Prophylactic effects of probiotics or synbiotics on postoperative ileus after gastrointestinal cancer surgery: A meta-analysis of randomized controlled trials

Gang Tang; Wang Huang; Jie Tao; Zhengqiang Wei

doi:10.1371/journal.pone.0264759

Peer Review History

Original SubmissionJune 20, 2021
8 Sep 2021 Decision Letter - Laura Pasin, Editor PONE-D-21-20250Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled TrialsPLOS ONE Dear Dr. Wei, 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 26/09/2021. 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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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that this manuscript is a systematic review or meta-analysis; our author guidelines therefore require that you use PRISMA guidance to help improve reporting quality of this type of study. Please upload copies of the completed PRISMA checklist as Supporting Information with a file name “PRISMA checklist [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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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 ****** 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 ****** 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: Thank you for your work. The manuscript is interesting and well written. As underlined by authors in the discussion, the two main limitations are the heterogeneity of included studies ( very different types of surgery) and the small sample size of included studies. I would like to ask to the authors if they performed a trial sequential analysis, to better evaluate the results of their study. Thank you Reviewer #2: GENERAL COMMENT Thanks for the opportunity to review this article. The authors conducted a systematic review and meta-analysis of randomized controlled trials investigating the effect of probiotics or synbiotics on early postoperative recovery of gastrointestinal function in patients with gastrointestinal cancer. They found that perioperative supplementation of probiotics or synbiotics can effectively promote the recovery of gastrointestinal function after gastrointestinal cancer surgery. The research question is clinically relevant and original. However, I would have the following major comments: - I would suggest the authors to perform an extensive English language editing of the manuscript. - Further efforts should be carried out to explore the reasons for the moderate-high heterogeneity detected among the studies, as the authors appropriately pointed out in the limitations section. This would significantly strengthen the authors’ findings. - The Risk of Bias tool the authors employed is not the most recent one. The recommended tool for assessing risk of bias of RCTs is the RoB 2 (https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2?authuser=0). Please provide the risk of bias assessment by using this tool. - A GRADE assessment is very important to better inform the reader about the overall certainty of evidence. Please perform a GRADE assessment. Online tools are available for this, e.g., https://gradepro.org/. MINOR COMMENTS Line 77: “Our meta-analysis was conducted based on” The meta-analysis is reported based on PRISMA Checklist, rather than conducted based on it. Please modify accordingly. Line 81: “Additionally, the reference lists of related reviews were also searched” It seems to me that this sentence should be placed afterwards or removed, considering the last sentence of the paragraph. Lines 110-111: “the random-effects model was selected when I^2 was >50 %” It is not recommended to choose the model based on the I^2 value. A random-effects model should be applied regardless of the I^2, unless the authors anticipate there to be very small heterogeneity. Otherwise, sensitivity analyses with different I^2 thresholds should be performed. Line 113: “Egger's test” Along with the Egger’s test, should there be a significant number of included studies (> 10), funnel plots should be provided as well. Lines 145-146: “and there was significant heterogeneity (I^2 = 55.8%, P = 0.13) between subgroups. In addition, heterogeneity was significantly reduced in the synbiotics subgroup (I^2 = 27%, P = 0.25)” In my opinion, the authors should report that the p-value allows to conclude that there was no subgroup difference. The difference in heterogeneity between the groups cannot really be compared and stated as significant. Line 152: “with significant heterogeneity” The authors should provide the I^2 and the p-value relative to the I^2 test, like for the time to first flatus outcome. The same should be considered for Lines 178-179. ****** 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 [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. https://doi.org/10.1371/journal.pone.0264759.r001
Revision 1
26 Sep 2021 Author Response Replies to the Reviewer Thank you very much for taking time to review our manuscript. We have carefully read your comments and suggestions, which have been of great help. We have revised the manuscript according to the comments and responded point-by-point to the comments, as listed below. Additionally, we have highlighted all revised text. Reviewer #1: Thank you for your work. The manuscript is interesting and well written. As underlined by authors in the discussion, the two main limitations are the heterogeneity of included studies ( very different types of surgery) and the small sample size of included studies. I would like to ask to the authors if they performed a trial sequential analysis, to better evaluate the results of their study. Thank you Answer: Thanks again to the reviewer, we did not performe a trial sequential analysis in our meta-analysis. This is the first meta-analysis on this topic, so we did not consider using a trial sequential analysis when making our study protocol. Reviewer #2: GENERAL COMMENT Thanks for the opportunity to review this article. The authors conducted a systematic review and meta-analysis of randomized controlled trials investigating the effect of probiotics or synbiotics on early postoperative recovery of gastrointestinal function in patients with gastrointestinal cancer. They found that perioperative supplementation of probiotics or synbiotics can effectively promote the recovery of gastrointestinal function after gastrointestinal cancer surgery. The research question is clinically relevant and original. However, I would have the following major comments: - I would suggest the authors to perform an extensive English language editing of the manuscript. Answer: With the help of the Taylor & Francis Editing Services, we perform an extensive English language editing of the manuscript. The major revisions are highlighted in the manuscript, and the minor revisions made to fix grammatical errors and improve expressions do not affect the results. - Further efforts should be carried out to explore the reasons for the moderate-high heterogeneity detected among the studies, as the authors appropriately pointed out in the limitations section. This would significantly strengthen the authors’ findings. Answer: Thanks for the reviewer's suggestion. Due to the significant heterogeneity, we are prepared to conduct a subgroup analysis to explore the source of heterogeneity. As we mentioned in the discussion, different surgical methods, differences dose and species of probiotics or synbiotics, and different courses of treatment may be the source of heterogeneity. However, due to the limited number of studies, we were unable to conduct subgroup analysis of these factors. In the future, we will conduct more detailed analyses with more studies. In the discussion section of the manuscript : “Significant heterogeneity was observed in our study, which may be related to significant differences in type of surgery (radical colorectomy, liver resection, esophagectomy, colorectal cancer resection, gastrectomy and pancreatoduodenectomy), duration of probiotics or synbiotics supplementation (from 3 days to 28 days), species of probiotics or synbiotics and dose of probiotics or synbiotics. Future research should explore the specific species of probiotics or synbiotics with the greatest benefit for gastrointestinal function recovery, as well as the most appropriate course and dose of probiotics or synbiotics supplementation.” - The Risk of Bias tool the authors employed is not the most recent one. The recommended tool for assessing risk of bias of RCTs is the RoB 2 (https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2?authuser=0). Please provide the risk of bias assessment by using this tool. Answer: As suggested by reviewers, we have used the latest tools for bias evaluation (figure 2). “Risk of bias for eligible studies was assessed by the ROB-2 tool available in the Cochrane Handbook, including the following domains: (1) Randomization process, (2) Deviations from intended interventions, (3) Missing outcome data, (4) Measurement of the outcome, (5) Selection of the reported result, and (6) Overall.” “Ten of the studies [22, 23, 27-29, 31-33, 35, 37] conducted an appropriate randomization process. Deviations from intended interventions were evaluated as a low bias risk in six studies [20, 22, 31, 32, 35, 37].Missing outcome data, measurement of the outcome, and selection of the reported result in all studies were assessed as a low bias risk (Fig 2). The overall risk of 10 studies [22, 23, 27-29, 31-33, 35, 37] was assessed as low risk of bias.” - A GRADE assessment is very important to better inform the reader about the overall certainty of evidence. Please perform a GRADE assessment. Online tools are available for this, e.g., https://gradepro.org/. Answer: Thanks you for your comments, we have performed a GRADE assessment and revised the manuscript. As follow: “ GRADE Assessment To grade the quality of evidence, a GRADE assessment was performed through GRADEpro online tools (https://gradepro.org/). GRADE assessed the evidence as four levels: very low, low, medium, and high. The two researchers (Gang Tang and Jie Tao) independently assess the certainty of the evidence, and if there was dispute, they would discuss and resolve it.” “GRADE analysis We evaluated the quality of evidence in this study (Fig 11). A part of the evidence (the time to first flatus , days to first fluid diet , incidence of abdominal distension and incidence of postoperative ileus) was in a medium level, one (length of postoperative hospital stay) was very low, one (the time to first defecation) was low, one (days to first solid diet) was high” MINOR COMMENTS Line 77: “Our meta-analysis was conducted based on” The meta-analysis is reported based on PRISMA Checklist, rather than conducted based on it. Please modify accordingly. Answer: Thanks to the reviewers for pointing out these details, we have revised them in the manuscript . As follow: “The meta-analysis is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement” Line 81: “Additionally, the reference lists of related reviews were also searched” It seems to me that this sentence should be placed afterwards or removed, considering the last sentence of the paragraph. Answer: As suggested by the reviewer, we deleted this sentence. Lines 110-111: “the random-effects model was selected when I^2 was >50 %” It is not recommended to choose the model based on the I^2 value. A random-effects model should be applied regardless of the I^2, unless the authors anticipate there to be very small heterogeneity. Otherwise, sensitivity analyses with different I^2 thresholds should be performed. Answer: We revised the manuscript as suggested by the reviewers. As follow: “The random effect model was used in all quantitative analyses, and the fixed effect model was selected only when heterogeneity was low” Line 113: “Egger's test” Along with the Egger’s test, should there be a significant number of included studies (> 10), funnel plots should be provided as well. Answer: We have made the following revisions. “In addition, funnel plots were used when the number of included studies > 10.” “Visual inspection of the funnel plot (length of postoperative hospital stay) identified basically symmetric (Fig 10).” Lines 145-146: “and there was significant heterogeneity (I^2 = 55.8%, P = 0.13) between subgroups. In addition, heterogeneity was significantly reduced in the synbiotics subgroup (I^2 = 27%, P = 0.25)” In my opinion, the authors should report that the p-value allows to conclude that there was no subgroup difference. The difference in heterogeneity between the groups cannot really be compared and stated as significant. Answer: We fully agree with the reviewer's point of view, and we have deleted this sentence Line 152: “with significant heterogeneity” The authors should provide the I^2 and the p-value relative to the I^2 test, like for the time to first flatus outcome. The same should be considered for Lines 178-179. Answer: We revised the manuscript based on suggestions from reviewers, and we have provided the I^2 and the p-value relative to the I^2 test. Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0264759.r002
17 Feb 2022 Decision Letter - Laura Pasin, Editor Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled Trials PONE-D-21-20250R1 Dear Dr. wei, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Laura Pasin Academic Editor PLOS ONE Additional Editor Comments (optional): 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 #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: (No Response) Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #3: 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: (No Response) Reviewer #3: 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: (No Response) Reviewer #3: 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: (No Response) Reviewer #3: Thank you for allowing me to review this manuscript entitled “Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled Trials” I have read with interest the article, which is overall well written, and I believe the findings are clinically significant. The methodology appears to be mostly sound and the conclusions are supported by the data. A few comments: I suggest providing funnel plots for all outcomes and performing a visual inspection, as this can be useful to interpret the results of Egger’s test, which is also not recommended in the Cochrane handbook when there are less than 10 studies (I suggest the relevant chapter in the cochrane handbook: https://training.cochrane.org/handbook/archive/v6/chapter-13). I suggest adding to the limits that the subgroup analysis for the type of surgery, dose and species of probiotics/synbiotics was not possible due to the limited number of studies, as mentioned in the answer to Reviewer 1. Aside from these aspects which in my opinion could benefit from clarification, I believe the manuscript is overall sound and interesting to read. I congratulate the authors for their interesting research. ****** 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 #3: No https://doi.org/10.1371/journal.pone.0264759.r003
Formally Accepted
21 Feb 2022 Acceptance Letter - Laura Pasin, Editor PONE-D-21-20250R1 Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled Trials Dear Dr. Wei: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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. Laura Pasin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0264759.r004

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