Reviewer ’s report  
 
Title: Linear growth failure induced by systemic inflammation inhibiting IGF -1/IGFBP axis in  
rats with asymptomatic colitis  
 
Version: 0 Date: 29 Dec  2018  
 
Reviewer: Philip Sherman  
 
Reviewer's report:  
 
The manuscript submitted by Sheng and colleagues summarizes experiments indicating that 
decreased growth of rats using a model of hapten -induced acute mucosal  inflammation is 
mediated by reduced insulin growth factor -1 (IGF -1) signaling.  
 
General Comments:  
 
1. Given previous reports indicating that pro -inflammatory cytokines and reduced IGF -1 mediate 
impaired growth velocity in various settings of inflammation ( Nat Rev Gastroenterol Hepatol 
2014;11:801 -810), the novel aspects of the reported findings must be highlighted.  
 
2. To provide additional confirmation of the presence of asymptomatic colitis, levels of 
neutrophils, pro -inflammatory and anti -inflammatory cyt okines, and regulatory T cells in colonic 
homogenates should be measured.  
 
Specific Comments:  
 
1. Abstract: quantification and statistical analyses of principal findings should be included in the 
results section of the Abstract.  
 
2. Introduction, lines 63 -65: there is no evidence to suggest calprotectin is a mediator of growth 
arrest. Rather, as noted by the authors on line 62, fecal calprotectin is employed as a biomarker 
of gut inflammation.  
 
3. Introduction, line 78: the findings in this report do not addr ess underling mechanisms of 
action. Accordingly, the third stated objective should be deleted and the issue considered in the 
Discussion section of the manuscript as a limitation to be addressed in future research.  
 
4. Methods, line 81: justification for te sting only male animals must be provided. Alternatively, 
the studies should repeated in female rats of the same age and from the same commercial source.  
 
5. Methods, lines 88 -98: it is surprising that TNBS was diluted in phosphate -buffered saline. 
Normally,  TNBS is delivered in ethanol as vehicle and ethanol alone then used in control 
animals. At a minimum, PBS alone should have been administered intracolonically, in the same 
volume and at the same frequency, to animals included the control group.  
 
6. Results , line 166: rather than reporting that the rats were in "good spirits", it is more 
appropriate to indicate that the animals "appeared well".  
 
7. Results, line 176 and legend to Figure 1: "hemangiectasia" requires definition. Arrows and 
arrowheads should be employed to point the reader to the observed morphological changes. 
Approximate original magnifications must be included for all of the photographs provided in 
panel A.  
 
8. Results, Figure 3: changes in body weight (measured as noted in the Methods on line 99) must 
be presented as an additional panel in this figure.  
 
9. Discussion, lines 272 -279 and Figure 6: a positive correlation between two variables does not 
indicate a cause -and-effect relationship. Gene knockout, RNA interference, antibody blockade, 
and pharmacological inhibition studies are required to elucidate underlying mechanisms of 
action mediating effects on linear growth (Proc Natl Acad Sci USA 2005;102:13269 -13275).  
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the  manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of w ritten English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
 
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open pe er review policy of the journal  
Reviewer ’s report  
 
Title: Linear growth failure induced by systemic inflammation inhibiting IGF -1/IGFBP axis in  
rats with asymptomatic colitis  
 
Version: 0 Date: 29 Dec  2018  
 
Reviewer: Philip Sherman  
 
Reviewer's report:  
 
The manuscript submitted by Sheng and colleagues summarizes experiments indicating that 
decreased growth of rats using a model of hapten -induced acute mucosal  inflammation is 
mediated by reduced insulin growth factor -1 (IGF -1) signaling.  
 
General Comments:  
 
1. Given previous reports indicating that pro -inflammatory cytokines and reduced IGF -1 mediate 
impaired growth velocity in various settings of inflammation ( Nat Rev Gastroenterol Hepatol 
2014;11:801 -810), the novel aspects of the reported findings must be highlighted.  
 
2. To provide additional confirmation of the presence of asymptomatic colitis, levels of 
neutrophils, pro -inflammatory and anti -inflammatory cyt okines, and regulatory T cells in colonic 
homogenates should be measured.  
 
Specific Comments:  
 
1. Abstract: quantification and statistical analyses of principal findings should be included in the 
results section of the Abstract.  
 
2. Introduction, lines 63 -65: there is no evidence to suggest calprotectin is a mediator of growth 
arrest. Rather, as noted by the authors on line 62, fecal calprotectin is employed as a biomarker 
of gut inflammation.  
 
3. Introduction, line 78: the findings in this report do not addr ess underling mechanisms of 
action. Accordingly, the third stated objective should be deleted and the issue considered in the 
Discussion section of the manuscript as a limitation to be addressed in future research.  
 
4. Methods, line 81: justification for te sting only male animals must be provided. Alternatively, 
the studies should repeated in female rats of the same age and from the same commercial source.  
 
5. Methods, lines 88 -98: it is surprising that TNBS was diluted in phosphate -buffered saline. 
Normally,  TNBS is delivered in ethanol as vehicle and ethanol alone then used in control 
animals. At a minimum, PBS alone should have been administered intracolonically, in the same 
volume and at the same frequency, to animals included the control group.  
 
6. Results , line 166: rather than reporting that the rats were in "good spirits", it is more 
appropriate to indicate that the animals "appeared well".  
 
7. Results, line 176 and legend to Figure 1: "hemangiectasia" requires definition. Arrows and 
arrowheads should be employed to point the reader to the observed morphological changes. 
Approximate original magnifications must be included for all of the photographs provided in 
panel A.  
 
8. Results, Figure 3: changes in body weight (measured as noted in the Methods on line 99) must 
be presented as an additional panel in this figure.  
 
9. Discussion, lines 272 -279 and Figure 6: a positive correlation between two variables does not 
indicate a cause -and-effect relationship. Gene knockout, RNA interference, antibody blockade, 
and pharmacological inhibition studies are required to elucidate underlying mechanisms of 
action mediating effects on linear growth (Proc Natl Acad Sci USA 2005;102:13269 -13275).  
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the  manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of w ritten English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
 
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open pe er review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Linear growth failure induced by systemic inflammation inhibiting IGF -1/IGFBP axis in  
rats with asymptomatic colitis  
 
Version: 0 Date: 29 Dec  2018  
 
Reviewer: Philip Sherman  
 
Reviewer's report:  
 
The manuscript submitted by Sheng and colleagues summarizes experiments indicating that 
decreased growth of rats using a model of hapten -induced acute mucosal  inflammation is 
mediated by reduced insulin growth factor -1 (IGF -1) signaling.  
 
General Comments:  
 
1. Given previous reports indicating that pro -inflammatory cytokines and reduced IGF -1 mediate 
impaired growth velocity in various settings of inflammation ( Nat Rev Gastroenterol Hepatol 
2014;11:801 -810), the novel aspects of the reported findings must be highlighted.  
 
2. To provide additional confirmation of the presence of asymptomatic colitis, levels of 
neutrophils, pro -inflammatory and anti -inflammatory cyt okines, and regulatory T cells in colonic 
homogenates should be measured.  
 
Specific Comments:  
 
1. Abstract: quantification and statistical analyses of principal findings should be included in the 
results section of the Abstract.  
 
2. Introduction, lines 63 -65: there is no evidence to suggest calprotectin is a mediator of growth 
arrest. Rather, as noted by the authors on line 62, fecal calprotectin is employed as a biomarker 
of gut inflammation.  
 
3. Introduction, line 78: the findings in this report do not addr ess underling mechanisms of 
action. Accordingly, the third stated objective should be deleted and the issue considered in the 
Discussion section of the manuscript as a limitation to be addressed in future research.  
 
4. Methods, line 81: justification for te sting only male animals must be provided. Alternatively, 
the studies should repeated in female rats of the same age and from the same commercial source.  
 
5. Methods, lines 88 -98: it is surprising that TNBS was diluted in phosphate -buffered saline. 
Normally,  TNBS is delivered in ethanol as vehicle and ethanol alone then used in control 
animals. At a minimum, PBS alone should have been administered intracolonically, in the same 
volume and at the same frequency, to animals included the control group.  
 
6. Results , line 166: rather than reporting that the rats were in "good spirits", it is more 
appropriate to indicate that the animals "appeared well".  
 
7. Results, line 176 and legend to Figure 1: "hemangiectasia" requires definition. Arrows and 
arrowheads should be employed to point the reader to the observed morphological changes. 
Approximate original magnifications must be included for all of the photographs provided in 
panel A.  
 
8. Results, Figure 3: changes in body weight (measured as noted in the Methods on line 99) must 
be presented as an additional panel in this figure.  
 
9. Discussion, lines 272 -279 and Figure 6: a positive correlation between two variables does not 
indicate a cause -and-effect relationship. Gene knockout, RNA interference, antibody blockade, 
and pharmacological inhibition studies are required to elucidate underlying mechanisms of 
action mediating effects on linear growth (Proc Natl Acad Sci USA 2005;102:13269 -13275).  
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the  manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of w ritten English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
 
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open pe er review policy of the journal  
assistant