A Predictive Tool Based on DNA Methylation Data for Personalized Weight Loss through Different Dietary Strategies: A Pilot Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this study, the authors aim to find epigenetic characteristics predictive of weight loss after dietary intervention in a cohort of obese individuals. To this aim, they analyzed DNA methylation data produced for individuals recruited in the ObeKit study before the dietary interventions. They found 20 and 34 CpGs associated with percentage of BMI loss after Low Fat (LF) diet and Moderately High Protein diet (MHP), respectively. Building on these findings, the authors develop a model to predict the efficacy of the two dietary interventions on a per-sample basis.

The study affords a topic which is of great interest to the scientific community. It is well conceived, and the results are mostly reported in a clear manner. Strengths and limitations of the study are stated in the discussion.

Here are some comments that the authors should consider in finalizing their manuscript.

1)     Regarding the cohort: the starting cohort includes 306 individuals that met inclusion criteria. However, this number is reduced upon follow-up due to low adherence or drop out form the study of some individuals. Since such individuals are definitely not informative for this study, my suggestion is to limit the cohort to only informative individuals from the beginning (excluding individuals which have not been followed up from Table 1, for example).

2)     Regarding the modeling of BMI loss as a function of diet, the authors should consider dividing each of the two diet groups into two subgroups, one to set up model parameters and one to validate the model. A 75-25 design should be suitable for their cohort.

3)     The modeling strategy and its rationale should be better explained and discussed. Why didn’t the authors simply compare the predicted BMI loss of the two diets to establish the most effective intervention, instead of constructing the total methylation score? And why did they build the total methylation score as the difference between the two sub-scores?

Furthermore, consider to

1)     merge section 3.2 with 3.3.

2)     state the absence of overlap between CpGs correlated to BMI loss in the LF and MHP groups in Results.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Although the review concerning bioengineering and vascularization strategies for islet organoids: advancing toward diabetes therapy very interesting, numbers of points need clarifying and certain statements require further justification. These are given below.

1.      In Tables 1, 2, and Supplementary Table 1, glucose concentrations were expressed by “mg/dL”. Glucose concentrations should be expressed by “mmol/L”. Please re-calculate the values of glucose concentrations.

2.      In Table 1, 2, and Supplementary Table 1, “TNF” may indicate “TNF-α”. If so, please describe “TNF-α”.

3.      In Supplementary Table 1, “BMI (kg/m2)” should be changed to “BMI (kg/m²)”.

4.      DNA methylation is a typical epigenetic factor, and it shows somewhat a maternal inheritance. Therefore, the research in this area should be accounted for maternal inheritance. Ideally, the research design would be to conduct a study using twins. I think it would be better to add research that takes this perspective into account, even if it is only a small number of cases.

5.      Addition of DNA methylation status just before the study may strengthen this study. 

6.      Some important papers in this area such as Ling, C. & Rönn, T. “Epigenetics in human obesity and Type 2 diabetes” (Cell Metab. 2019, 29, 1028-1044), Mahmoud, A.M. “An overview of epigenetics in obesity: Th role of lifestyle and therapeutic interventions” (Int. J. Mol. Sci. 2022, 23, 1341), Lecorguillé, M. et al. “Maternal dietary quality and dietary inflammation associated with offspring growth, placental development, and DNA methylation” (Nutrients2021, 13, 3130), and Ungaro, P. et al. “Epigenome modulation induced by ketogenic diets” (Nutrients 2022, 14, 3245).

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Most of points were suitably revised in Nutrients-2710096-v2. A few points to be changed to improve the work.

1.      In Ref. 26, there is no journal name. “2012, 13, 86” should be changed to “BMC Bioinformatics 2012, 13, 86”.