Gut microbiota composition in preterm infants with and without necrotizing enterocolitis: A systematic review and narrative synthesis
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Aim Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in preterm infants with a high mortality rate. The etiology of NEC appears to be multifaceted; however, gut microbiota dysbiosis likely plays a significant role. This systematic review aimed to describe how the gut microbiota of preterm infants with NEC differs from infants without NEC (PROSPERO: CRD42022344126). Methods Databases were searched from inception to 22 June 2022 to identify eligible studies that examined the gut microbiota composition of preterm infants with and without NEC using sequencing methods. Results were described narratively. Results Twenty-eight eligible studies were included. Overall, findings were heterogeneous and no single gut microbiota signature was associated with NEC in all studies. Three studies reported no difference in the gut microbiota composition between NEC and healthy infants, while twenty-five studies reported a difference using one or more analytical method (i.e. alpha diversity, beta diversity or differential abundance analysis). Of note, NEC (or development of NEC) was positively associated with increased detection and/or abundance of Enterobacteriaceae (n=11 studies), Clostridium (n=8), and Proteobacteria (n=2). Conclusion The taxa most frequently associated with NEC (Enterobacteriaceae, Clostridium, and Proteobacteria) may play an important role in the pathogenesis of NEC and should be further explored.
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Comments to Author
1. Methodological rigour, reproducibility and availability of underlying data Line 83: The definition of preterm has been expanded to include low birthweight individuals. This is prospectively included in the PROSPERO protocol and is clearly a focus from the outset, but not in the title or abstract. Should have some inclusion of the low birthweight rationale or mention earlier than methods to show that this wasn't a post hoc expansion of the scope of the SR at the data collection stage. Recommend including references to show these definitions and that preterm and low birth weight are related e.g. WHO definition. General Methodology: Very thorough systematic review. Should mention whether grey literature was used. Line 91: Other exclusion criteria are included in the protocol not mentioned here. These …
Comments to Author
1. Methodological rigour, reproducibility and availability of underlying data Line 83: The definition of preterm has been expanded to include low birthweight individuals. This is prospectively included in the PROSPERO protocol and is clearly a focus from the outset, but not in the title or abstract. Should have some inclusion of the low birthweight rationale or mention earlier than methods to show that this wasn't a post hoc expansion of the scope of the SR at the data collection stage. Recommend including references to show these definitions and that preterm and low birth weight are related e.g. WHO definition. General Methodology: Very thorough systematic review. Should mention whether grey literature was used. Line 91: Other exclusion criteria are included in the protocol not mentioned here. These should also be motioned or the search parameters listed as an appendix. Line 78: Two studies were selected by 'reference screening,' this should feature in the methodology. Line 78: The methodology should clearly state that it was stool, meconium or both which were sampled. Line 86: It is not clear some of the reasons why the excluded papers did not have appropriate case or control group. Examples should be given 2. Presentation of results Table 1: This should include the type of sequencing used Table S2 It is good that the papers excluded at full text are included as an Appendix Line 139: The International representation is not relevant, and can be featured as an appendix unless there is a suggestion that this will bias the results in some way e.g. evidence of variance in microbiota composition by geography Line 172: there should be comment if the difference in cases/controls was in Shotgun metagenomics or 16S or both, and if this was significant. Line 327: A less definite statement about the pathogenicity of Clostridiae would be more appropriate as this reference indicates only a contributing role to NEC from these pathogens General results: the different headings of "Microbial diversity in control and NEC groups," "Comparison of gut microbiota composition between NEC and control groups" ect should feature in an overview table that shows how many studies associated each domain with cases, how many studies associated each domain with controls and how many were equivocal/inconclusive. Domains would include richness, alpha diversity, bet diversity and potentially specific taxa. This could be corrected to remove those with high rish of bias with total numbers in brackets. 3. How the style and organization of the paper communicates and represents key findings The Review is thoroughly conducted and the narrative approach is appropriate for the nature of the results, and it has good publication potential. It remains difficult to get an overview of the whole area except in the area of risk of bias, which is not as relevant for a narrative. The results section should have the narrative shortened overall, as it seems to be describing the individual results section of each included study. This is actually included already and clearly in the supplementary material in Table 1. There should be more of an attempt to summarise the overall findings as per the comments above about the results. 4. Literature analysis or discussion Line 380: The parentheses here can be excluded as this should be self evident "and it is important to note that no approach is completely free from bias" Line 383: This should instead read that a limitation of the study is the unknown time of sampling which the SR is unable to factor in due to lack of data availability General Discussion: Phrases such as "these are the strengths of the paper" should be limited, and instead the strengths or limitations of data commented on should only be included and any inherent strengths to be self evident. The discussion is also too long, with paragraph 285-297 being preferably included in the results. Lines 344-350 this can also be excluded as it is stating what is evident elsewhere. 5. Any other relevant comments
Please rate the manuscript for methodological rigour
Good
Please rate the quality of the presentation and structure of the manuscript
Satisfactory
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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The reviewers were positive about your manuscript, acknowledge it makes an important contribution to the literature and highlight the rigour with which the manuscript was composed. I would like you revise the manuscript in line with the reviewer comments, and please provide a point-by-point response to their comments with your resubmission. I'm looking forward to reading your revised manuscript.
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Comments to Author
I want to commend the authors for a job well done in writing a systematic review on Necrotizing enterocolitis (NEC). The article is a very informative one, I have some recommendations 1) The authors should state the year of inception(on NEC studies)that was used in this article. 2) Is there no research on NEC in any African country? 3) For the 3 studies that reported no difference in gut microbiota, what approach was used to draw their conclusions? 4) The authors should follow the journal's guidelines on referencing most especially in the body of the article.
Please rate the manuscript for methodological rigour
Very good
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported …
Comments to Author
I want to commend the authors for a job well done in writing a systematic review on Necrotizing enterocolitis (NEC). The article is a very informative one, I have some recommendations 1) The authors should state the year of inception(on NEC studies)that was used in this article. 2) Is there no research on NEC in any African country? 3) For the 3 studies that reported no difference in gut microbiota, what approach was used to draw their conclusions? 4) The authors should follow the journal's guidelines on referencing most especially in the body of the article.
Please rate the manuscript for methodological rigour
Very good
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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