Review Reports - Medium-Chain Triglycerides: Scientific and Regulatory Perspectives from Germany and Japan with a US Context—A Concise Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present an aspect of the use of MCTs, a comparison between two countries with different legislation and considerations.

The authors accurately and comprehensively analyze the possible mechanisms, but a definitive opinion on the matter would also be helpful; in my opinion, the Japanese claims are far too optimistic, so the authors should make an effort to provide an opinion on whether they are plausible and therefore worth recommending to other countries or should be disregarded for now.

A note on the ketogenic diet: it's true that MCTs promote ketosis, but it should be emphasized that this state can also be achieved without the use of MCTs.

In this scenario, their use in sports, at least for endurance sports, should be mentioned.

Comments on the Quality of English Language

just a revision needed

Author Response

Reviewer comment No. 1

The authors present an aspect of the use of MCTs, a comparison between two countries with different legislation and considerations. The authors accurately and comprehensively analyze the possible mechanisms, but a definitive opinion on the matter would also be helpful; in my opinion, the Japanese claims are far too optimistic, so the authors should make an effort to provide an opinion on whether they are plausible and therefore worth recommending to other countries or should be disregarded for now.

Response No. 1

We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion to provide a more explicit evaluation of the plausibility of the Japanese claims regarding the metabolic and regulatory implications of MCT consumption.

While the Japanese regulatory perspective presents a comparatively optimistic view of the benefits of MCTs, we now emphasize that the currently available scientific evidence remains heterogeneous and, in some cases, limited in strength. Although several studies suggest potential benefits, we conclude that the current evidence does not yet justify broad policy recommendations for other countries without further well-controlled clinical studies.

This clarification has been added to the following sections of the revised manuscript:

Section 4.2. Insights from Japan – please see lines 391-393
Section 5.2. The case of MCTs in Japan – please see lines 656-665

In addition, within Section 5 we have included a new subsection:

Section 5.3. Critical appraisal of evidence supporting Japanese functional claims

Furthermore, the evidence base is summarized in the newly created Table 3: Studies included in the systematic literature reviews.

Reviewer comment No. 2

A note on the ketogenic diet: it's true that MCTs promote ketosis, but it should be emphasized that this state can also be achieved without the use of MCTs.

Response No. 2

We agree with the reviewer and have clarified this point in the revised manuscript. The text now explicitly states that ketosis can also be achieved through dietary carbohydrate restriction alone and that MCTs represent only one possible strategy to facilitate or accelerate ketone body production rather than a necessary component of ketogenic diets.

This clarification has been added to the following section:

Section 4.1.2. Ketogenic diet (KD) – please see lines 255–259

Reviewer comment No. 3

In this scenario, their use in sports, at least for endurance sports, should be mentioned.

Response No. 3

We thank the reviewer for highlighting this relevant aspect. The revised manuscript now briefly discusses the potential role of MCT supplementation in sports nutrition, particularly in the context of endurance exercise. The respective regulatory and scientific perspectives are addressed for both countries discussed in the manuscript.

This information has been added in the following sections:

Germany – please see lines 315 and 327–336
Japan – please see lines 428–452

Reviewer 2 Report

Comments and Suggestions for Authors

Aging disorders constitute a major problem of public health that is associated with increased risk of mortality and poor quality of life. Poor dietary and habitual lifestyles are considered critical issues that worsen the prognosis of patients suffering from low-grade inflammatory diseases (i.e., aging and even lipid metabolic disorders). In this aspect, the present report aims to evaluate the potential therapeutic application on the medium chain oil in Germany and Japan. However, such reviewed information was well-known knowledge and was focused on both German and Japan regulation, but not worldwide. Regarding these limitations, I do have some questions about the manuscript.

The topic setup for the associations among the MCT, human diseases, and possible fatty acid metabolism should be more precise.
The trend of the research article should provide updated information and importance in the related area. Unfortunately, some information did not be included in the critical issues. For example, the application in the US and the European Union should be revealed and compared. Some chronic diseases, as well as health promotion purposes in normal subjects, affect and result in lipid metabolic dysfunction in selected diseases, which may be attributed to the alternative metabolism of lipids. Such information should be updated and clarified. Please compare to the regulations of MCT products in other industrial countries, not only Germany and Japan.
From the translational medicine aspect, authors may provide and focus on the study in animal and even clinical trials. However, information from the in vitro experiments may not be good evidence to support the benefits of MCT oil.

Author Response

Reviewer comment No. 1

Aging disorders constitute a major problem of public health that is associated with increased risk of mortality and poor quality of life. Poor dietary and habitual lifestyles are considered critical issues that worsen the prognosis of patients suffering from low-grade inflammatory diseases (i.e., aging and even lipid metabolic disorders). In this aspect, the present report aims to evaluate the potential therapeutic application of medium-chain oil in Germany and Japan. However, such reviewed information was well-known knowledge and was focused on both German and Japanese regulation, but not worldwide.

Response No.1

We thank the reviewer for this thoughtful comment. The aim of the present review is to comparatively analyze the regulatory frameworks and scientific evidence related to medium-chain triglycerides (MCTs) in Germany and Japan, two countries with notably different approaches to functional food regulation. We agree that providing a broader international context is valuable. Therefore, we have included additional insights regarding the regulatory and clinical use of MCTs in the United States.

This information has been added in the following sections:

Title – please see line 3
Abstract – please see lines 20–22
Introduction – please see lines 46–49, 52–54, 55–57
3. Insights in the United States – please see lines 454–505
4.3. Clinical practice in the United States – please see lines 543–555
4. The Case of MCTs in the United States – please see lines 673–740
6. Challenges, Limitations, Future Directions, and Recommendations – please see lines 857–862
7. Conclusions – please see lines 957–959, 976

Reviewer comment No. 2

The topic setup for the associations among the MCT, human diseases, and possible fatty acid metabolism should be more precise.

Response No. 2

We appreciate this suggestion and have revised the relevant sections of the manuscript to provide a clearer description of the relationships between MCTs, fatty acid metabolism, and their potential implications for metabolic health.

To improve clarity and structure, we have reorganized Section 4: Application of medium-chain fatty acids and created several more precise subsections describing specific clinical contexts:

1.1 Gastrointestinal and liver disorders
1.2 Ketogenic diet (KD)
1.3 Long-chain fatty acid oxidation disorders (LC-FAODs)
1.4 Further applications

These structural changes allow a more precise presentation of the metabolic and clinical contexts in which MCTs may play a role.

Reviewer comment No. 3

The trend of the research article should provide updated information and importance in the related area. Unfortunately, some information was not included in the critical issues. For example, the application in the US and the European Union should be revealed and compared. Please compare the regulations of MCT products in other industrial countries, not only Germany and Japan.

Response No. 3

We thank the reviewer for this important suggestion. In response, we have expanded the manuscript to include additional information on the regulatory and clinical context of MCT use in the United States, which provides further international perspective.

Please see Response No. 1, where the respective additions and their locations in the revised manuscript are described in detail.

Reviewer comment No. 4

From the translational medicine aspect, authors may provide and focus on studies in animal and clinical trials. However, information from in vitro experiments may not be good evidence to support the benefits of MCT oil.

Response No. 4

We fully agree with the reviewer that evidence derived from animal models and human clinical studies is more relevant for translational and regulatory considerations than findings from in vitro experiments alone.

To address this point, we have summarized the available evidence from human studies in the newly created Table 3: Studies included in the systematic literature reviews, which focuses on clinical research evaluating the effects of MCTs. Please see line 671 in the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

Ccongratulations on an interesting review paper. Below are some comments that may make the reception of the paper more attractive.

The manuscript entitled “Medium-Chain Triglycerides: Scientific and Regulatory Perspectives from Germany and Japan – A Concise Review” provides a comprehensive and well-structured overview of medium-chain triglycerides (MCTs), integrating biochemical metabolism, industrial production, clinical applications, and regulatory frameworks in Germany and Japan. The topic is timely and relevant to Nutrients, especially in the context of functional foods, aging societies, and regulatory divergence between regions.

While the manuscript is extensive, parts of the review remain overly descriptive, particularly in Sections 3 (Industrial synthesis) and 5 (Regulatory frameworks). For a review article in Nutrients, a more critical synthesis is expected.I suggest reduce technical detail in industrial synthesis and emphasize relevance for nutritional quality, safety, and regulatory acceptance.

The manuscript appropriately highlights differences between Germany and Japan regarding functional claims. However, the strength and limitations of the clinical evidence underlying Japanese FOSHU and Foods with Function Claims require clearer critical appraisal. Clearly distinguish between short-term metabolic outcomes and clinically meaningful endpoints.

The manuscript correctly notes chain-length–dependent metabolic effects but does not consistently integrate this distinction throughout clinical and regulatory discussions. Strengthen the discussion on C8 vs. C10 vs. C12 and consider adding a summary table.

The comparison between German FSMPs and Japanese functional foods is a major strength. However, translational implications could be made more explicit. Clarify whether elements of the Japanese preventive model could be transferable to the EU context.

Several authors are employees of a company producing MCT products. While transparently disclosed, the manuscript would benefit from an explicit statement addressing how interpretive bias was minimized.

Additional Comments:

- Terminology consistency between MCTs and MCFAs should be ensured,

- Figures could be improved with clearer labeling,

- Epidemiological data sources should be specified,

- Minor language tightening is recommended.

Author Response

General - Reviewer comment

Congratulations on an interesting review paper. Below are some comments that may make the reception of the paper more attractive.

Response

We thank the reviewer for the positive evaluation of our manuscript and for the constructive suggestions, which have helped us improve the clarity and critical perspective of the review. All comments have been carefully addressed in the revised manuscript, as detailed below.

Reviewer comment No. 1

While the manuscript is extensive, parts of the review remain overly descriptive, particularly in Sections 3 (Industrial synthesis) and 5 (Regulatory frameworks). For a review article in Nutrients, a more critical synthesis is expected. I suggest reducing technical detail in industrial synthesis and emphasizing relevance for nutritional quality, safety, and regulatory acceptance.

Response No. 1

We thank the reviewer for this helpful suggestion. In the revised manuscript, we have streamlined Section 3 (Industrial synthesis) by reducing some of the technical descriptions of production processes and placing greater emphasis on aspects relevant to nutrition science, including implications for nutritional quality, safety considerations, and the regulatory acceptance of MCT-containing products.

In addition, the discussion in Section 6 has been revised to strengthen the critical synthesis of regulatory frameworks (please see lines 863–870).

Reviewer comment No. 2

Response No. 2

We fully agree with the reviewer that a clearer distinction between short-term metabolic outcomes and clinically meaningful health endpoints is important when evaluating the evidence supporting functional claims.

Therefore, we have expanded the discussion in Section 5 and included a new subsection:

Section 5.3. Critical appraisal of evidence supporting Japanese functional claims
Furthermore, the evidence base is summarized in the newly created Table 3: Studies included in the systematic literature reviews.

Reviewer comment No. 3

Response No. 3

We appreciate this important suggestion. In the revised manuscript, we have strengthened the discussion of chain-length–dependent metabolic differences among C8, C10, and C12 fatty acids, particularly with regard to absorption, ketogenesis, and their relevance in clinical and nutritional contexts.

This distinction is now addressed more consistently throughout the manuscript, including in:

Section 4.1.2. Ketogenic diet (KD)
• Section 5.3. Critical appraisal of evidence supporting Japanese functional claims
• Table 3: Studies included in the systematic literature reviews

Reviewer comment No. 4

Response No. 4

We thank the reviewer for highlighting this important aspect. In the revised manuscript, we have expanded the discussion on the translational implications of the Japanese preventive nutrition model, particularly with respect to its potential relevance for the European regulatory environment.

Please see Section 6: Challenges, Limitations, Future Directions, and Recommendations (lines 835–836; 854–856; 920–925)
and Section 7: Conclusions (lines 978–981).

Reviewer comment No. 5

Response No. 5

We thank the reviewer for raising this important point. While potential conflicts of interest were already disclosed in the manuscript, we have now added an explicit statement describing the measures taken to minimize potential interpretive bias (please see lines 997–999).

Reviewer comment No. 6

Terminology consistency between MCTs and MCFAs should be ensured.

Response No. 6

We thank the reviewer for this comment. The terminology has been revised throughout the manuscript to ensure the consistent and accurate use of MCTs (medium-chain triglycerides) and MCFAs (medium-chain fatty acids).

Reviewer comment No. 7

Figures could be improved with clearer labeling.

Response No. 7

We agree with the reviewer and have revised the figures and tables to improve labeling and overall clarity.

Reviewer comment No. 8

Epidemiological data sources should be specified.

Response No. 8

We thank the reviewer for this suggestion. The sources of epidemiological data have now been specified more clearly in the relevant sections of the manuscript.

Reviewer comment No. 9

Minor language tightening is recommended.

Response No. 9

The manuscript has been carefully revised for language and readability, and minor stylistic improvements have been implemented throughout the text.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors replied the considerations smoothly. I have no further comment.