Gut Microbiota-Derived Metabolites and Their Role in the Pathogenesis of Necrotizing Enterocolitis in Preterm Infants: A Narrative Review
and Giacomo Cavallaro 1Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe review is in the attached file.
Comments for author File: 
Comments.pdf
Author Response
Dear Reviewer,
Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.
General Comment: The manuscript provides a review of the metabolites produced by the gut microbiota and their role in the pathogenesis of necrotising enterocolitis in premature infants. The manuscript is well written and organised. However, it may benefit from further clarification of the novelty and contribution of the work to the field. It would be fair to say that a substantial number of review articles have already been published on the metabolites produced by the gut microbiota and their role in the pathogenesis of necrotising enterocolitis in premature infants, including:
Catassi, G.; Aloi, M.; Giorgio, V.; Gasbarrini, A.; Cammarota, G.; Ianiro, G. The Role of Diet and Nutritional Interventions for the Infant Gut Microbiome. Nutrients 2024, 16, 400. https://doi.org/10.3390/nu16030400
Kaplina, A.; Kononova, S.; Zaikova, E.; Pervunina, T.; Petrova, N.; Sitkin, S. Necrotizing Enterocolitis: The Role of Hypoxia, Gut Microbiome, and Microbial Metabolites. Int. J. Mol. Sci. 2023, 24, 2471. https://doi.org/10.3390/ijms24032471
Alsharairi, N.A. Therapeutic Potential of Gut Microbiota and Its Metabolite Short-Chain Fatty Acids in Neonatal Necrotizing Enterocolitis. Life 2023, 13, 561. https://doi.org/10.3390/life13020561
Yang, J.; Chen, X.; Liu, T.; Shi, Y. Potential role of bile acids in the pathogenesis of necrotizing enterocolitis. Life Sciences, 2023, 122279.
Bosco, A.; Piu, C.; Picciau, M.E.; Pintus, R.; Fanos, V.; Dessì, A. Metabolomics in NEC: An Updated Review. Metabolites 2024, 14, 14. https://doi.org/10.3390/metabo14010014
Cifuentes, M. P., Chapman, J. A., Stewart, C. J. Gut microbiome derived short chain fatty acids: promising strategies in necrotising enterocolitis. Current Research in Microbial Sciences, 2024, 100219.
Point 1: It would be beneficial to include a discussion of the recent reviews on this topic, including the authors' own review in Nutrients, and to present the present work in a way that clearly delineates its novel contributions.
Response 1: Thank you for point this out. We appreciate this valuable suggestion. We have now included discussions of the reviews mentioned and positioned our work to highlight its unique contributions to the field, as detailed in the revised manuscript.
Point 2: It is recommended that section 3 (Gut microbiota and gut microbiota-derived metabolites) be reorganised into three subsections (3.1. Metabolites produced by gut bacteria from dietary components; 3.2. Metabolites produced by the host and modified by gut bacteria; 3.3. Metabolites synthesized de novo by gut bacteria) without division into subsections.
Response 2: We agree with this suggestion and have reorganized Section 3 accordingly, improving the structure of the manuscript (line 184; 196; 212; 225).
Point 3: The full stop in the title of the article should be removed.
Response 3: Thank you for point this out. The title has been revised, with the full stop removed and a colon added for clarity (lines 3-4).
Point 4: Page 1, line 34 - include a reference.
Response 4: Thank you for point this out. The relevant reference has been added (lines 54-55).
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript is well designed; however, some modification is needed to improve it.
Table 1. Classification of gut microbiota-derived metabolites according to their production. The author mentioned a limited metabolite; please check other manuscripts such as https://doi.org/10.1016/j.chom.2022.04.003; 10.1080/10408398.2016.1220913.
As a review, more updated manuscripts are expected to be used.
Maternal, neonatal, dysbiosis factors and NEC features should be mentioned in the figure and the text.
Fig 1 was so preliminary. They can show the crosstalk between microbiota and the immune system, etc., more interestingly.
It would be better to illustrate the role of gut microbiota-derived Metabolites in changing the immune system and pathogenesis of necrotizing enterocolitis in the schematic photo.
Please check other reviews to improve the article.
https://doi.org/10.1038/s41392-022-00974-4
https://doi.org/10.1038/s41423-021-00661-4
doi: 10.2217/fmb.15.136.
Author Response
Dear reviewer,
Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the resubmitted files.
The manuscript is well designed; however, some modification is needed to improve it.
Comment 1: Table 1. Classification of gut microbiota-derived metabolites according to their production. The author mentioned a limited metabolite; please check other manuscripts such as https://doi.org/10.1016/j.chom.2022.04.003; 10.1080/10408398.2016.1220913.
Response 1: Thank you for this suggestion. We reviewed the cited manuscripts and incorporated relevant references throughout the manuscript. For Table 1 (now Table 2), we chose to focus on key metabolites most strongly associated with NEC.
Comment 2: As a review, more updated manuscripts are expected to be used.
Response 2: Thank you for point this out. We have significantly increased the number of references in the manuscript, adding recent publications to ensure comprehensive coverage of the topic (from a total of 128 to 167).
Comment 3: Maternal, neonatal, dysbiosis factors, and NEC features should be mentioned in the figure and the text.
Response 3: Thank you for your valuable suggestion. In response, we have revised Figure 1 (now Table 1) to include a more comprehensive classification of NEC risk factors. This revised table now addresses maternal, neonatal, and dysbiosis factors, along with additional prenatal and perinatal risk factors that contribute to NEC pathogenesis. These changes have been incorporated into both the figure and the corresponding text to provide a more complete overview of the factors involved in NEC.
Comment 4: Fig 1 was so preliminary. They can show the crosstalk between microbiota and the immune system, etc., more interestingly.
It would be better to illustrate the role of gut microbiota-derived Metabolites in changing the immune system and pathogenesis of necrotizing enterocolitis in the schematic photo.
Response 4: We fully agree with the suggestion and have redesigned Figure 1 to provide a more detailed schematic representation of the interactions between gut microbiota, gut microbiota-derived metabolites, and the immune system (Figure legend, lines 263-268). This updated figure emphasizes the role of these metabolites in modulating immune responses and their contribution to NEC pathogenesis. In addition, we have added a new section titled “Gut microbiota-derived metabolites in the regulation of immune response” (lines 234-261), which elaborates on the immune-modulatory effects of these metabolites in the context of NEC. To further clarify the role of gut microbiota and its metabolites in NEC pathogenesis, we have also revised the introduction of Section 4 (lines 271-290).
Comment 5: Please check other reviews to improve the article
https://doi.org/10.1038/s41392-022-00974-4
https://doi.org/10.1038/s41423-021-00661-4
doi: 10.2217/fmb.15.136.
Response 5: Thank you for the helpful suggestion. We have reviewed the recommended articles and incorporated citations from them throughout the manuscript, enhancing the depth and relevance of our literature review.
