Impact of Gut–Brain Axis on Hepatobiliary Diseases in Fetal Programming

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The presented literature review provides information on the impact of pathologic conditions of the digestive system of pregnant women on fetal development. The authors consider some mechanisms of such influence. Despite the relevance of the problem, the review has several serious shortcomings.

1. Different sections often contain the same information, the authors need to clearly distinguish between the sections and the information contained in them.

2 The authors should be specific about the data presented, rather than reducing the findings to a general conclusion that maternal condition affects fetal development.

3 The authors should update the reference list. Very many articles are older than 10 years.

The review cannot be published as submitted, resubmission is encouraged after revisions.

 

Author Response

Author’s notes to reviewer 1

The presented literature review provides information on the impact of pathologic conditions of the digestive system of pregnant women on fetal development. The authors consider some mechanisms of such influence. Despite the relevance of the problem, the review has several serious shortcomings.

Response: Thank you for your constructive feedback on our literature review regarding the impact of pathologic conditions of the digestive system of pregnant women on fetal development. We appreciate the opportunity to address your concerns and make necessary revisions to improve the quality of our manuscript. Below is a point-by-point response to your comments.

 

1. Different sections often contain the same information, the authors need to clearly distinguish between the sections and the information contained in them.

Response: Many thanks for your comment. As per reviewers’ suggestion, we have revised few sections of the manuscript to prevent the repetition of information. Example: Section 2, line 132-136, Section 3, line 191-195, Section 4, line 207-218, Section 5, line 273-284.

 

2 The authors should be specific about the data presented, rather than reducing the findings to a general conclusion that maternal condition affects fetal development.

Response: Thank you for your valuable comment. We have made changes throughout the article to be more data-specific. For example, Section 3: line 170-175, Section 5: line 248-272.

 

3 The authors should update the reference list. Very many articles are older than 10 years.

Response: Thank you for your comment. We have updated the reference list by replacing older articles with newer articles with more recent findings.

For example:

1. Brandes JM (1967) First-trimester nausea and vomiting as related to outcome of pregnancy. Obstet Gynecol 30: 427-431 is replaced with newer study Fiaschi, L., Nelson‐Piercy, C., Gibson, J., Szatkowski, L., & Tata, L. J. (2018). Adverse maternal and birth outcomes in women admitted to hospital for hyperemesis gravidarum: a population‐based cohort study. Paediatr. Perinat. Epidemiol. 32: 40-51. https://doi.org/10.1111/ppe.12416.

 

2. Zhang J, Cai WW (1991) Severe vomiting during pregnancy: antenatal correlates and fetal outcomes. 454-457.https://www.jstor.org/stable/20065727 is replaced with Jansen, L. A., Nijsten, K., Limpens, J., van Eekelen, R., Koot, M. H., Grooten, I. J., ... & Painter, R. C. (2023). Perinatal outcomes of infants born to mothers with hyperemesis gravidarum: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. https://doi.org/10.1016/j.ejogrb.2023.03.004.

 

Other examples of new references include:

1. Oudman, E., Wijnia, J. W., Oey, M., van Dam, M., Painter, R. C., & Postma, A. (2019). Wernicke’s encephalopathy in hyperemesis gravidarum: A systematic review.Eur J Obstet Gynecol Reprod Biol. 236: 84-93. https://doi.org/10.1016/j.ejogrb.2019.03.006
2. dos Santos, R. D. G. C., Viana, M. L., Generoso, S. V., Arantes, R. E., Davisson Correia, M. I. T., & Cardoso, V. N. (2010). Glutamine supplementation decreases intestinal permeability and preserves gut mucosa integrity in an experi-mental mouse model. J Parenter Enteral Nutr. 34: 408-413. https://doi.org/10.1177/0148607110362530
3. Cheng, C., Wei, H., Xu, C., Xie, X., Jiang, S., & Peng, J. (2018). Maternal soluble fiber diet during pregnancy changes the intestinal microbiota, improves growth performance, and reduces intestinal permeability in piglets. Appl. Environ. Microbiol. 84: e01047-18. https://doi.org/10.1128/AEM.01047-18
4. Lee SM, Cho GJ, Wi WY, Norwitz ER, Koo BK, Lee J, Jung YM, Kwak SH, Park CW, Jun JK, Joo SK, Oh MJ, Kim W, Park JS. Metabolic dysfunction-associated fatty liver disease as a risk factor for adverse outcomes in subsequent pregnancy: a nationwide cohort study. Hepatol Int. 2023 Apr;17(2):367-376. doi: 10.1007/s12072-022-10458-w. Epub 2022 Dec 21. PMID: 36542262.
5. Sarkar M, Grab J, Dodge JL, Gunderson EP, Rubin J, Irani RA, Cedars M, Terrault N. Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes. J Hepatol. 2020 Sep;73(3):516-522. doi: 10.1016/j.jhep.2020.03.049. Epub 2020 Jun 9. PMID: 32531415; PMCID: PMC7438303.

 

The review cannot be published as submitted, resubmission is encouraged after revisions.

Response: Thank you for your valuable comments. We carefully revised the manuscript as per the reviewer’s suggestions one by one.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a concise review on hepatobiliary diseases (HBD) with emphasis on so-called fetal programming during fetal's growth as a major causative role. This review offers many perspectives on the significance of fetal programming in general and is of interest to the readership of JMP.

Some amendments are recommended:

1. The authors mention a low birth weight as a detrimental effect along with diabetes as one of the major diseases associated with any impairment of the hepatobiliary system. The authors indicate throughout the manuscript that malnutrition, such as a low protein diet (l.117-122) represents a major reason for developing insulin resistance and other effects of fetal programming.

It is well known that the birth-weight range of newborns in India/South Asia is significantly lower than in Western countries. This reviewer learnt from correspondences that the birth weights in India had been higher in former times (perhaps until the Second World War). If these anecdotal hints can be confirmed, it will be of interest whether a causative correlation with the widespread occurrence of diabetes in India that started in the second half of last century can be corroborated from data in the literature. Concerning the prevalence of diabetes, mass vaccinations starting after the war might be involved as well, e.g. via epigenetic effects which are discussed as a molecular mechanism of fetal programming.

2. Additionally (and possibly conncected to diabetes as described above), large-scale famines frequently happened in India during colonial times (the last one known as the Bengal famine in 1943-45), thus long-lasting epigenetic effects seem to be plausible and would be of interest to be discussed as well. Similarly, large-scale starvation had been significant in some parts of Europe during the years after both World Wars. In this respect, the authors should thoroughly check the available literature how maternal nutrition influences epigenetics and modify the respective statements if necessary.

3. The emphasis on biomedicines, such as probiotics, as promising therapeutics to cope with fetal programming is appreciable. In this respect, any recommendations from Ayurveda as a holistic health concept would be of interest to be mentioned.

4. The text should be carefully edited as some sentences might not be correctly understood, e.g. l. 117-119, l. 166-167, 258-260, 332-333.

Comments on the Quality of English Language

Refer to point 4 in the report.

Author Response

Author’s Notes to Reviewer 2

The authors present a concise review on hepatobiliary diseases (HBD) with emphasis on so-called fetal programming during fetal's growth as a major causative role. This review offers many perspectives on the significance of fetal programming in general and is of interest to the readership of JMP. Some amendments are recommended:

Response: Thank you for your thoughtful review of our manuscript on hepatobiliary diseases (HBD) and fetal programming. We appreciate your insightful comments and suggestions for improvement. Below is a point-by-point response to each of your recommendations.

 

1. The authors mention a low birth weight as a detrimental effect along with diabetes as one of the major diseases associated with any impairment of the hepatobiliary system. The authors indicate throughout the manuscript that malnutrition, such as a low protein diet (l.117-122) represents a major reason for developing insulin resistance and other effects of fetal programming.

It is well known that the birth-weight range of newborns in India/South Asia is significantly lower than in Western countries. This reviewer learnt from correspondences that the birth weights in India had been higher in former times (perhaps until the Second World War). If these anecdotal hints can be confirmed, it will be of interest whether a causative correlation with the widespread occurrence of diabetes in India that started in the second half of last century can be corroborated from data in the literature. Concerning the prevalence of diabetes, mass vaccinations starting after the war might be involved as well, e.g. via epigenetic effects which are discussed as a molecular mechanism of fetal programming.

 

Response: We acknowledge the importance of considering historical trends in birth weight and their potential correlation with the prevalence of diabetes in India. We will conduct further research to corroborate anecdotal hints regarding birth weights in India and their potential relationship with the rise in diabetes incidence in the second half of the last century. Additionally, we will explore the role of mass vaccinations and other environmental factors in influencing epigenetic effects associated with fetal programming and diabetes.

 

2. Additionally (and possibly conncected to diabetes as described above), large-scale famines frequently happened in India during colonial times (the last one known as the Bengal famine in 1943-45), thus long-lasting epigenetic effects seem to be plausible and would be of interest to be discussed as well. Similarly, large-scale starvation had been significant in some parts of Europe during the years after both World Wars. In this respect, the authors should thoroughly check the available literature how maternal nutrition influences epigenetics and modify the respective statements if necessary.

Response: We recognize the significance of large-scale famines in India and Europe during colonial times and their potential long-lasting effects on epigenetics. In our revised manuscript, we will thoroughly review the available literature on how maternal nutrition during famine periods influences epigenetic mechanisms and discuss the implications for fetal programming and hepatobiliary diseases.

 

3. The emphasis on biomedicines, such as probiotics, as promising therapeutics to cope with fetal programming is appreciable. In this respect, any recommendations from Ayurveda as a holistic health concept would be of interest to be mentioned.

Response: We appreciate your suggestion to include recommendations from Ayurveda as a holistic health concept, particularly in the context of addressing fetal programming and hepatobiliary diseases. In our revised manuscript, we humbly decline the Ayurvedic approaches as their active component, their pharmacovigilance (especially in pregnant women), as well as their mode of action, is yet to be conclusively explained.

 

4. The text should be carefully edited as some sentences might not be correctly understood, e.g. l. 117-119, l. 166-167, 258-260, 332-333.

Response: We apologize for any confusion caused by unclear sentences in the manuscript. We have carefully reviewed and edited the text to ensure clarity and improve understanding, particularly in the sections highlighted by the reviewer. In the new revised file, the changes are in line 132-136, line 191-195, 324-326, line 400-403).

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All comments were answered satisfactorily.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have sufficiently addressed the raised points.