Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The presented manuscript is a review of the role of lactate as an energy substrate and signaling molecule, with particular emphasis on brain metabolism and the potential use of exogenous lactate after traumatic brain injury (TBI). The topic under consideration is relevant and of interest, since disorders of cerebral energy metabolism after TBI and the search for alternative energy substrates remain important areas of fundamental and translational research. The authors also raise the important question of the possibility of using lactate as an alternative energy substrate in cases of impaired cerebral metabolism.

However, in its current form, the manuscript requires significant revision. The main problem is that in a number of sections the authors move from data demonstrating the uptake and oxidation of lactate by the brain to much stronger statements about the “preference” of lactate over glucose and the potential therapeutic effectiveness of lactate administration. These levels of evidence need to be more clearly delineated.

Comments

1. The manuscript does not contain a sufficiently clear description of how the search, selection and evaluation of literary sources was carried out. In this regard, it is not entirely clear whether this work should be considered a systematic, scoping or narrative review. Authors should explicitly indicate the type of review and briefly describe the principles for selecting literature. It is advisable to clarify which sources or databases were used, what time period was covered, and what criteria were used to select studies on cerebral lactate metabolism and its role in TBI. This is especially important because several of the manuscript's key conclusions rely on a relatively limited number of studies and, in some cases, on previous work by the authors themselves.
2. The abstract describes the conversion of glucose to lactate as the “so-called Warburg effect.” This formulation is conceptually imprecise. The formation of lactate during glycolysis is not itself a Warburg effect. The Warburg effect generally refers to increased aerobic glycolysis to produce lactate in the presence of oxygen, primarily in the context of tumor metabolism and some rapidly proliferating cells. The authors should reconsider this formulation and clearly distinguish between the normal formation of lactate during glycolysis and the specific concept of the Warburg effect.
3. One of the central findings of the manuscript is that the brain exhibits a “preference” for lactate over glucose. However, much of the evidence presented rather suggests that lactate uptake and oxidation by the brain increases as its availability in the circulation increases and that lactate is able to partially replace glucose as an oxidative substrate. However, an increase in lactate uptake and a decrease in glucose consumption when an alternative substrate is administered is not in itself sufficient evidence of a universal physiological “preference” for lactate. Currently, the wording in a number of sections is too categorical and should be softened.
4. The manuscript provides a physiological rationale for the potential use of lactate after TBI. However, evidence that the injured brain is able to take up and oxidize lactate does not provide evidence that lactate administration improves clinical outcomes. It is recommended that the use of exogenous lactate be presented as a promising metabolic strategy that requires further controlled clinical evaluation.
5. Figure 4 combines images obtained from healthy subjects with images from a patient with TBI before and during lactate administration. However, the text indicates that the patient's pre-injury data are not available. Therefore, the illustration presented is not a direct comparison of the same individual before injury, after injury, and after lactate administration. In addition, images of healthy participants and the TBI patient were obtained from different individuals. Therefore, using this figure as evidence for a “preference for lactate over glucose as brain fuel” appears to be an overinterpretation. The authors should either substantially revise the figure and its legend, or more clearly label it as an illustrative example only. Limitations associated with comparing data across different participants must be explicitly stated.
6. The Astrocyte–Neuron Lactate Shuttle concept is one of the important elements of the overall logic of the manuscript. However, its discussion in this article remains relatively brief, and the reader is encouraged to refer to other publications. In its current form, the part of the argument that is significant for understanding the general concept is moved outside the manuscript itself.
7. The section on various lactate delivery options including arginyl lactate, lactate glycerides and potential new compounds is of interest. However, at present, it does not clearly distinguish between approaches that have experimental confirmation and predominantly hypothetical proposals.

The manuscript addresses a current and potentially important topic and provides an interesting historical and conceptual overview of the development of ideas about the role of lactate in energy metabolism. However, before publication, the authors need to make the argument more balanced and clearly distinguish evidence for the ability of the brain to take up and oxidize lactate from evidence for the therapeutic effectiveness of its administration after traumatic brain injury.

Author Response

The Reviewers and Editor are thanked for the critical commentary.  Reviewer’s comments are reiterated in black font and author responses are in blue Ital Font.

But what is confusing is that there were to reviewer reports. Hence, A combined Reviewer 1 and 2 response is attached.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review paper discusses whether exogenous lactate can bypass impaired cerebral glucose uptake after traumatic brain injury and serve as an alternative cerebral energy substrate. The manuscript presents a clear central hypothesis and summarizes a substantial body of literature on lactate metabolism and lactate shuttle theory. However, the current version is not sufficiently balanced or systematic as a scientific review. The discussion relies heavily on the author’s own framework and previously published studies, while alternative interpretations, clinical limitations, safety concerns, and translational uncertainties are not adequately evaluated. Major revision is required before the manuscript can be considered further. The comments in details are shown below:

1. Lines 22–38: The available evidence supports a plausible hypothesis, but not a clinically established intervention. The authors should distinguish clearly between physiological evidence, preliminary clinical observations, and unproven therapeutic claims.
2. Lines 42–82: The Introduction is difficult to follow and contains several grammar problems. The study objective should be stated more clearly. Is this a historical review, a mechanistic review, or a translational argument for lactate therapy after TBI?
3. The review methodology is not described, like search strategy, inclusion criteria, database coverage, or criteria for selecting studies. If this is intended as a narrative review, that should be explicitly stated.
4. Lines 83–152: A large portion of the manuscript is devoted to the history of lactate shuttle theory. This background is useful but too long relative to the stated TBI-focused question. The manuscript should be more tightly organized around TBI pathophysiology, cerebral substrate metabolism, lactate delivery, and clinical translation.
5. Lines 184–213: The discussion of human TBI evidence relies heavily on a small number of studies with limited sample sizes. For example, the cited TBI study included 12 TBI patients and 6 controls. The authors should discuss sample size, injury heterogeneity, timing after injury, disease severity, and limitations of extrapolating these data to broad clinical use.
6. Lines 223–243: The rationale for lactate supplementation is interesting, but the manuscript does not adequately discuss key clinical uncertainties, including optimal timing after TBI, dose, route of administration, infusion duration, blood lactate targets, monitoring strategy, and patient selection.
7. Lines 291–318: The section on lactate delivery vehicles is speculative. Sodium lactate, arginyl lactate, glycerol lactate, and novel lactate-keto-glyceride analogs are discussed, but the safety, pharmacokinetics, regulatory status, and clinical feasibility of these approaches are not critically evaluated.
8. Lines 299–313: The discussion of amino acid carriers and glycerides should be more cautious because the author later discloses patents and company involvement related to nutrition compounds. Potential conflicts of interest should be considered when presenting these compounds as possible delivery vehicles.
9. Lines 319–333: The comparison between lactate, ketones, and pyruvate is too one-sided. A more balanced discussion is needed, including the advantages and limitations of ketone bodies, glucose control, insulin therapy, enteral nutrition, and other metabolic support strategies after TBI.
10. Lines 350–353: The manuscript appropriately states that lactate supplementation must be tested rigorously in multiple centers before becoming standard of care. This caution should be reflected throughout the manuscript, including the Abstract, Highlights, Discussion, and Conclusion.
11. Figures 1–5: The figures do not provide a clear integrative synthesis of the review. Most figures are reproduced or redrawn from previous studies, and there is no conceptual figure summarizing how exogenous lactate may bypass impaired cerebral glucose uptake after TBI. For a review centered on a mechanistic and translational hypothesis, the authors should provide a comprehensive schematic showing the proposed pathway from systemic lactate delivery to BBB transport, neuronal or astrocytic uptake, mitochondrial oxidation, interaction with glucose metabolism, potential signaling effects, and key clinical uncertainties.
12. Figure 4, lines 447–478: The use of MRI/PET images from Wikipedia and Radiopaedia should be handled carefully. The authors must ensure appropriate permissions, image quality, citation accuracy, and suitability for publication.
13. Lines 384–417: The figure legends are overly long and contain formatting issues. They should be shortened and standardized.

 

Comments on the Quality of English Language

The manuscript needs substantial editing. There are many awkward phrases and grammatical errors, such as “Intent of this paper is,” “sparse,” “exercise-induce,” “it this work emphasis,” “after bran injuries,” and “may will be considered.”

Author Response

Please see the attached.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors did considerable work revising the manuscript and responded satisfactorily to all comments.

In particular, I evaluate the following improvements:

The manuscript is now clearly and consistently positioned as a hypothesis-generating work, which makes it possible to clearly distinguish between physiological data and unproven therapeutic statements.

The terminology has been corrected: the incorrect use of the term "Warburg effect" has been removed, and the categorical word "preference" has been replaced with more accurate formulations about "substrate competition" and "alternative" energy sources.

Potential conflicts of interest associated with hypothetical means of lactate delivery have been appropriately addressed by removal/reduction of this specific section.

The addition of a new integrative scheme (Figure 6) significantly improves the conceptual generalization of the review material.

In its current form, the manuscript is a balanced, grounded and scientifically competent review of lactate shuttle theory and its potential translational significance in traumatic brain injury (TBI). recommend the manuscript for publication in the journal

Reviewer 2 Report

Comments and Suggestions for Authors

The author revised the manuscript in response to the comments and significantly improved its quality. Recommend it for publication.