-->PONE-D-25-23211-->-->Molecular and Immunological Heterogeneity of Eosinophilic Esophagitis: Insights and Subtyping-->-->PLOS ONE

Dear Dr. Ullah,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 26 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Wan-Tien Chiang

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: > Overall Assessment:

The manuscript is well-written and presents a significant contribution to the field. It is generally acceptable; however, some revisions are necessary to enhance its readability, clarity, and adherence to journal standards. Below are specific comments to assist in improving the manuscript:

> Title:

The title is clear, concise, and accurately reflects the content of the manuscript. No changes are necessary.

> Abstract:

The abstract is well-written and effectively conveys the study's objective, methodology, and findings.

The state-of-the-art nature of the study is also clear.

Suggestion: Ensure that the keywords adequately represent the study and enhance its discoverability in relevant research areas.

> Discussion:

While the discussion section provides valuable insights, it lacks a detailed examination of the important topics and implications of the study.

Recommendation: Include a systematic discussion of the study's limitations to provide a balanced perspective and guide future research in this area.

> Conclusion:

The conclusion effectively summarizes the study's findings and their significance. No major revisions are necessary in this section.

> References:

Several references do not adhere to the journal's formatting guidelines.

Recommendation: Carefully check and update all references to conform to the required style, including journal abbreviations and citation formats.

Avoid citing outdated references; instead, prioritize high-quality, relevant publications, particularly those from 2023, to strengthen the manuscript's credibility and relevance.

> Language and Readability

Although the manuscript is generally well-written, numerous sentences contain minor typographical and grammatical errors.

Suggestion: Utilize a professional English editing service to refine the language and improve overall readability.

Reviewer #2: Dear Author

Thank you for your manuscript submission. The current manuscript is well-designed and well-presented. However, a Minor Revision is needed as below:

1. As the current work is an in silico one, please do add the terms of "in silico" and "Dry Lab" to Methodology section. In this regard, the following paper is a useful reference for the current manuscript:

Respiratory Tularemia: Francisella Tularensis and Microarray Probe Designing. Open Microbiol J. 2016 Nov 30;10:176-182. doi: 10.2174/1874285801610010176. PMID: 28077973; PMCID: PMC5204066.

2. Please do add a flow chart to Methodology section to show all the procedures done within the current study.

3. It is recommended to add a flow chart to Results section to show the main outcomes obtained from the current study.

4. Please do add the strength and the limitation of the current study.

5. Please do interpret the results of the statistical analyses within the current study.

Reviewer #3: Introduction:

1. For conventional eosinophilic esophagitis (EoE) and its subtypes—EoE-like esophagitis, lymphocytic esophagitis, and nonspecific esophagitis, can authors demonstrate what are common features of immunology, genetics, and epigenetics?

2. How do findings show molecular heterogeneity of esophageal inflammatory disorders? Can authors make more detailed descriptions?

Methods:

1. For Figure 1, do TF analysis, WGCNA, DE analysis and ML analysis share a parallel relationships? If not, can authors modify this figure?

2. For Differential Gene Expression, why do authors select “Genes exhibiting |log2 fold change (FC)| > 1.5 and a p-adjusted value of p < 0.05 were considered statistically significant”?

3. For Gene Ontology and Functional Analysis, if it is a kind of ORA analysis, authors should indicate this point?

4. Do Dorothea and WGCNA share similar application conditions?

5. “gene lists from the modules of interest into the STRING”, do they come from WGCNA analysis?

RESULTS:

1. Explain why are belt shape for A and C are different from B and D in Figure 2?

2. “GO-BP revealed distinct clustering patterns and varying correlation levels”, can authors explain by disease mechanisms research progress?

3. What are common/different findings between DE-GO analysis and WGCNA-GO analysis?

4. How are hub genes identified in PPI network by WGCNA module related with findings from DE analysis?

5. Have authors try unsupervised learning?

6. Can results of TF analysis explain the results in DE/WGCNA analysis?

DISCUSSION

1. How are the immune mechanisms in EoE related with ECM remodeling, and cell motility and organ morphogenesis,

especially for Th2-mediated inflammation?

2. How are Epigenetic modifications involved in EoE? Are they connected to immune?

3. Why is EoE-like esophagitis are different from cEoE, by mechanisms? How are about Lymphocytic Esophagitis, Nonspecific Esophagitis? Can authors link them together using your findings?

4. For TF results, again, can authors link them together using your findings?

Reviewer #4: The submitted manuscript presents a comprehensive and insightful multi-omics investigation into the molecular and immunological heterogeneity of eosinophilic esophagitis (EoE) and its subtypes. The integrative approach utilizing differential gene expression profiling, weighted gene co-expression network analysis (WGCNA), and machine learning techniques is robust and methodologically sound.

Strengths:

- The study addresses an important diagnostic gap in distinguishing between EoE subtypes.

- Identification of subtype-specific biomarkers such as DNAH11, CXCL10, and zinc transporters (SLC39A1, SLC39A2) is novel and therapeutically promising.

- The inclusion of both metabolic and immune-related signatures adds depth to the mechanistic understanding of each subtype.

- The manuscript is well-organized and clearly written, with logical progression from background to results and implications.

Minor Revisions Suggested:

- While the overall analysis is clearly outlined, the authors should provide more detail on the machine learning models used—especially the type, validation strategy, and performance metrics (e.g., accuracy, AUC).

- If any qPCR or external validation datasets were used to confirm key findings (e.g., POSTN, DNAH11 expression), they should be briefly described. If not performed, suggest acknowledging this as a limitation.

- Although the statement claims full availability, including a link to the raw and processed gene expression data repository (e.g., GEO accession number) would improve transparency.

- Consider adding a visual summary or schematic figure outlining the subtype-specific molecular mechanisms for easier reader interpretation.

**********

-->6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: Yes: Payam BEHZADI

Reviewer #3: No

Reviewer #4: No

**********

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-->PONE-D-25-23211R1-->-->Molecular and Immunological Heterogeneity of Eosinophilic Esophagitis: Insights and Subtyping-->-->PLOS ONE

Dear Dr. Ullah,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 07 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Austin W.T. Chiang

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #4: (No Response)

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #4: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #4: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #4: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #4: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The manuscript is well-written, clearly structured, and presents original research findings that are relevant to the field. The study design, methodology, data analysis, and interpretation are appropriate and thorough. Figures and tables are well-prepared, and the discussion accurately reflects the findings while placing them in context with prior literature. The references are comprehensive and up-to-date, and the conclusions are well-supported by the data.

I found no major issues related to dual publication, plagiarism, or research ethics. The authors appear to have followed proper ethical standards. No concerns regarding publication ethics were identified.

Recommendation: Accept the manuscript in its current form.

Reviewer #2: (No Response)

Reviewer #4: The manuscript “Molecular and Immunological Heterogeneity of Eosinophilic Esophagitis: Insights and Subtyping” provides a comprehensive integrative multi-omics and bioinformatics approach to disentangling the heterogeneity of EoE and its related subtypes. The study is timely and addresses an important unmet need in gastroenterology and immunology, namely the lack of clear molecular criteria to differentiate overlapping esophageal inflammatory disorders.

Strengths:

- The integrative approach using gene expression profiling, WGCNA, enrichment studies, and machine learning provides robust cross-validation of findings.

- Identification of novel players such as DNAH11 and zinc pathway alterations adds originality and translational relevance.

- The clear delineation of subtype-specific pathways (e.g., immune dysregulation in EoE-like, mitochondrial impairment in lymphocytic esophagitis) is of high significance for potential precision medicine.

- The manuscript is generally well-written and logically structured.

Points for Improvement:

- While analyses appear rigorous, the manuscript would benefit from clearer reporting of sample sizes, adjusted p-values, and validation across independent datasets where possible. This will strengthen confidence in subtype-specific conclusions.

- Pathway maps or schematic diagrams summarizing the distinct molecular landscapes of each subtype would enhance clarity for readers less familiar with systems biology.

- The connection between altered zinc homeostasis and epithelial dysfunction is compelling but currently speculative. Additional evidence or literature support should be added to avoid overinterpretation.

- Minor grammatical edits are needed (e.g., in the Results section, a few sentences are overly long and could be broken down for clarity).

- The conclusion should emphasize how these findings could realistically be applied in clinical diagnostics or therapeutic development. A short section outlining potential biomarkers suitable for clinical validation would be valuable.

This manuscript is technically sound, presents novel insights, and makes a meaningful contribution to the understanding of EoE heterogeneity. Pending minor revisions (clarity, reporting detail, and expanded discussion on translational relevance), it is suitable for publication.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .-->

Reviewer #1: No

Reviewer #2: Yes: Payam BEHZADI

Reviewer #4: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.-->

-->PONE-D-25-23211R2-->-->Molecular and Immunological Heterogeneity of Eosinophilic Esophagitis: Insights and Subtyping-->-->PLOS One

Dear Dr.  Man Ullah,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.-->--> -->-->==================================

Number 3 of the POS One publications criteria required that "Experiments, statistics, and other analyses are performed to a high technical standard and are described in sufficient detail."-->

• -->While the analyses appear rigorous, the manuscript should include clear reporting of sample sizes, adjusted p-values, and validation across independent datasets where possible. -->

To address no. 4 "Conclusions are presented in an appropriate fashion and are supported by the data.", please include additional literature for the connection between zinc homeostasis and epithelial dysfunction.

5. is that  "The article is presented in an intelligible fashion and is written in standard English."

• Minor grammatical edits are needed (e.g., in the Results section, a few sentences are overly long and could be broken down for clarity).

-->

==============================

Please submit your revised manuscript by Feb 27 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Claudia D. Andl, Ph.D.

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

While the reviewers overall agree that this manuscript is of interest and technically sound, it would benefit from clearer reporting of sample sizes, adjusted p-values, and validation across independent datasets where possible to support the subtype-specific conclusions.

Similarly, to enhance the connection between altered zinc homeostasis and epithelial dysfunction, additional evidence from the literature should be added to avoid overinterpretation.

Minor grammatical edits are needed (e.g., in the Results section, a few sentences are overly long and could be broken down for clarity).

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #2: All comments have been addressed

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #2: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #2: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #2: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #2: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #2: Dear Author

Thank you for your effective revision. Hence, the current manuscript can be published in present form

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .-->

Reviewer #2: Yes: Payam BEHZADI

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Molecular and Immunological Heterogeneity of Eosinophilic Esophagitis: Insights and Subtyping

PONE-D-25-23211R3

Dear Dr. Aman Ullah,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Claudia D. Andl, Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: