Thyroid–Microbiome Allostasis and Mitochondrial Performance: An Integrative Perspective in Exercise Physiology

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript offers a synthesis of thyroid allostasis, gut microbiota, and exercise physiology, being conceptually strong. The narrative is rigorous and generally well organized, and the mechanistic depth—particularly the detailed treatment of deiodinase dynamics, mitochondrial signaling, and microbial metabolic pathways—is well reported . 

However, the manuscript requires substantial revision before it can be considered for publication. First, the review’s breadth often comes at the expense of critical appraisal. Many claims are presented with mechanistic certainty despite limited or preliminary evidence, especially in sections on microbial modulation of thyroid activity and micronutrient-dependent endocrine responses. These require clearer distinction between well-supported mechanisms and theoretical extrapolations. Second, the text frequently introduces complex pathways (e.g., SCFA-D2 signaling, Nrf2/SIRT1 interactions) without summarizing the level of evidence or the strength of human data, making it difficult for readers to interpret translational relevance.

Additionally,  chapter 1.3 also deserves a figure summarizing the gut thyroid axis. 

Overall, the review has high potential, but some modifications would increase its level. 

Author Response

We sincerely thank Reviewer 01 for the careful assessment of our manuscript and for the constructive comments provided. The reviewer’s observations were highly valuable in refining the conceptual accuracy, evidentiary clarity, and structural coherence of the review. In the revised version, we have addressed each point in detail, incorporating textual revisions, conceptual clarifications, and new illustrative material where required. Below, we respond to all comments point by point, with our replies presented in italics for clarity.

Response to reviewer 01.

This manuscript offers a synthesis of thyroid allostasis, gut microbiota, and exercise physiology, being conceptually strong. The narrative is rigorous and generally well organized, and the mechanistic depth—particularly the detailed treatment of deiodinase dynamics, mitochondrial signaling, and microbial metabolic pathways—is well reported .

However, the manuscript requires substantial revision before it can be considered for publication.

• First, the review’s breadth often comes at the expense of critical appraisal. Many claims are presented with mechanistic certainty despite limited or preliminary evidence, especially in sections on microbial modulation of thyroid activity and micronutrient-dependent endocrine responses. These require clearer distinction between well-supported mechanisms and theoretical extrapolations.

In the revised manuscript, we re-evaluated 3.1 and 3.2 to ensure that all mechanistic statements accurately reflect the strength of existing evidence. Overly deterministic expressions were replaced by precise qualifiers indicating whether findings derive from experimental work, associative human studies, or theoretical models. We clarified the mechanistic uncertainty underlying microbial modulation of thyroid activity, micronutrient-dependent endocrine regulation, and thyroid–mitochondrial crosstalk.

• Second, the text frequently introduces complex pathways (e.g., SCFA-D2 signaling, Nrf2/SIRT1 interactions) without summarizing the level of evidence or the strength of human data, making it difficult for readers to interpret translational relevance.

We revised all mechanistic sections to explicitly indicate the strength of evidence supporting each pathway, differentiating preclinical mechanisms from associative human findings. Additionally, we added a new paragraph at the beginning of Section 3 that summarizes the evidence gradient for SCFA–D2, AMPK–SIRT1, Nrf2, and bile-acid signaling pathways.

• Additionally, chapter 1.3 also deserves a figure summarizing the gut thyroid axis.

Following this recommendation, we have added a new conceptual figure to Section 1.3 that summarizes the key components and interactions of the gut–thyroid axis. The figure integrates the four main regulatory modules described in this section (gut microbiota, barrier and immune function, micronutrient bioavailability, and neuroendocrine (HPT) signaling) around a central node representing thyroid function. The figure has been included as Figure 1 in the revised manuscript.

Overall, the review has high potential, but some modifications would increase its level.

Reviewer 2 Report

Comments and Suggestions for Authors

The purpose of the article is to integrate multidisciplinary evidence to characterize the thyroid–microbiome–mitochondrial axis as a key regulator of the allostatic state in athletic physiological response.

It is expected that this study will contribute significantly to understanding the exercise stress response mechanism from the perspective of the thyroid–microbiome–mitochondrial axis. However, the following points require further improvement:

1. While the overall coverage is broad, some aspects are somewhat insufficient and require further detailed analysis. Specifically, the following points require further information:

Chronic adaptations to training load

Type and intensity of exercise

Cellular mechanisms of overload

Physiological correlates and performance outcomes

Recovery and reversibility

Energetic and nutritional status

Prebiotic fibers and microbial resilience

 

If additional information is difficult to obtain, it would be helpful to reorganize the detailed items.

2. For important content, please add illustrations to help understand the interconnectedness.

Author Response

We thank Reviewer 02 for the thorough evaluation of our manuscript and for constructive comments. The reviewer’s observations were instrumental in sharpening the paper's conceptual structure, improving the clarity of key physiological mechanisms, and strengthening the connection among thyroid regulation, microbial dynamics, and exercise physiology. In the revised manuscript, we have addressed each point individually through targeted textual refinements and additional contextual explanations. Below, we respond point by point, with our replies presented in italics for clarity.

Response to reviewer 02.

The purpose of the article is to integrate multidisciplinary evidence to characterize the thyroid–microbiome–mitochondrial axis as a key regulator of the allostatic state in athletic physiological response.

It is expected that this study will contribute significantly to understanding the exercise stress response mechanism from the perspective of the thyroid–microbiome–mitochondrial axis. However, the following points require further improvement:

While the overall coverage is broad, some aspects are somewhat insufficient and require further detailed analysis. Specifically, the following points require further information:

• Chronic adaptations to training load

Section 2.3.2 has been clarified by adding a concise introductory sentence that distinguishes chronic endocrine adaptations from transient responses to acute exercise. This refinement enhances the conceptual separation between short-term fluctuations and long-term recalibration of the HPT axis without altering the structure or content of the section.

• Type and intensity of exercise

Section 2.3.3 has been refined to more directly explain how exercise type and intensity influence thyroid responses, removing redundant phrasing. The updated opening clearly states the specific roles of endurance, resistance, high-intensity interval, and prolonged high-effort exercise in shaping HPT-axis dynamics.

• Cellular mechanisms of overload

The manuscript explains the cellular processes behind overload, specifically the shift toward D3 dominance, increased inflammatory signaling, redox imbalance, and suppression of mitochondrial biogenesis. To make this information clearer, we added a brief introductory statement at the start of Section 2.4 clarifying that the following paragraphs describe the cellular mechanisms through which energetic and inflammatory overload decrease T₃ availability and mitochondrial function.

• Physiological correlates and performance outcomes

To make the performance implications of thyroid regulation more evident, we refined the opening of Section 2.4.3 so that the link between endocrine downregulation and its physiological correlates is stated upfront. The revised introduction highlights how shifts in T₃ availability, mitochondrial efficiency, redox balance, and inflammatory status influence endurance, substrate handling, and recovery capacity.

• Recovery and reversibility

The mechanisms allowing athletes to return from a low-T₃ state to normal thyroid and metabolic function were already described across Section 2.5 and related subsections. To make this trajectory more explicit, we added a brief introductory statement clarifying that recovery reflects a progressive re-establishment of deiodinase activity, mitochondrial efficiency, inflammatory balance, and gut–thyroid communication. This addition highlights the inherently reversible nature of these adaptations under adequate rest and nutritional support, thereby improving the visibility of the concept without altering the scientific content.

• Energetic and nutritional status

To improve clarity, we added a brief introductory sentence to Section 2.4.2 explicitly outlining how caloric intake, macronutrient balance, and micronutrient availability modulate the transition toward a low-T₃, energy-conserving state.

• Prebiotic fibers and microbial resilience

Although the manuscript already discussed how SCFA restoration and microbial recovery support endocrine and metabolic rebalancing, the specific role of prebiotic fibers was not explicitly stated. To clarify this connection, we added a concise introductory sentence to Section 3.1.4, emphasizing the role of fermentable fibers in promoting microbial resilience and aiding the normalization of gut–thyroid interactions.

 If additional information is difficult to obtain, it would be helpful to reorganize the detailed items.

• For important content, please add illustrations to help understand the interconnectedness.

In response, we have added a new schematic figure in Section 1.3 that illustrates the core components of the gut–thyroid axis and their interdependent regulatory pathways. This visual summary clarifies how barrier integrity, microbial composition, micronutrient handling, bile acid–mediated hormone recycling, and neuroimmune signaling converge on thyroid function. The figure is intended to help readers navigate the interconnected mechanisms described throughout the section.

Reviewer 3 Report

Comments and Suggestions for Authors

This comprehensive review is well prepared and well written containing very interessting topics of thyroid hormone regulation by various interdependent actions. The present reviewer enjoyed reading the present review which will be very improtant for not only scientists but graduate and undergradugate students. No critical comments on this review. Only one suggesting is to check the guide for the authors concerning the style of Refences.

Author Response

We sincerely thank Reviewer 03 for the positive and encouraging evaluation of our manuscript. We appreciate the reviewer’s recognition of the scientific relevance and educational value of the work. As suggested, we carefully reviewed the reference formatting to ensure full compliance with the journal’s guidelines. Since no additional modifications were requested, no further scientific changes were required. Replies appear in italics for consistency with the responses to other reviewers.

Response to reviewer 03.

This comprehensive review is well prepared and well written containing very interessting topics of thyroid hormone regulation by various interdependent actions. The present reviewer enjoyed reading the present review which will be very improtant for not only scientists but graduate and undergradugate students. No critical comments on this review. Only one suggesting is to check the guide for the authors concerning the style of Refences

Reviewer 4 Report

Comments and Suggestions for Authors

This manuscript with title „Thyroid–microbiome allostasis and mitochondrial performance: an integrative perspective in exercise physiology” presents an extensive narrative review integrating the thyroid system, gut microbiota, and mitochondrial function into a unified model of “thyroid–microbiome allostasis” in the context of exercise physiology. It proposes that thyroid hormones interact bidirectionally with microbial metabolites and mitochondrial pathways to maintain energy balance across training phases, and that disruptions in this triad contribute to adaptive vs. maladaptive responses in athletes.
Some changes are needed for better understanding and clearer presentation of results. Thus:
The manuscript presents many claims without adequate references or without indicating the hierarchy of evidence. Please add appropriate references.
For example, claims such as exercise-induced dysbiosis “temporarily reduces thyroid activity to conserve energy” or SCFA levels “promote TRH sensitivity” are interesting but require clearer presentation of supporting data and types of studies (human, animal, mechanistic) (Sections 3.1.2, 3.1.4).
The description of transient low T3 in athletes as resembling “early Hashimoto’s or Graves’-like conditions” may be misleading and should be tempered or better contextualized (Abstract, Section 3.1.5).
Figures and tables require clearer justification and connection to the evidence.
Figure 1 is conceptually strong, but appears to present a model, not data; the manuscript should explicitly state that it is hypothetical and based on integrative interpretation, not measurements (page 8).
Similarly, Tables 1-2 contain functional groupings that require more explicit support from the literature for each association.
The narrative is dense and at times repetitive. Please remove redundant parts.
Concepts such as D1/D2-D3 balance, SCFA effects, and AMPK-SIRT1-PGC1α pathways are repeated in several sections (2.1, 2.2, 3.1, 3.3), which could be simplified for clarity.
Clearer methodological inclusion/exclusion criteria for referenced studies are needed.
As a review, the manuscript does not define how studies were selected, whether the evidence comes primarily from athletes, clinical cohorts, animal models, or in vitro experiments. This affects interpretability (Section 1.4). Please clarify or discuss as a limitation.
Some sections could benefit from a clearer distinction between acute and chronic findings.
For example, acute T3 reductions during prolonged exercise versus chronic upregulation during overtraining are mixed into several paragraphs (Sections 2.3, 2.4)
The introduction is long and could be more focused by reducing the overlap between Sections 1.1–1.3.
Terms such as “adaptive recalibration,” “microbial drift,” “endocrine buffering,” and “mitochondrial coherence” are frequently used but not clearly defined.
A glossary or brief definitions would be helpful.
Check for consistency of abbreviations.

Author Response

We thank Reviewer 04 for the careful and constructive evaluation of our manuscript. The comments were highly valuable for improving clarity, precision, and interpretability. Below, we address each point in detail. All revisions appear in italics within the manuscript.

Response to reviewer 04.

This manuscript with title “Thyroid–microbiome allostasis and mitochondrial performance: an integrative perspective in exercise physiology” presents an extensive narrative review integrating the thyroid system, gut microbiota, and mitochondrial function into a unified model of “thyroid–microbiome allostasis” in the context of exercise physiology. It proposes that thyroid hormones interact bidirectionally with microbial metabolites and mitochondrial pathways to maintain energy balance across training phases, and that disruptions in this triad contribute to adaptive vs. maladaptive responses in athletes.

Some changes are needed for better understanding and clearer presentation of results. Thus:

• The manuscript presents many claims without adequate references or without indicating the hierarchy of evidence. Please add appropriate references. For example, claims such as exercise-induced dysbiosis “temporarily reduces thyroid activity to conserve energy” or SCFA levels “promote TRH sensitivity” are interesting but require clearer presentation of supporting data and types of studies (human, animal, mechanistic) (Sections 3.1.2, 3.1.4).

In the revised manuscript, the cited sections (3.1.2 and 3.1.4) have been rewritten to clearly show the hierarchy of evidence supporting each physiological interaction. Statements that previously sounded mechanistic or definitive have been softened, reformulated, or removed, and we now explicitly indicate when findings come from animal studies, indirect human data, or conceptual models.

 

• The description of transient low T3 in athletes as resembling “early Hashimoto’s or Graves’-like conditions” may be misleading and should be tempered or better contextualized (Abstract, Section 3.1.5).

We have refined and clarified the discussion of transient low-T3 states in athletes. We now explicitly distinguish these adaptive, reversible responses from autoimmune conditions such as Hashimoto’s or Graves’ disease. The text highlights that, although some immunometabolic pathways may be conceptually similar, athletes do not show immune fixation or tissue damage.

 

• Figures and tables require clearer justification and connection to the evidence
  1. Figure 1 is conceptually strong, but appears to present a model, not data; the manuscript should explicitly state that it is hypothetical and based on integrative interpretation, not measurements (page 8).

We now explicitly state that Figure 1 represents a conceptual model based on an integrative interpretation of the literature rather than direct experimental measurements. We also adjusted the accompanying text and figure legend to ensure the model is clearly presented as hypothetical and to synthesize existing evidence.

1. Similarly, Tables 1-2 contain functional groupings that require more explicit support from the literature for each association.

In the revised manuscript, both Table 1 and Table 2 have been strengthened by providing clearer bibliographic support for the functional associations they summarise. For Table 1, key mechanistic links between micronutrient availability, microbial activity, and thyroid–mitochondrial regulation are now explicitly grounded in the corresponding literature. For Table 2, we added clarifying text around the table that frames the four phenotypes as mechanistic constellations rather than diagnostic entities, and we cited representative evidence for the endocrine, microbial, mitochondrial, and performance-related features assigned to each state.

• The narrative is dense and at times repetitive. Please remove redundant parts. Concepts such as D1/D2-D3 balance, SCFA effects, and AMPK-SIRT1-PGC1α pathways are repeated in several sections (2.1, 2.2, 3.1, 3.3), which could be simplified for clarity.

We appreciate the reviewer’s observation regarding narrative density and potential redundancy. In the revised manuscript, sections 2.1–3.3 have been streamlined by removing repeated mechanistic descriptions and clarifying the specific contribution of each pathway within its respective context. Mentions of D1/D2–D3 dynamics, SCFA-mediated effects, and AMPK–SIRT1–PGC1α signalling have been consolidated or rephrased to avoid overlap while preserving scientific accuracy. These modifications have improved clarity and narrative flow without altering the review's conceptual structure.

 

• Clearer methodological inclusion/exclusion criteria for referenced studies are needed. As a review, the manuscript does not define how studies were selected, whether the evidence comes primarily from athletes, clinical cohorts, animal models, or in vitro experiments. This affects interpretability (Section 1.4). Please clarify or discuss as a limitation.

We have incorporated a dedicated paragraph in Section 1.4 that outlines how evidence was selected for this review. This addition specifies the mechanistic rationale guiding study inclusion, the hierarchy applied to human versus preclinical data, and the thematic exclusion criteria used to omit studies outside the scope of thyroid–mitochondrial–microbial interactions under exercise stress. This clarification enhances interpretability while remaining consistent with the article's narrative and integrative nature.

 

• Some sections could benefit from a clearer distinction between acute and chronic findings. For example, acute T3 reductions during prolonged exercise versus chronic upregulation during overtraining are mixed into several paragraphs (Sections 2.3, 2.4)

We thank the reviewer for pointing out the need for a clearer temporal distinction. In the revised manuscript, we refined the introductions to Sections 2.3 and 2.4 to explicitly differentiate acute, short-lived hormonal fluctuations from cumulative changes that arise with repeated training exposure. We also clarified the conceptual transition from physiological adaptation to allostatic overload, ensuring that mechanisms associated with sustained suppression are presented separately from those linked to transient responses.

 

• The introduction is long and could be more focused by reducing the overlap between Sections 1.1–1.3.

In the revised manuscript, Sections 1.1–1.3 have been refined to sharpen their conceptual boundaries and minimize unintended overlap. Specifically, Section 1.1 now focuses exclusively on general allostatic and metabolic principles, without anticipating mechanisms that are developed later. In contrast, Sections 1.2 and 1.3 have been streamlined by removing redundant wording and clarifying their distinct physiological scopes. In addition, a new figure has been incorporated into Section 1.3, allowing several mechanistic elements to be conveyed visually rather than repeated textually. These adjustments improve the focus and readability of the introduction while preserving the scientific depth and narrative structure of the review.

 

• Terms such as “adaptive recalibration,” “microbial drift,” “endocrine buffering,” and “mitochondrial coherence” are frequently used but not clearly defined.

In the revised manuscript, terms that are used consistently, such as “adaptive recalibration” and “endocrine buffering”, are now briefly defined at their first appearance to clarify the physiological meaning intended in this review. The other expressions mentioned by the reviewer (“microbial drift” and “mitochondrial coherence”) no longer appear in the current version of the text following editorial refinement, and therefore do not require definition. These adjustments improve conceptual precision without altering the structure or scientific interpretation of the manuscript.

• A glossary or brief definitions would be helpful.

To improve clarity without adding a separate glossary, the revised manuscript now provides concise definitions at the first appearance of terms that may be unfamiliar or conceptually loaded, such as “adaptive recalibration” and “endocrine buffering.” Additionally, wording throughout Sections 1–3 has been refined to remove ambiguous expressions, reduce reliance on metaphorical terminology, and replace potentially unclear constructs with more precise physiological descriptions.

 

• Check for consistency of abbreviations.

In the revised manuscript, all abbreviations have been checked for consistency, including first-use definitions, formatting, and uniform application throughout the text, tables, and figures. Any discrepancies identified in earlier drafts have been corrected to ensure coherence and adherence to journal style guidelines.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Improvements have been done.

However, I believe that something is still lacking for a general  comprehension of a difficult and very technical topic. A graphical abstract could be suitable. 

Figure 1 needs an abbreviations' legend.

Author Response

Dear reviewer,

We revised the main figure and included a graphical abstract to enhance visual clarity and facilitate understanding of the integrative framework presented in the manuscript.