Review Reports - Ellagitannins and Their Derivatives: A Review on the Metabolization, Absorption, and Some Benefits Related to Intestinal Health

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript offers an exhaustive and structured review of ellagitannins, covering chemistry, metabolism, microbiota interaction, and clinical relevance.

These are my observations for the Authors:

Introduce a short “Scope and Structure of Review” paragraph at the end of Introduction, guiding the reader through the content flow.

In each disease section (e.g., IBS, Gastritis), add a brief 'Future Directions' paragraph pointing out gaps (e.g., lack of human trials).

In methodology part, please specify exact number of papers screened and selected. Any PRISMA flow diagram? (Even a small one could help). Date range of publications considered.

Make all figures fully self-explanatory (expand figure legends). Mention figure numbers properly inside the main text when first cited.

No summary tables for major bacteria involved in urolithin production? Similar, no tables for effects on specific digestive diseases. Add at least two summary tables: one showing bacterial strains linked to specific urolithins, and one mapping ellagitannins/derivatives to diseases and effects.

Cite more primary research studies especially when discussing recent findings (e.g., individual bacterial species studies). Search for 2023–2025 studies on microbiota and ellagitannins.

Author Response

Reviewer 1

These are my observations for the Authors:

Introduce a short “Scope and Structure of Review” paragraph at the end of Introduction, guiding the reader through the content flow.

R: Dear reviewer, we greatly appreciate your comments. The first comment was addressed as recommended in lines 65–70.

In each disease section (e.g., IBS, Gastritis), add a brief 'Future Directions' paragraph pointing out gaps (e.g., lack of human trials).

R: The comment was addressed as recommended; a future directions section was added for each of the diseases (the sections discussing 'cancer' were treated as a single one). The changes can be seen from pages 13 to 18.

In methodology part, please specify exact number of papers screened and selected. Any PRISMA flow diagram? (Even a small one could help). Date range of publications considered.

R: The requested information (number of articles and the date range considered) was added to the text. A flow diagram was also included in the methodology section on page 3 to help the reader properly understand the content.

Make all figures fully self-explanatory (expand figure legends). Mention figure numbers properly inside the main text when first cited.

R: The figure captions were enlarged, and the figure numbers are properly referenced within the main text.

No summary tables for major bacteria involved in urolithin production? Similar, no tables for effects on specific digestive diseases. Add at least two summary tables: one showing bacterial strains linked to specific urolithins, and one mapping ellagitannins/derivatives to diseases and effects.

R: The two requested tables were added: the first one on page 10, in section 7.1 “Bacteria capable of degrading ellagitannins into ellagic acid and urolithins”, where Table 2 “Some urolithin-producing bacterial strains” was included; and the second table on page 14, in section 9 “Impact of Ellagitannins, Ellagic Acid, and Urolithins on Intestinal Health”, where Table 3 “Ellagitannins and their derivatives: positive effects on digestive diseases” was added.

Cite more primary research studies especially when discussing recent findings (e.g., individual bacterial species studies). Search for 2023–2025 studies on microbiota and ellagitannins.

R: More recent articles were cited.

Reviewer 2 Report

Comments and Suggestions for Authors

The review article is interesting, well structured and evaluates an important topic for the field. I'd like to highlight a few points:
- The introduction section could better contextualize the study question. I miss findings related to bowel disorders and aspects already elucidated with the use of Ellagitannins and Their Derivatives.
- Why were these databases chosen " ScienceDirect, Wiley Online, MDPI, ResearchGate, Springer Nature, and Taylor & Franci" and not databases such as PUBMED, Scopus, Embase for example.
Doesn't the method adopted restrict the eligible articles too much?
- When were the articles searched? Was it carried out by 2 researchers? How was the data synthesized? This wording is valuable for readers' understanding.
- The eligibility criteria for the studies could be better described. It is not clear. The exclusion criteria presented are not real reasons for not including the studies.
- The body of the manuscript is very well detailed, as well as being presented with interesting figures.
- The article fails to mention limitations of the approaches, future perspectives and the evidence currently available for clinical applicability.
-The conclusion section could be more direct and objective. Insert additional information in the body of the manuscript.
-Some references could be updated.

Author Response

Reviewer 2

The review article is interesting, well structured and evaluates an important topic for the field. I'd like to highlight a few points:

The introduction section could better contextualize the study question. I miss findings related to bowel disorders and aspects already elucidated with the use of Ellagitannins and Their Derivatives.

R: Dear reviewer, we sincerely appreciate your observations, which will help improve the quality of the work. The introduction section, pages 1–2, was modified to better contextualize the problem that prompted this research, incorporating data related to digestive diseases and why ellagitannins could be a potential alternative.

Why were these databases chosen "Elsevier, Wiley Online, MDPI, ResearchGate, Springer Nature, and Taylor & Francis" and not databases such as PUBMED, Scopus, Embase for example. Doesn't the method adopted restrict the eligible articles too much?

R: Kindly addressing your concern, the PubMed and Scopus databases were also used for the preparation of this article; however, their mention was initially omitted from the text and has now been added. These databases were selected due to their high level of reliability, strict quality filters, clear policies, and transparency in authorship. Additionally, some aspects of the wording in the selection criteria that caused doubts about the proper selection of articles were corrected.

When were the articles searched? Was it carried out by 2 researchers? How was the data synthesized? This wording is valuable for readers' understanding.

R: Thank you for your observation. In the methodology section, lines 71–87, the time range of the articles used for the review was added. The article search was conducted by more than one author, and the information was synthesized based on the inclusion and exclusion criteria mentioned in the methodology section.

The eligibility criteria for the studies could be better described. It is not clear. The exclusion criteria presented are not real reasons for not including the studies.

R: We appreciate your observation. We have restructured the text and expanded the eligibility criteria to make them more explicit and consistent with the research question. The changes can be seen in the methodology section on pages 2–3, lines 71–87.

The body of the manuscript is very well detailed, as well as being presented with interesting figures.

R: Thank you very much for your comment.

The article fails to mention limitations of the approaches, future perspectives and the evidence currently available for clinical applicability.

R: Dear reviewer, various future perspectives have been added in the conclusions section. Additionally, specific discussions about future perspectives were incorporated for each of the diseases mentioned. It is worth noting that the sections related to ‘cancer’ were treated collectively. The changes made are between pages 13 and 18.

The conclusion section could be more direct and objective. Insert additional information in the body of the manuscript.

R: The future perspectives and conclusions section was revised to be more objective, and some important points mentioned throughout the manuscript were added. The changes can be seen on pages 19–20, lines 566–595

-Some references could be updated.

R: Some references were updated.

Reviewer 3 Report

Comments and Suggestions for Authors

The Manuscript ID: microbiolres-3607626 reviews ellagitannins and their derivatives: metabolization, absorption, and some benefits related to intestinal health. The procedures described and figures/table utilized in their work properly treat the main question addressed by the review. They presented ellagitannins and their derivatives, e.g. ellagic acid and urolithins, as promising molecules in intestinal health, backed by several scientific articles. It was stressed that not all individuals can metabolize ellagitannins into urolithins due to differences in the composition of the intestinal microbiota. Moreover, ellagitannins bioavailability remains challenging despite significant advances achieved through research on the relevant molecules. They indicated that knowledge gap exists regarding the interaction between ellagitannins and digestive enzymes, underscoring the need to further related research.

The subject is worth publication and the authors did a good job. Yet, further insights might improve the study and specific improvements should be considered:

The authors would better review the current state of knowledge on pros and cons of ellagitannins and their derivatives. For example, the most likely side effect of urolithin A is muscle aches. Negative results were also reported for measures of physical function, including grip strength, gait speed, and maximum oxygen consumption, VO2 max, as in: https://www.nad.com/news/urolithin-a-side-effects-benefits-and-dosage
This does not negate the need to focus on their benefits because they far outweigh the side effects, so this should be made clear as well.
Scientific names should be written in tilted form or at least underlined; e.g.: “Lactiplantibacillus plantarum 89, Lacticaseibacillus paracasei 116, and Enterococcus faecium 126 were identified.” Should be “Lactiplantibacillus plantarum 89, Lacticaseibacillus paracasei 116, and Enterococcus faecium 126 were identified.”
Also, “Gordonibacter urolithinfaciens DSM27213 and Gordonibacter pamelaeae DSM19378,…” Should be “Gordonibacter urolithinfaciens DSM27213 and Gordonibacter pamelaeae DSM19378,…”
“Ellagibacter, within the species Ellagibacter isourolithinifaciens, with the capacity to degrade ellagic acid” Should be “Ellagibacter, within the species Ellagibacter isourolithinifaciens, with the capacity to degrade ellagic acid”

Therefore, I would suggest accepting it after minor revision.

Author Response

Reviewer 3

The subject is worth publication and the authors did a good job. Yet, further insights might improve the study and specific improvements should be considered:

The authors would better review the current state of knowledge on pros and cons of ellagitannins and their derivatives. For example, the most likely side effect of urolithin A is muscle aches. Negative results were also reported for measures of physical function, including grip strength, gait speed, and maximum oxygen consumption, VO2 max, as in: https://www.nad.com/news/urolithin-a-side-effects-benefits-and-dosage. This does not negate the need to focus on their benefits because they far outweigh the side effects, so this should be made clear as well.

R: Dear reviewer, we greatly appreciate your comments. A brief paragraph was added at the end of the section 'Food Products with Ellagitannins and Their Derivatives as Bioactive Ingredients,' lines 559–565, discussing the positive and negative effects of using this type of compounds.

Scientific names should be written in tilted form or at least underlined; e.g.: “Lactiplantibacillus plantarum 89, Lacticaseibacillus paracasei 116, and Enterococcus faecium 126 were identified.” Should be “Lactiplantibacillus plantarum 89, Lacticaseibacillus paracasei 116, and Enterococcus faecium 126 were identified.”

R: Thank you very much for your observation. The names of the bacteria were corrected as requested in lines 257–258.

Also, “Gordonibacter urolithinfaciens DSM27213 and Gordonibacter pamelaeae DSM19378,…” Should be “Gordonibacter urolithinfaciens DSM27213 and Gordonibacter pamelaeae DSM19378…”

R: Thank you very much for your observation. The names of the bacteria were corrected as requested in lines 263–264.

“Ellagibacter, within the species Ellagibacter isourolithinifaciens, with the capacity to degrade ellagic acid” Should be “Ellagibacter, within the species Ellagibacter isourolithinifaciens, with the capacity to degrade ellagic acid”

R: Thank you very much for your observation. The names of the bacteria were corrected as requested in lines 273–274.