Genotoxic Bacteria and Oncogenic Viruses in Colorectal Cancer: Evidence, Gaps, and a Proposed Interaction Model

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review focuses on the interaction between viruses and bacteria in the epithelium of colon and rectum and possible influence on CRC development. Overall, the review is clearly written and well structured. I have some observations and propositions that I believe may help to further strengthen the clarity of the review, which are detailed below:

1. Cancer statistics from the first lines of the introduction are from 2022 GLOBOCAN report. Please make sure this is clear. There is no need to state the year in every sentence but please rewrite in a way that makes clear that this entire part shows statistics from a few years ago, since the panorama could be much worse now (as you state later with second cite). Also, move the cite number 2 to the end of the previous sentence. It should not be at the end of the sentence explaining your current work.
2. In the second paragraph of the introduction section, the authors state the facts about CRC and at the end of the paragraph propose the outline of the review. This is perfectly structured. However, the third paragraph goes back to genetics and microbial interactions. Please integrate third paragraph into the second and keep all introductory facts about CRC in the same part of the introduction. This sentence is more appropriate to be the last of the introduction : “In the following sections, we review the major genotoxic viruses and bacteria implicated in colorectal carcinogenesis, analyse their individual and combined mechanisms of action, and address a model of bacterial-viral interaction based on emerging evidence.”
3. Please make sure that all the abbreviations are clarified on their first appearance in the manuscript. Also please clarify the abbreviations used in the tables.
4. In table 1, the authors show “Adenoma (+JCPyV)) and then state that it is not available in any of the papers they revise. Why did the authors add it to the table if they had no information on it?
5. Please clarify CCR abbreviation in table 1, 2, 3, 5 and 6. Also, check it throughout the text.
6. The conclusion section needs to be rewritten. The authors realistically highlight current limitations and methodological challenges in the field. However, it ended up sounding weak and without take-home message. This section could be strengthened by stating more clearly the main conceptual advances provided by this review and by offering a more forward-looking perspective on how the identified interactions could guide future research.

Author Response

Response to reviewer 1

1. Cancer statistics from the first lines of the introduction are from 2022 GLOBOCAN report. Please make sure this is clear. There is no need to state the year in every sentence but please rewrite in a way that makes clear that this entire part shows statistics from a few years ago, since the panorama could be much worse now (as you state later with second cite). Also, move the cite number 2 to the end of the previous sentence. It should not be at the end of the sentence explaining your current work.

 

Response: We appreciate the reviewer’s observation. The requested correction has been implemented: we revised the introduction to clearly indicate that the cancer statistics presented correspond to the 2022 GLOBOCAN report. This modification ensures that the temporal context of the data is explicit, without repeating the year in every sentence. Additionally, we repositioned citation number 2 as suggested, placing it at the end of the sentence referring to the cited article rather than at the end of the sentence describing our current work.

 

1. In the second paragraph of the introduction section, the authors state the facts about CRC and at the end of the paragraph propose the outline of the review. This is perfectly structured. However, the third paragraph goes back to genetics and microbial interactions. Please integrate third paragraph into the second and keep all introductory facts about CRC in the same part of the introduction. This sentence is more appropriate to be the last of the introduction : “In the following sections, we review the major genotoxic viruses and bacteria implicated in colorectal carcinogenesis, analyse their individual and combined mechanisms of action, and address a model of bacterial-viral interaction based on emerging evidence.”

Response: We appreciate the reviewer’s helpful suggestion. The recommended modification has been completed: the original second and third paragraphs of the introduction have been integrated into a single, coherent section to ensure that all introductory information on colorectal cancer is presented together. Additionally, the revised outline sentence has been placed at the end of the introduction, providing a clear and appropriate transition into the main body of the review.

 

1. Please make sure that all the abbreviations are clarified on their first appearance in the manuscript. Also please clarify the abbreviations used in the tables.

Response: We thank the reviewer for this observation. The suggested correction has been implemented: all abbreviations have now been defined upon their first appearance in the manuscript, and all abbreviations included in the tables have been fully clarified.

 

1. In table 1, the authors show “Adenoma (+JCPyV)) and then state that it is not available in any of the papers they revise. Why did the authors add it to the table if they had no information on it?

Response: We appreciate the reviewer’s observation. The suggested correction has been implemented: the unnecessary column labeled “Adenoma (+JCPyV)” was removed from Table 1, as it contained no supporting information in the studies reviewed.

 

1. Please clarify CCR abbreviation in table 1, 2, 3, 5 and 6. Also, check it throughout the text.

Response:  We appreciate the reviewer’s observation. The issue has been corrected: the incorrect abbreviation CCR was revised to CRC in Tables 1, 2, 3, 5, and 6, as well as throughout the entire manuscript.

 

 

1. The conclusion section needs to be rewritten. The authors realistically highlight current limitations and methodological challenges in the field. However, it ended up sounding weak and without take-home message. This section could be strengthened by stating more clearly the main conceptual advances provided by this review and by offering a more forward-looking perspective on how the identified interactions could guide future research.

Response: We appreciate the reviewer’s insightful suggestion. The conclusion section has been substantially revised and strengthened. In the updated version, we clearly highlight the main conceptual advances provided by this review and offer a more forward‑looking perspective on how the identified bacterial–viral interactions may guide future research in colorectal carcinogenesis. This revised conclusion now provides a more robust and cohesive take‑home message, addressing both current challenges and promising directions for the field.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors presented a review article summarizing current knowledge about most common bacteria and virus strains impact on hosts cells with their possible implication in development of colorectal cancer and chronic inflammation processes in gastrointestinal tract.

The presented review paper is comprehensive, with key points clearly and systematically presented through tables. Overall, the manuscript is well written.

However, in my opinion, there are some points that need to be addressed by the authors.

1. The title does not represent what is discussed in the manuscript, to the fullest. There is only one example of Genotoxic Bacterial–Viral Interactions in section 4. Interactions between viruses and bacteria. Authors are encouraged to change article title to match the content presented in the text.
2. Figure 1. It claims that image was adapted from the literature with reference [167] however in that manuscript there is no similar image. Please revise what you meant by stating that.
3. Section 4. Interactions between viruses and bacteria. The majority of information provided in this part was already mentioned beforehand. Except for that one example of genotoxic bacterial-viral interaction. All other new information should be stated in the sections before. 

4. Figures 2. and 3. should be divided, and genotoxic and inflammatory mechanisms and involved signalling pathways for each bacteria and virus mentioned should be presented and placed right next to the text were being discussed first.
5. Please check figures for citoplasm=cytoplasm!

Author Response

Response to reviewer 2

1. The title does not represent what is discussed in the manuscript, to the fullest. There is only one example of Genotoxic Bacterial–Viral Interactions in section 4. Interactions between viruses and bacteria. Authors are encouraged to change article title to match the content presented in the text.

Response: We appreciate the reviewer’s constructive comment. The suggested modification has been implemented: the title has been revised from a plural to a singular form to more accurately reflect the scope of the manuscript and the fact that only one example of a genotoxic bacterial–viral interaction is discussed in Section 4. This adjustment ensures a clearer alignment between the title and the content presented in the review.

 

1. Figure 1. It claims that the image was adapted from the literature with reference [167]; however, in that manuscript, there is no similar image. Please revise what you meant by stating that.

Response: We thank the reviewer for this clarification request. The issue has been addressed as suggested. Since the referenced manuscript did not contain a figure summarizing the mechanism, we revised our statement accordingly. The figure included in our review has now been explicitly described as an original schematic created by the authors, based on the integrated information synthesized from the cited literature, rather than adapted from a specific figure in reference [167].

 

1. Section 4. Interactions between viruses and bacteria. The majority of information provided in this part was already mentioned beforehand. Except for that one example of genotoxic bacterial-viral interaction. All other new information should be stated in the sections before. 

Response: We thank the reviewer for this valuable observation. The suggested correction has been implemented. All new information previously concentrated in Section 4 has now been integrated into the earlier sections of the manuscript, ensuring a more coherent and non‑redundant structure. Section 4 now focuses exclusively on the single example of a genotoxic bacterial–viral interaction, while the full context of the interaction and the microorganisms involved is presented in the appropriate preceding sections.

 

1. Figures 2. and 3. should be divided, and genotoxic and inflammatory mechanisms and involved signalling pathways for each bacteria and virus mentioned should be presented and placed right next to the text were being discussed first.

Response: We thank the reviewer for this detailed and helpful suggestion. To address the comment, we improved the clarity and structure of both Figures 2 and 3. Specifically, we added more explicit labels for each bacterium and virus, highlighted their corresponding genotoxic and inflammatory mechanisms, and visually aligned each signaling pathway with the section of the text where it is first discussed. In addition, we reorganized the manuscript so that the discussion of each microorganism now appears immediately before or after the relevant panel within the figure. We believe these changes meet the reviewer’s request for greater clarity and alignment between text and visuals, without the need to split the figures into separate components.

 

1. Please check figures for citoplasm=cytoplasm!

Response: We thank the reviewer for pointing this out. The suggested correction was verified. Upon reviewing the figures, we confirmed that the term was spelled correctly as cytoplasm, and no correction was required. Nevertheless, we re‑checked all figure labels to ensure consistent and accurate terminology throughout the manuscript.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors addressed most of the questions that were raised by the authors but few still remain:

1. Article title still doesn't full reflect the content of the manuscript and in my opinion, changing plural to singular didn't affect the fact that manuscript is focused on most common bacterial and viral infections that could be connected with colorectal cancer development and progression and one single example of bacterial-viral interaction. The title is unfortunately misleading.
2. Authors did not check figures 1, 2 and 3 and have not corrected citoplasm into cytoplasm.
3. Authors did not make substantial changes in section 4. even though it is needed because majority of information provided there is repetitive or content does not reflect the section title. Also authors have put text in yellow to mark changes they have made however the majority of the text is the same as in previous version of the manuscript.

Author Response

Response reviewer

1.Article title still doesn't full reflect the content of the manuscript and in my opinion, changing plural to singular didn't affect the fact that manuscript is focused on most common bacterial and viral infections that could be connected with colorectal cancer development and progression and one single example of bacterial-viral interaction. The title is unfortunately misleading.

R: We sincerely appreciate your comment regarding the title of the manuscript. We agree that the previous version could be misleading and did not fully capture the scope of the work. In line with your suggestion, we have completely revised the title to better reflect the content and objectives of the manuscript. The new title is:

“Genotoxic Bacteria and Oncogenic Viruses in Colorectal Cancer: Evidence, Gaps, and a Proposed Interaction Model”

2.Authors did not check figures 1, 2 and 3 and have not corrected citoplasm into cytoplasm.

R: We sincerely appreciate your observation regarding the figures. This was an oversight on our part, and we have now corrected the spelling error by changing citoplasm to cytoplasm in Figures 1, 2, and 3.

3. Authors did not make substantial changes in section 4. even though it is needed because majority of information provided there is repetitive or content does not reflect the section title. Also authors have put text in yellow to mark changes they have made however the majority of the text is the same as in previous version of the manuscript.

R: We sincerely appreciate your observation regarding Section 4. In the revised version of the manuscript, we have substantially modified this section by removing repetitive content and simplifying the paragraphs. The section has been restructured to provide a more concise discussion, with a clearer focus on Figures 2 and 3. We believe these changes make the section more coherent and aligned with its title.

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Authors addressed all questions and suggestions raised by the reviewer and in my opinion, in current form it can be accepted for publication.