Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Scope and Conceptual Clarity

1. Scope of the Review: The article is offered as a mini-review. Is the depth of information adequate, given the topic's breadth—Precision Nutrition (PN), three different B vitamins, maternal/fetal health, and epigenetics? Could all of these intricately linked issues be sufficiently covered by the brief review format?
2. Selection of Nutrients: Why were cobalamin (B12), thiamine (B1), and folic acid (B9) specifically picked for a thorough examination? The study points out that folate, iron, and vitamin D are among the nutritional deficiencies in the Middle East and North Africa (MENA) region. Please justify omitting essential micronutrients, such as vitamin D and iron, from the in-depth genetic/epigenetic analysis.
3. Precision Nutrition Model Consistency: According to the introduction, modifiable factors (physical activity, dietary choices) have a "greater influence on health outcomes" than non-modifiable elements (genomics, sex). However, nutrigenetics and nutrigenomics are the main topics of the review. Please explain this seeming contradiction: is the deeper, genotype-specific third level of PN the primary focus of attention, or is the main message that PN should concentrate on modifiable factors?

Evidence and Regional Specificity (MENA)

1. Folic Acid Fortification Paradox: Despite folic acid fortification initiatives, the study highlights a high prevalence of neural tube defects (NTDs) in the Middle East (1 to 3.3 per 1,000 births). How would a Precision Nutrition strategy targeting genetic variations, such as the MTHFR C677T polymorphism, address or avoid the shortcomings of current population-wide fortification initiatives, according to the authors?
2. Data Gaps for Thiamine and B12: The review explicitly states that information was "unable to be found" for SLC19A2/SLC19A3 thiamine mutations and that there was "could not find information" regarding the AMN, CUBN, GIF, and TCN2 vitamin B12 genes in any Middle Eastern population. Given the paper's key highlight on the MENA region, how can the authors strengthen the regional relevance for these two vitamins, or should the conclusion be adjusted to acknowledge this lack of data as a significant limitation explicitly?
3. Homocystinuria Prevalence: A missense mutation and high consanguinity rates are associated with the high prevalence of homocystinuria in Qatar (1:1800 newborns). Could the authors elaborate on the role PN plays in pre-conception genetic screening in these societies, and whether consanguinity rates also significantly affect other genetic diseases linked to B-vitamin metabolism in the MENA region?

 

Future Directions

1. Neurochemical and Behavioral Links: According to the conclusion, future research should examine the relationship between genes and the neurochemical changes that occur during pregnancy, and how these changes affect mothers' eating habits. This biological field is exceptionally vast and intricate. Could the authors offer one or two specific, mechanistic theories that relate a measurable neurochemical alteration that can conceivably influence a mother's eating habits to a known nutrient-gene interaction (such as MTHFR and folate-driven methylation)?
2. Role of Artificial Intelligence (AI): The use of cutting-edge technology and AI's contributions to PN advancement are briefly discussed. Since this domain is currently underrepresented in the literature, please provide an example of a specific, non-trivial application of AI in this subject (e.g., optimizing nutrient dose based on multi-omics data or detecting novel gene-environment correlations in large cohorts).

Comments on the Quality of English Language

The English could be improved to convey the research better.

Author Response

Please find our responses enclosed in the attached document. 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

Your work brings together three strands in one place: B-vitamins critical in the periconceptional period, the nutrigenetic–epigenetic framework, and the concept of precision nutrition. This combination is needed because clinical practice too often remains locked into a one-size-fits-all paradigm. I appreciate the clear recap of the roles of B9/B1/B12 and the associated biomarkers, with emphasis on the preconception window and first trimester. It is also valuable that you sensitize the reader to the MENA/GCC context—from folate education to challenges arising from consanguinity and uneven flour fortification. The genetic and epigenetic sections organize mechanisms (MTHFR, B12 transport, MEG3) and provide a solid backdrop for a precision-nutrition approach. It is helpful that you include a section on possible adverse effects of high folate intakes and the risk of masking B12 deficiency—this signals the need for prudent monitoring. The section on AI and multidimensional data aptly reflects where precision nutrition and clinical nutrition counseling are headed.

At the same time, as a mini-review, the manuscript is narrative in character and at points diffuses into side themes (neurochemistry of eating behavior, human milk, AI) without a single, firm axis for evidence selection. The main limitation is the lack of an explicit search and selection methodology, which makes it challenging to assess completeness and potential selection bias. Limiting the scope to three vitamins is didactically reasonable, but it requires an explicit justification (e.g., why not include at least brief coverage of choline/iodine, which are neurodevelopmentally critical). Practical recommendations are sometimes general; the reader would benefit from a table mapping “gene–nutrient–biomarker–phenotype–clinical implications.” Some conclusions extend beyond the evidence presented—please modulate the language to reflect strength of evidence and study design. It would also help to close the AI thread with an implementation frame: data sources, validation, privacy, and an example of concrete decision pathways in prenatal care.

In sum, you present a solid outline of a review connecting precision nutrition, B-vitamins, and population context; to unlock its full potential, please add a minimal methodology and sharpen the practical implications. I kindly ask you to respond point-by-point to the above suggestions and indicate where the changes have been implemented in the manuscript.

Best regards,

The reviewer.

Author Response

Please find our responses enclosed in the attached document. 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

here are some comments and suggestions

in line 59 - previous studies... could benefit to place the corresponding citations after each of the factors/variables - instead of in the figure

the notion of one size fit all in line 64 should also be cited or elaborated

in the abstract the author/s mentioned mini review ... but the paper is 26 pages long, would recommend to drop "mini"

for the succeeding sections, there should be some logic provided into why the succeeding sections are vitamins... then genetics... then...

why specific a section 3.4, but within the previous sections there are already notion of regional/country comparisons (maybe rewording of the heading is needed) Homocystinuria??

overall the paper is very informative, however, the bulk of information provided should have some overarching framework to make reading more logical

 

Author Response

Please find our responses enclosed in the attached document. 

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

Reviewer Comments:

1. The manuscript oscillates between a mini-review and a systematic scoping review. The selection criteria for the included studies, the search strategy, and the methodology for synthesizing evidence are not described, which limits the reproducibility and scholarly rigor of the work.
2. The review lacks a clear, logical narrative flow. It reads more like a collection of disjointed facts on folic acid, thiamine, and B12 rather than a synthesized analysis, jumping between genetics, public health, and technology without strong transitional links.
3. While the title and introduction emphasize precision nutrition, the core of the manuscript is largely a summary of well-established knowledge on three B vitamins. The "precision" aspect (e.g., specific, actionable genetic-guided interventions) is not deeply explored and remains superficial.
4. A stated aim is to focus on the MENA region, but for thiamine and B12, the authors explicitly note a lack of region-specific genetic data. This undermines the central premise and highlights a significant evidence gap that should be more critically discussed as a limitation.
5. Figures 1, 2, and 3 are conceptually helpful but poorly executed. They lack sufficient detail, clear legends, and are not effectively integrated into the text to explain or enhance the narrative. Their self-explanatory power is low.
6. Several statements are made without direct citation or strong evidence. For example, the claim that modifiable factors have a "greater impact" than non-modifiable ones in Figure 1 is a broad generalization that is not supported with references or nuanced discussion in the text.
7. The section on AI and machine learning (Section 7) is tacked on and descriptive rather than analytical. It lists possibilities but fails to critically evaluate current applications, limitations, or the practical pathway for integrating these technologies into maternal PN in clinical or public health settings.
8. The document frequently repeats basic information about the vitamins (e.g., recommended intakes, deficiency symptoms) across different sections without adding new layers of analysis or a precision-focused perspective.
9. The conclusion is generic and does not effectively summarize the key findings or provide a strong, forward-looking perspective. It calls for future research but fails to articulate a clear, prioritized research agenda based on the gaps identified in the review itself.

Author Response

Please find our responses enclosed in the attached document. 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you very much for addressing my comments.

Best regards,

The reviewer.

Reviewer 3 Report

Comments and Suggestions for Authors

after going over the point by point response of the authors the paper is now adequate for acceptance

Reviewer 4 Report

Comments and Suggestions for Authors

Accept in present form