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The authors have conducted great work on this manuscript, incorporating feedback from reviewers to enhance the clarity and depth of the content. They have successfully elucidated the role of gut microbiome-immune interactions in the development of rheumatoid arthritis, providing a detailed and comprehensive explanation of this complex biological process. This manuscript now offers a clearer and more insightful understanding of the mechanisms at play, thanks to the thoughtful integration of the reviewers' suggestions.
[# PeerJ Staff Note - this decision was reviewed and approved by Valeria Souza, a PeerJ Section Editor covering this Section #]
The authors incorporated revisions based on the feedback from reviewers, modifying both the experimental design and findings in the manuscript. This impact is particularly meaningful in the context of rheumatoid arthritis research.
Please address the remaining comments from Reviewer 2.
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Dear Authors,
Upon reviewing the updated version of your manuscript, I am pleased to acknowledge the comprehensive nature of the changes you have implemented. The enhancements you have made are considerable, and the potential of your research to advance our field is noteworthy. Consequently, I wholeheartedly endorse the publication of your work.
I appreciate your receptiveness to my suggestions and your commitment to refining your manuscript. I look forward to the dissemination of your significant findings and am optimistic about the beneficial influence it will exert on our field of science. Wishing you the best in your future endeavors.
The abstract lacks some essential information, such as the specific population studied (e.g., ethnicity, age range, gender) and the country where the research was conducted. Including these details would help readers better understand the context and generalizability of the findings
The methods section does not provide sufficient detail on the inclusion and exclusion criteria for the study participants. The authors should clearly state how they defined "healthy controls" and whether they matched the controls to the RA patients by age, gender, and other relevant factors
The authors mention that they used the American College of Rheumatology 2010 classification criteria for RA, but they do not specify how they assessed disease activity (e.g., DAS28 score) or whether they collected information on disease duration and treatment history. These factors could potentially influence the gut microbiome and should be considered in the analysis
The results section highlights some key findings, such as the lower alpha diversity in the RA group and the importance of Lachnospiraceae and Oscillospiraceae families in distinguishing between the two groups. However, the authors do not provide any information on the potential functional implications of these taxonomic differences. Incorporating data on predicted metabolic pathways (e.g., using PICRUSt) could strengthen the biological relevance of the findings.
The authors report correlations between specific taxa and immunological markers (e.g., Sellimonas with IL5), but they do not clarify whether these associations were significant after adjusting for multiple testing. Applying appropriate statistical corrections (e.g., FDR) is crucial to avoid false-positive results.
The manuscript would benefit from a more in-depth discussion of the potential mechanisms linking the gut microbiome, immune system, and RA pathogenesis. The authors should cite relevant literature to support their interpretations and highlight the novelty of their findings in the context of previous studies.
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The paper clearly introduced the background, knowledge gap and hypothesis. The paper is well written and structured.
Rigorous investigation is performed in this study. The methods are clearly described
The results were thoroughly discussed, and conclusions were linked to the research question. The findings from this study advance understanding of RA development.
All the comments were comprehensively addressed.
Dear authors,
We kindly request that you carefully review the comments provided by the reviewers. Their valuable suggestions offer insights to enhance your manuscript. Updating your work in accordance with their inputs will significantly strengthen its content.
Thank you.
**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
The language used in the manuscript is clear and unambiguous. The authors provide sufficient background information on rheumatoid arthritis (RA), the gut microbiome, and their relevance to RA pathogenesis. The introduction effectively sets the stage for the study by summarizing relevant literature and establishing the study's rationale.
There are no obvious typos or grammatical errors in the provided text. However, the full manuscript should be reviewed for such issues, as only a portion is available here.
The research question is well-defined, relevant, and meaningful. The study aims to investigate the connections between the gut microbiome, immunological markers, and metabolic pathways in the context of RA, which is a significant area of research with potential therapeutic implications.
The experimental design appears to be well-structured, with a clear description of the study population, sample collection, DNA extraction, sequencing, and data analysis. The methods are detailed enough to be reproducible, which is critical for scientific research.
The findings seem to be impactful, providing new insights into the relationship between the gut microbiome and RA. The identification of specific microbial taxa and their correlations with immunological markers and metabolic pathways is novel and contributes to the understanding of RA pathogenesis. However, there are certain areas of improvement:
1) While the study's strengths are well articulated, it may benefit from a more detailed discussion of the specific limitations and how they might be addressed in future research. For example, the authors could suggest strategies for including patients in the early stages of RA or discuss the potential impact of medication on the microbiome.
2) The manuscript could be improved by providing more context on how the identified microbial taxa and metabolic pathways compare to those found in other populations or ethnicities, which could help in understanding the generalizability of the findings.
3) The authors mention the use of 16S rRNA sequencing and suggest that further metagenomic sequencing is required. It would be beneficial to discuss how metagenomic sequencing could provide a more comprehensive understanding of the functional capabilities of the microbiome and its impact on RA.
4) It may be useful to include a more detailed discussion of how the identified biomarkers could be translated into clinical practice or therapeutic strategies, which would add practical value to the research.
5) The study focuses on a female Kazakhstani population; therefore, it would be pertinent to discuss the implications of these demographic factors on the study's findings and their relevance to other populations.
The manuscript on "Gut microbiome-immune interactions and their role in rheumatoid arthritis development" provides valuable insights into the complex interplay between the gut microbiota and immune responses in RA patients. The study's design, involving comprehensive microbial and immunological profiling, is robust and contributes significantly to our understanding of RA's etiology. However, for a major revision, I recommend enhancing the methodological details to improve reproducibility, such as clearer descriptions of sequencing depth and statistical thresholds. Additionally, expanding on the discussion of how these findings could translate into clinical practice or guide future research would be beneficial. The potential for personalized treatment strategies based on gut microbiota composition is intriguing and warrants further exploration. Lastly, considering the homogeneity of the study population, discussing the findings' applicability to broader, more diverse populations would strengthen the manuscript's impact.
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The knowledge gap is not clearly discussed in the introduction section. The paper did a good job introducing RA and gut microbiome background, however, it’s unclear for the motivation of the study and which knowledge gap is addressed.
Some conclusions cannot be derived from the findings. The paper claimed Lachnospiraceae and Oscillospiraceae (LO) families have better predictive accuracy than the other bacteria. However, the LO families have poor AUC scores (0.57 and 0.59) that are only slightly better than random guess. These AUC scores were also lower than using all genera (AUC=0.72 and 0.63). So, these results do not lead to the conclusion that LO families can predict rheumatoid arthritis groups.
In the paper “Gut microbiome-immune interactions and their role in rheumatoid arthritis development”, the study found fecal microbiome, chemokines/cytokines and metabolic pathways were associated with rheumatoid arthritis (RA). The study used rigorous criteria to select the study cohort with matching sex, age and ethnicity between RA and control groups. However, some major improvements are still needed.
Major comments:
1. The paper needs to improve on results presentation. In both the results and discussion sections, the paper listed all the findings from their correlation analyses. Please choose the most important findings to highlight and provide in-depth discussion for these findings. Otherwise, it’s hard for readers to focus on the most important messages need to be delivered.
2. Some important details are missing from the paper.
a. Since the study compared between RF positive/negative form and ACPA positive/negative form, the paper should explain these different categories.
b. The paper should be explicit on the whether the bacterial taxa correlated with cytokines/chemokines are also associated with RA/RA forms. If these taxa don’t correlate with RA/RA forms, the correlation identified may not be relevant for RA.
c. The paper discussed on the metabolic pathways in RA. However, the paper did not give enough information for how the metabolic pathways were defined? From what datasets?
3. Some conclusions cannot be derived from the findings.
a. In results section 3.5, the paper claimed LO families have better predictive accuracy than the other bacteria. However, the LO families have poor AUC scores (0.57 and 0.59) that are only slightly better than random guess. These AUC scores were also lower than using all genera (AUC=0.72 and 0.63). So, these results do not lead to the conclusion that LO families predict RA better than the other bacteria.
b. The paper claimed LO families are important. However, it’s not clear for how these two families are selected for the downstream analyses as many other bacterial taxa also showed associations with RA groups and cytokines/chemokines.
4. The knowledge gap is not clearly discussed in the introduction section. The paper did a good job introducing RA and gut microbiome background, however, it’s unclear for the motivation of the study and which knowledge gap is addressed.
5. OTU for 16s rRNA gene analysis is out of date, please use ASV instead.
Minor comments:
1. Please add details for the 16s rRNA sequencing depth.
2. It’s not necessary to show insignificant p values (LINE 187-189) .
3. Figure 4, I would suggest using different color panels for panels A and B, avoid using same color (green and yellow) to indicate different groups in panel A and B. The lower half of the error bars are not shown
4. Figure 5. it’s unclear for how the correlation analyses are done. Were the correlations carried out for each group separately? Why there are bars showing different groups (purple and green) in the figure?
5. Overall, I would suggest removing higher taxonomic levels if a finer resolution is shown. For example, for f__Ruminococcaceae.g__Ruminococcus, only show Ruminococcus is sufficient and adding too many higher taxonomic levels doesn’t help readers to follow.
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