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  • Nasim Hatamzade Esfahani 1 and
  • Andrew S. Day 2,*

Reviewer 1: Anonymous Reviewer 2: Archana Saxena Reviewer 3: Daniela Elena Serban

Round 1

Reviewer 1 Report

TGF-β plays a very important role in the pathogenesis of IBD, and this paper systematically summarizes and describes the latest findings. I hope that this paper will be published as soon as possible, as it is of great interest to physicians who treat IBD and is fully expected to be translated into clinical practice.

Author Response

REVIEWER 1

 

We thank the reviewer for their complimentary comments

Reviewer 2 Report

The article entitled “The Role of TGF-β, Activin and Follistatin in Inflammatory Bowel Disease” has been prepared in an acceptable way, but some minor concerns were risen.

Minor concerns:

1.       Conclusion needs to be modified. I would suggest to concise it. 

2.       Line 32: Although the pathogenesis of these conditions is not full elucidated… improve the language of this sentence. 

3.       I think no need to start line 32 as a new paragraph.

4.       Line 47: change the heading -Overview of TGF-β. It is not looking good.

5.       Line 67: it is not appropriate to say molecular mechanism. Author should write here the signaling mechanism. Author should add a figure to explain the signaling mechanism of TGF-β then it would be interesting and easy to understand for other readers.

6.       Author should merge paragraphs where it is not required to start the sentence as a new paragraph. Please read the manuscript carefully to do this, eg. Line 181 to 220 this should be in paragraph only.

7.       In table 1: in each column author should write the line in sentence case.

8.       Revise the heading for the overview of activin and Follistatin.

9.       Could author correlate the interconnection among these 3 during inflammation? Author should add a complete signaling mechanism figure for this review.

10.    Line 44: In place of these proteins author should write above mentioned proteins.

11.    Line 56: Explain the sentence and from this line role of TGF-β in injury is not clear.

12.    Please check the references style and add some recent references related to this study.

13.    Please improve the grammar and English language. Read carefully the full manuscript for typos and grammar. Please revise the abstract after including more details in the review.

 

 

 

Author Response

as in letter

Author Response File: Author Response.pdf

Reviewer 3 Report

This manuscript represents a very comprehensive review on TGF-beta, Activin and Follistatin, not only in IBD. Without any doubt, the authors used a lot of references, to support their manuscript. I appreciate all the hard work the authors invested in this review. I sincerely hope my remarks will be taken as being constructive and will become useful for a revision. I have listed some comments/suggestions for consideration below:

a. Lines 27-29: Reference [2] refers to classification in children. However, in children, there are specific subclasses of pIBD (see Birimberg-Schwartz et al, 2017, Ledder O, et al, 2020). Please revise or choose a different reference.

b. Aim (by the end of Introduction): please state it clearly and present a more generous aim (like in Abstract) of your review.

c. While I agree that the authors wrote about all the mechanisms of actions of these three molecules, they are just enumerated. They have to be summarized in illustrative figures. This is imperative. Not easy, but needed.

d. Please insert if the main text place of Tables 1 and 2.

e. Table 2. Title – please replace “IBD” with “CD”. Reference 7 represents a meta-analysis; please correct. Also, there are many more recent studies with polymeric formulas containing TGF-beta in both children and adults with IBD. Please add to table 2. Please correct “eternal” with “enteral”. Please revise entirely the column “route of administration” - as just writing “enteral nutrition” or “polymeric diet” does not represent “route of administration”. Also, there are some unintentional mistakes: (e.g. – ref. 80 – “Exclusive or enteral nutrition” – please correct, as all children received exclusive nutrition). I also suggest to include only the studies that used exclusive nutrition with formula. Otherwise, the table will have to contain many more studies. Moreover, there are more recent systematic-reviews and meta-analyses regarding polymeric formulas in patients with CD, used as induction therapy. Please add in the text.

e. "Activin Signaling as an Emerging Target for Therapeutic Interventions": The authors mentioned many examples of inhibitors of the activin receptor signaling pathway (IASPs), but I did not find any reference related to IBD per se. I do not see their relevance for this manuscript. Please revise.

f. Same for follistatin.

g. Conclusion appears too long. Moreover, it does not appear convincing about potential therapeutics involving activin and follistatin. This was the second aim of the review – “to outline the potential role of therapeutic manipulation of these pathways”. In addition, as the authors mentioned, even with formulas enriched with TGF- beta, it cannot be proven that the good effects of these formulas (or what type of effects) are related to TGF-beta. In fact, this was questioned lately, as other polymeric formulas gave the same results. It could be just the fact that formulas were done as exclusive nutrition or these formulas, in fact, avoided consumption of bad components of an ordinary diet. This is also supported by the recent wonderful results with Crohn’s disease exclusion diet (which includes Modulen, I agree, in conjunction with mandatory, allowed and disallowed foods – but no effect of TGF-beta was proven as well) and other diets.

h. Please check Clinicaltrials.gov and insert registered studies involving these pathways, in order to give more strength to your review.

 

Author Response

as in cover letter

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

I congratulate the authors for their improved manuscript, especially the figures (very illustrative) and the sentences regarding follistatin and activin. There are only two aspects that require to be corrected/ clarified:

1. The Authors wrote “Comment 1: An amendment to the references has been made”, but reference 2 was not changed. Please revise.

2. The Authors wrote: Comment 5: “The table has not been expanded, as this was not intended to review all studies utilising this protein, but to illustrate with representative studies”. With all due respect, I would kindly ask the Authors to mention what the “selection criteria” were, to include only “representative studies”. This is important, as a review should include all studies. The readers of this review need to know what “selected studies” mean and how they were chosen. Please insert.

Thank you.

Author Response

Thank you for your comments. 

  1. The reference and the wording in the INTRODUCTION have been amended. 
  2. The intention was to illustrate these points with a series of relevant publications within the context of this review, with several key messages (such as that various enteral formulae containing TGF-b have been assessed and are documented to lead to various outcomes).