in the Introduction, the authors do not provide a clear definition and refer to them as “new probiotics” (L. 71). I recommend including a precise definition of postbiotics and highlighting the distinction between probiotics and postbiotics in the introduction. This would strengthen the scientific soundness of the article and improve its clarity for readers.

Author Response

1) Retitle (“Clinical Review” → “Comprehensive/Updated Overview”)
Response: Thank you for the title refinement; it better reflects scope and content. We adopted: “Akkermansia muciniphila in Cardiometabolic Medicine: Mechanisms, Clinical Studies, and Therapeutic Outlook.”

2) Define “postbiotics” in the Introduction and distinguish from probiotics
Response: Thank you for requesting this clarification; it improved conceptual precision for readers. We revised the Introduction to include ISAPP-aligned definitions of probiotics (live microorganisms) and postbiotics (preparations of inanimate microorganisms and/or their components) and explained the relevance to pasteurized A. muciniphila.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have somewhat addressed reviewer's comments

Comments on the Quality of English Language

The manuscript would benefit from being read through by a native English speaker.