The urinary microbiome in association with diabetes and diabetic kidney disease: A systematic review

Tiscar Graells; Yi-Ting Lin; Shafqat Ahmad; Tove Fall; Johan Ärnlöv

doi:10.1371/journal.pone.0317960

Peer Review History

Original SubmissionOctober 11, 2024
19 Nov 2024 Decision Letter - Zongxin Ling, Editor PONE-D-24-45699The urinary microbiome in association with diabetes and diabetic kidney disease: A systematic reviewPLOS ONE Dear Dr. Graells, 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 Jan 03 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. 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Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected. [Note: HTML markup is below. Please do not edit.] 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: Partly Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A Reviewer #3: 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 ****** 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: Yes Reviewer #2: Yes Reviewer #3: 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: The authors reviewed urinary microbiome in patients with diabetic kidney disease. This review is valuable. However, there are still some issues. 1. Line 91. As a systematic review, SCOPUS and PUBMED databases are not enough. Databases such as PubMed/Medline, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials should be included. 2. The abundance of urine microbiome is relatively low, so different detection methods may bring large errors. There is a big gap between the technology of 20 years ago and the technology of today, which may produce a large bias in the analysis. It is suggested that the authors change the search range to nearly 10 years. For example, from 2014 to 2024. 3. There is only one figure and one table in the manuscript. Why did the authors include so much data in the supplementary material? Some data should be moved from the supplementary material. Reviewer #2: This is a well-structured and informative review of the current knowledge on the urobiome and its association with diabetes mellitus and diabetic kidney disease. The review effectively highlights the emerging field of urobiome research and its potential implications for understanding and managing kidney disease. Here are some areas for potential improvement: While the review provides a good overview of the trends in the literature, a deeper analysis of the specific microbial taxa and functional pathways associated with diabetes and kidney disease could be beneficial. The review could discuss in more detail the methodological limitations of the included studies, such as potential biases in sample collection and processing, and the impact of these limitations on the overall findings. The review could conclude with a discussion of future research directions, including the need for larger, well-designed studies to confirm the findings and explore the mechanisms underlying the associations between the urobiome and diabetes. While you summarize results on richness, alpha/beta diversity, and specific bacterial taxa, consider offering a more interpretive analysis. Explore potential connections between specific microbial changes and diabetes or DKD. Discuss the limitations of the included studies, such as small sample sizes, cross-sectional design, and heterogeneity in sample collection methods. Consider how these limitations might affect the generalizability of the findings. Conclude by outlining potential future research directions. You could expand on specific areas of future research. This could include • investigating the influence of specific dietary patterns on the urobiome in diabetes. • exploring the potential for manipulating the urobiome through probiotics or other interventions. • investigating the role of the urobiome in the early stages of diabetes development. You could briefly mention the potential implications of these findings for understanding and managing diabetes and DKD. Briefly discuss potential mechanisms by which the observed changes in the urobiome might influence diabetes and DKD. For example, how could the decrease in butyrate-producing bacteria contribute to disease? Please provide a full search strategy for all databases. Reviewer #3: Graells et al. have performed a systematic review on the association of urinary microbiome with diabetes and diabetic kidney diseases. The study findings are interesting and the manuscript is well-written. These are my comments: - Abstract should have a structure of background, methods, results, and conclusion. - The introduction section is rather long in its current format. The authors should focus on the main ideas related to the topic and try to emphasize the gaps in knowledge. - The results section could be organized by adding subheadings. - A supplementary table containing the search strategy and the exact words searched in each database could be helpful for the reproducibility of the study. ****** 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. 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: No Reviewer #3: 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. 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Revision 1
19 Dec 2024 Author Response 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: Partly Reviewer #3: Yes 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A Reviewer #3: 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 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: Yes Reviewer #2: Yes Reviewer #3: 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: The authors reviewed urinary microbiome in patients with diabetic kidney disease. This review is valuable. However, there are still some issues. 1. Line 91. As a systematic review, SCOPUS and PUBMED databases are not enough. Databases such as PubMed/Medline, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials should be included. Authors’ response: Thank you for pointing out that fact. We have updated the Methods Search Strategy section to include these new database searches and to update the previous searches. We have now included until the end of November a search in MEDLINE Ovid, Web of Science and EMBASE where we found 38,86 and 87 records, respectively. Duplicates were 37, 45 and 63 in MEDLINE Ovid, Web of Science and EMBASE, respectively. One, 17 and 21 were articles types in MEDLINE Ovid, Web of Science and EMBASE, respectively, not included in our analyses such as reviews, conference abstracts. Twenty-one and three articles were excluded after screening title and abstract in Web of Science and EMBASE, respectively. Hence, in the end only three articles were eligible for full screening from Web of Science. In the end, none of them were included in the analysis after full screening as they did not fulfil the inclusion criteria. We have also searched the Cochrane Central Register of Controlled Trials where there were no matching for Reviews, Protocols, Trials, Editorials, Special collections or Clinical answers following a TITLE-ABS-KEY search [[ 0 Cochrane Reviews matching "urobiome" OR "urinary microbiome" OR "urinary microbiota" OR "urinary tract microb" OR "urine microb" OR "urogenital microbiome" OR "urogenital microbiota" in Title Abstract Keyword AND "kidney disease" OR "chronic kidney disease" OR "diabetes" OR "albuminuria" OR "diabetic nephropathy" OR "end stage renal disease" OR "renal disease" in Title Abstract Keyword - (Word variations have been searched) ]]. All this is specified in the Methods search strategy. 2. The abundance of urine microbiome is relatively low, so different detection methods may bring large errors. There is a big gap between the technology of 20 years ago and the technology of today, which may produce a large bias in the analysis. It is suggested that the authors change the search range to nearly 10 years. For example, from 2014 to 2024. Authors’ response: Thank you for this pointing this fact. It is completely true that technology has changed a lot in 20 years. And, we could have searched only one decade, but we did not want to miss anything that could have been published. However, the first article that fulfilled the inclusion criteria was published only 7 years ago, in 2017. Hence, although technology has changed in 20 years, we believe that this is not affecting our analysis as articles selected following the inclusion criteria are from 2017 onwards. 3. There is only one figure and one table in the manuscript. Why did the authors include so much data in the supplementary material? Some data should be moved from the supplementary material. Authors’ response: Thank you for noticing that we have conducted a thorough analysis of each of the articles. We have presented all data we have checked for each of the articles in the supplementary information. We believe that the summarized and key information is the one presented in Table 1. That is why, Table 1 is so extensive, and we decided still to make available all the data collected in the supplementary information for interested researchers. We believe that the article is easier and more attractive to read by summarizing the most important information in a single table in the main manuscript. However, we are willing to reorganize if the Editor agrees that this would be an improvement of the manuscript. Reviewer #2: This is a well-structured and informative review of the current knowledge on the urobiome and its association with diabetes mellitus and diabetic kidney disease. The review effectively highlights the emerging field of urobiome research and its potential implications for understanding and managing kidney disease. Here are some areas for potential improvement: While the review provides a good overview of the trends in the literature, a deeper analysis of the specific microbial taxa and functional pathways associated with diabetes and kidney disease could be beneficial. Authors’ response: Thank you for this comment. We have expanded the discussion and references with the following. “Generally, adults with diabetes and/or chronic kidney disease show lower abundance of short-chain fatty acids producing bacteria in the gut compared to healthy controls [4,45]. This systematic review reveals that diabetic individuals have similar trends but also differences in their urinary and urogenital microbiota with lower relative abundance of short-fatty acid butyrate-producing bacteria of the family Peptoniphilaceae. Butyrate is the main source of colonocyte metabolism, it is an enhancer of the integrity of the epithelium, and it decreases inflammation in the mucosa while promoting electrolyte absorption in the gut [46]. Moreover, dissociated butyric acid has an antibacterial effect [46] and butyryl-CoA regulates transcription and modifies proteins [46,47]. We hypothesize that butyrate could also promote epithelium integrity and reduce inflammation in the urinary tract. Hence, depletion of butyrate-producing bacteria such as Peptoniphilus, Anaerococcus, and Gallicola in diabetic individuals could induce inflammation and contribute to the high onset of urinary infections in diabetic individuals in the urinary tract and induce inflammation in the renal blood vessels which could worsen kidney disease. This theory will need further studies to be confirmed but it could help to understand if the use of butyrate as a postbiotic could improve urinary functionality in association with diabetes and kidney disease.” The review could discuss in more detail the methodological limitations of the included studies, such as potential biases in sample collection and processing, and the impact of these limitations on the overall findings. Authors’ response: Thank you for this comment. We have expanded the limitations section with lines 335-343. The review could conclude with a discussion of future research directions, including the need for larger, well-designed studies to confirm the findings and explore the mechanisms underlying the associations between the urobiome and diabetes. Authors’ response: Thank you for this comment. We have expanded the future perspectives section with lines 358-367. While you summarize results on richness, alpha/beta diversity, and specific bacterial taxa, consider offering a more interpretive analysis. Explore potential connections between specific microbial changes and diabetes or DKD. Authors’ response: Thank you for this comment. We have expanded the discussion and references with the following. “Generally, adults with diabetes and/or chronic kidney disease show lower abundance of short-chain fatty acids producing bacteria in the gut compared to healthy controls [4,45]. This systematic review reveals that diabetic individuals have similar trends but also differences in their urinary and urogenital microbiota with lower relative abundance of short-fatty acid butyrate-producing bacteria of the family Peptoniphilaceae. Butyrate is the main source of colonocyte metabolism, it is an enhancer of the integrity of the epithelium, and it decreases inflammation in the mucosa while promoting electrolyte absorption in the gut [46]. Moreover, dissociated butyric acid has an antibacterial effect [46] and butyryl-CoA regulates transcription and modifies proteins [46,47]. We hypothesize that butyrate could also promote epithelium integrity and reduce inflammation in the urinary tract. Hence, depletion of butyrate-producing bacteria such as Peptoniphilus, Anaerococcus, and Gallicola in diabetic individuals could induce inflammation and contribute to the high onset of urinary infections in diabetic individuals in the urinary tract and induce inflammation in the renal blood vessels which could worsen kidney disease. This theory will need further studies to be confirmed but it could help to understand if the use of butyrate as a postbiotic could improve urinary functionality in association with diabetes and kidney disease.” Discuss the limitations of the included studies, such as small sample sizes, cross-sectional design, and heterogeneity in sample collection methods. Consider how these limitations might affect the generalizability of the findings. Authors’ response: Thank you for this comment. We have expanded the limitations section with lines 335-343. Conclude by outlining potential future research directions. You could expand on specific areas of future research. This could include • investigating the influence of specific dietary patterns on the urobiome in diabetes. • exploring the potential for manipulating the urobiome through probiotics or other interventions. • investigating the role of the urobiome in the early stages of diabetes development. Authors’ response: Thank you for this comment. We have expanded the future perspectives section with lines 358-367. You could briefly mention the potential implications of these findings for understanding and managing diabetes and DKD. Briefly discuss potential mechanisms by which the observed changes in the urobiome might influence diabetes and DKD. For example, how could the decrease in butyrate-producing bacteria contribute to disease? Authors’ response: Thank you for this comment. We have expanded the discussion and references with the following. “Generally, adults with diabetes and/or chronic kidney disease show lower abundance of short-chain fatty acids producing bacteria in the gut compared to healthy controls [4,45]. This systematic review reveals that diabetic individuals have similar trends but also differences in their urinary and urogenital microbiota with lower relative abundance of short-fatty acid butyrate-producing bacteria of the family Peptoniphilaceae. Butyrate is the main source of colonocyte metabolism, it is an enhancer of the integrity of the epithelium, and it decreases inflammation in the mucosa while promoting electrolyte absorption in the gut [46]. Moreover, dissociated butyric acid has an antibacterial effect [46] and butyryl-CoA regulates transcription and modifies proteins [46,47]. We hypothesize that butyrate could also promote epithelium integrity and reduce inflammation in the urinary tract. Hence, depletion of butyrate-producing bacteria such as Peptoniphilus, Anaerococcus, and Gallicola in diabetic individuals could induce inflammation and contribute to the high onset of urinary infections in diabetic individuals in the urinary tract and induce inflammation in the renal blood vessels which could worsen kidney disease. This theory will need further studies to be confirmed but it could help to understand if the use of butyrate as a postbiotic could improve urinary functionality in association with diabetes and kidney disease.” Authors’ response: Thank you for this comment. Please provide a full search strategy for all databases. Authors’ response: Thank you for this comment. We have updated the Methods Search Strategy section to include new databases in this analysis. We have updated the information provided and we have made available our search strategy in the following lines: “A comprehensive literature search on different databases was conducted from 1st January 2000 until 28th November 2024. The search included the following terms [("urobiome" OR "urinary microbiome" OR "urinary microbiota" OR "urinary tract microb" OR "urine microb" OR "urogenital microbiome" OR "urogenital microbiota") AND ("kidney disease" OR "chronic kidney disease" OR "diabetes" OR "albuminuria" OR "diabetic nephropathy" OR "end stage renal disease" OR "renal disease")]. We used the ‘TITLE-ABS-KEY’ search in SCOPUS and Cochrane Central Register of Controlled Trials databases, the ‘Keyword’ in advanced search in MEDLINE-Ovid and EMBASE databases, while ‘ALL FIELDS’ were used in Web of Science and PUBMED databases.”. Reviewer #3: Graells et al. have performed a systematic review on the association of urinary microbiome with diabetes and diabetic kidney diseases. The study findings are interesting and the manuscript is well-written. These are my comments: - Abstract should have a structure of background, methods, results, and conclusion. Authors’ response: Thank you for this comment. Now, we have added these sections in the abstract. - The introduction section is rather long in its current format. The authors should focus on the main ideas related to the topic and try to emphasize the gaps in knowledge. Authors’ response: In the revised version of the manuscript, we have shortened the introduction part. - The results section could be organized by adding subheadings. Authors’ response: Thank you for this comment. Now, we have added these sections (3.1 Selected studies; 3.2 Diversity and richness indexes; and 3.3 Differences in microbial microbial taxa). - A supplementary table containing the search strategy and the exact words searched in each database could be helpful for the reproducibility of the study. Authors’ response: Thank you for this comment. We have updated the Methods Search Strategy section to include new databases in this analysis. We have updated the information provided including a supplementary table with the details of the search startegy and we have made available our search strategy in the following lines: “A comprehensive literature search on different databases was conducted from 1st January 2000 until 28th November 2024. The search included the following terms [("urobiome" OR "urinary microbiome" OR "urinary microbiota" OR "urinary tract microb" OR "urine microb" OR "urogenital microbiome" OR "urogenital microbiota") AND ("kidney disease" OR "chronic kidney disease" OR "diabetes" OR "albuminuria" OR "diabetic nephropathy" OR "end stage renal disease" OR "renal disease*")]. We used the ‘TITLE-A https://doi.org/10.1371/journal.pone.0317960.r002
8 Jan 2025 Decision Letter - Zongxin Ling, Editor The urinary microbiome in association with diabetes and diabetic kidney disease: A systematic review PONE-D-24-45699R1 Dear Dr. Graells, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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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: All comments have been addressed Reviewer #3: 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 #1: Yes Reviewer #2: Yes Reviewer #3: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: (No Response) ****** 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: Yes Reviewer #3: (No Response) ****** 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: Yes Reviewer #3: (No Response) ****** 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: Thank you very much. You guys solved all my problems. I think the present article is worth publishing. Reviewer #2: the aim of this systematic review is to gather available data and synthetise the main 80 findings about the urobiome, particularly, the urinary microbiota in association with diabetes and 81 kidney conditions derived from diabetes such as CKD or ESRD. All of my comments have been responded satisfactorily. Reviewer #3: (No Response) ****** 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: No Reviewer #3: No ******** https://doi.org/10.1371/journal.pone.0317960.r003
Formally Accepted
22 Jan 2025 Acceptance Letter - Zongxin Ling, Editor PONE-D-24-45699R1 PLOS ONE Dear Dr. Graells, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Zongxin Ling Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0317960.r004

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