Dual Regulation Mechanism of Obesity: DNA Methylation and Intestinal Flora

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors in the current review focus on two major topics - how DNA methylation and the intestinal flora can have impact on Obesity, thus providing a dual handle of regulation. The topic is important and worthy of consideration further; however major changes are recommended at this stage before the manuscript can be considered further. 

1. There are no figures in the manuscript, thus making it very difficult to understand the text. Please add few figures. 

2. The two aspects i.e. DNA methylation and host flora seem to be quite independent of each other and very minimum information is mentioned on how one factor can regulate or impact other, in both directions. 

3. Even in the conclusions, it appears that the authors have written in details two different aspects regulating obesity but the dots need to be connected on how these three factors - DNA methylation, intestinal flora and obesity are related and regulate each other.

4. Few examples from the disease conditions and few examples of therapeutics from recent discoveries need to be mentioned in conclusion section and at the same time, a future perspective is needed to end the story. 

Comments on the Quality of English Language

English language is fine.

Author Response

Dear reviewer

Thanks for your comments concerning our manuscript (Manuscript ID: biomedicines-3064540). According to your advice, we have made revisions. Modified and added sections are marked in purple font in the manuscript. The main revision in our manuscript and the respond to your comments are as detailed below:

Comment 1: - There are no figures in the manuscript, thus making it very difficult to understand the text. Please add few figures. 

Response: We have added 3 figures to the manuscript based on the text content.

Comment 2: - The two aspects i.e. DNA methylation and host flora seem to be quite independent of each other and very minimum information is mentioned on how one factor can regulate or impact other, in both directions. 

Response: For this point, we have provided detailed supplements in the text (see in section 4).

Comment 3: - Even in the conclusions, it appears that the authors have written in details two different aspects regulating obesity but the dots need to be connected on how these three factors - DNA methylation, intestinal flora and obesity are related and regulate each other.

Response: In Section 5, we have extensively discussed the latest research findings on gut microbiota and DNA methylation in the treatment of obesity. Additionally, future perspectives have been incorporated into the conclusion to ensure coherence throughout the article.

Comment 4: - Few examples from the disease conditions and few examples of therapeutics from recent discoveries need to be mentioned in conclusion section and at the same time, a future perspective is needed to end the story. 

Response: In Section 6, we have extensively discussed the latest research findings on gut microbiota and DNA methylation in the treatment of obesity. Additionally, future perspectives have been incorporated into the conclusion to ensure coherence throughout the article (see in section 7).

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review aimed to discuss the recent achievements in the area of the relevance of a variety of intestinal microbiota in the host epigenetic alterations on DNA methylation level in context of the development and medical treatment of obesity in humans.

In the introduction authors provide the definition of obesity and diagnose the reasons, tendencies, occurrence and health consequences of obesity worldwide. Second part of the paragraph introduce the factors of obesity development including environment, genetics and epigenetics. Authors mentioned reported influence of highcalorie diets and sedentary lifestyles on the variation of DNA methylation patterns relevant to the abnormal expression of genes involved in energy metabolism and fat deposition in the course of obesity development. They also referred to the presence of intestinal microflora as another factor of obesity mediation. Authors also described the relevance of a kind of microbiota to the alterations of DNA methylation patterns especially in regulatory elements of genes of lipid metabolism and inflammation, and its impact on pathogenesis of obesity.

In the paragraph DNA Methylation and Obesity authors described DNA methylation focusing on the role of this chemical modification of DNA in the regulation of gene expression, also in concern of undesired events of DNA methylation alterations leading to diseases. Next pathological mechanisms of obesity and the results of relevant studies were described including hypomethylation in in adipose tissue and blood of obese individuals, variation of DNA methylation patterns including body weight and waist circumference as the factor, cord blood DNA methylation differences between offsprings of obese mothers and mothers with normal weight and finding of variabily methylated CpG sites that have a causal relationship with the risk of obesity.

In the range of paragraphs authors extensively described literature relevant to function of DNA methylation in pregnancy, dietary patterns, and exercise, appetite regulation, energy balance, neurological regulation, adipose tissue development, differentiation, and function and lipid metabolism.

Second part of review begins with the characterisation of the variety of microbiota species and describes their role for the physiology of the host. It describes the differences in particular microbiota species present during embryo development, newborns and in the onthogeny until adulthood also underscoring the role of brest feeding for the building of the proper microbiota cultures important for further development. It specify the factors leading to the disturbances in proper microbiota cultures of intestine of the host and its influence on development of pathologic conditions. In this part authors described the role of Intestinal Flora in Obesity, Microbiota in Energy Metabolism and in the Transformation and Metabolism of White Adipose Tissue. Going further authors mentioned the functional mechanisms of intestinal microbiota in lipid, glucose and Vitamin D metabolism, insulin resistance and immune response.

The third part tackles Interactions between the presence of intestinal microbiota and DNA Methylation in obesity.

Authors concluded that further studies should concentrate on determination of particular microbiota species influencing functional DNA methylation alterations. Also it will be important to resolve the mechanisms of DNA methylation influencing the occurrence of particular gut microbiota species and how it influence the development of obesity.

In my opinion the whole content is interesting and very conceived being written in a very consecutive manner.

 

Please find two minor comments below.

 

1^st: Comment: “DNA methylation is closely related to the development of obesity by affecting gene expression, then disrupting the regulatory balance between obesity-promoting genes and anti-obesity genes. “ – what proteins are encoded by obesity-promoting genes and anti-obesity genes. Please cite appropriate literature.

 

 

2^nd: Sentence style: “The gut microbiota is often referred to as the invisible organ carrying the second genome of human body, and encodes around 3.3 million specific genes, and extending the genetic material of the human genome [96, 97].”

Despite of the great value of microbiota influence on the health of the host I think this is not a good expression. The human genome and the genome of microbiota should be treated separately.

 

Author Response

Dear reviewer

 

Thanks for your comments concerning our manuscript (Manuscript ID: biomedicines-3064540). According to your advice, we have made revisions. Modified sections are marked in red font in the manuscript. The main revision in our manuscript and the respond to your comments are as detailed below:

 

1^st: Comment: “DNA methylation is closely related to the development of obesity by affecting gene expression, then disrupting the regulatory balance between obesity-promoting genes and anti-obesity genes. “ – what proteins are encoded by obesity-promoting genes and anti-obesity genes. Please cite appropriate literature.

-Response: We reviewed the references and incorporated additional details into this section, see lines 118-120.

2^nd: Sentence style: “The gut microbiota is often referred to as the invisible organ carrying the second genome of human body, and encodes around 3.3 million specific genes, and extending the genetic material of the human genome [96, 97].” Despite of the great value of microbiota influence on the health of the host I think this is not a good expression. The human genome and the genome of microbiota should be treated separately.

-Response: After reviewing the literature, we thought that the previous statement was not appropriate either. Thus, we corrected this sentence, see lines 153-154.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The review presented by Yi Ren and collaborators, focuses on the current knowledge on the involvement of DNA methylation and intestinal microbiome in regulation of obesity. It is very interesting considering the immense health hazard posed by obesity.

Following are minor suggestions which need to be addressed before this work can be published:

- Although, in subsection 2.1. Overview of DNA Methylation, the authors address the function of DNA methylation in promoter regions and non-promoter regions, it may be useful for clarity to specify in the text where the changes in methylation were detected (for instance, the sentence " Genome-wide studies have found that DNA methylation patterns in adipose tissue and blood of obese individuals exhibited a hypomethylation." is followed by " Studies have shown that for every 0.1% increase in DNA methylation, BMI increased by 0.3 kg/m2, body weight increased by 0.16 kg, and waist circumference increased by 0.78cm.").

- Incomplete sentences should be corrected (for instance, " Because it is found that long-term aerobic exercise training is associated with decreased DNA methylation levels of some genes in blood and muscle cells.")

- In the subsection  "2.3.4. DNA Methylation and Adipose Tissue Development, Differentiation, and Function": "5'-zazcyti-dine-2'-deoxycytidine" should be corrected (5'-aza-cytidine?).

- In the subsection " 2.3.5. DNA methylation and lipid metabolism", the sentence " The methylation of cg06500161 loci may be in the causal path related to the obvious alleviation of lipid-lowering drugs and its myocardial infarction [68-70]." should be rewritten for clarity.

Comments on the Quality of English Language

Incomplete sentences should be corrected. Grammar should be carefully checked and corrected.

Author Response

Dear reviewer

 

Thanks for your comments concerning our manuscript (Manuscript ID: biomedicines-3064540). According to your advice, we have made revisions. Modified sections are marked in blue font in the manuscript. The main revision in our manuscript and the respond to your comments are as detailed below:

Comment 1: - Although, in subsection 2.1. Overview of DNA Methylation, the authors address the function of DNA methylation in promoter regions and non-promoter regions, it may be useful for clarity to specify in the text where the changes in methylation were detected (for instance, the sentence " Genome-wide studies have found that DNA methylation patterns in adipose tissue and blood of obese individuals exhibited a hypomethylation." is followed by " Studies have shown that for every 0.1% increase in DNA methylation, BMI increased by 0.3 kg/m2, body weight increased by 0.16 kg, and waist circumference increased by 0.78cm.").

Response 1: We have checked the references and added additional explanations to this part (see lines 118-120).

Comment 2: - Incomplete sentences should be corrected (for instance, " Because it is found that long-term aerobic exercise training is associated with decreased DNA methylation levels of some genes in blood and muscle cells.")

Response: We have checked and corrected this sentence (see lines 153-154).

Comment 3: - In the subsection "2.3.4. DNA Methylation and Adipose Tissue Development, Differentiation, and Function": "5'-zazcyti-dine-2'-deoxycytidine" should be corrected (5'-aza-cytidine?).

Response: We have checked the word and corrected it to “5'-aza-cytidine” (see line 215).

Comment 4: - In the subsection " 2.3.5. DNA methylation and lipid metabolism", the sentence " The methylation of cg06500161 loci may be in the causal path related to the obvious alleviation of lipid-lowering drugs and its myocardial infarction [68-70]." should be rewritten for clarity.

Response: We have checked this sentence and revised (see lines 262-265).

Comment 5: Comments on the Quality of English Language. Incomplete sentences should be corrected. Grammar should be carefully checked and corrected.

Response: We carefully checked the grammar and sentences in the manuscript and made corrections where errors were found.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

accept the revised manuscript