Review Reports - Microbiota–Gut–Brain Axis Disruption, Neuroinflammation, and Potential Antioxidant-Based Treatments in Metabolic Diseases

Round 1

Reviewer 1 Report

This study explores the association between metabolic diseases (such as obesity, type 2 diabetes, and dyslipidemia) and chronic systemic inflammation and oxidative stress, with a focus on the role of the microbiota–gut–brain (MGB) axis in the pathogenesis of neuroinflammation. The authors systematically summarize the pathophysiological mechanisms linking the MGB axis, metabolic disorders, and neuroinflammation, and evaluate the therapeutic potential of antioxidant strategies.

Overall, this review is relatively comprehensive, and the discussion of antioxidant strategies targeting the MGB axis holds both theoretical value and practical potential. The authors are encouraged to address the following minor points to improve the clarity and logical flow of the manuscript.

Methodology: The authors should provide the URLs of the resources such as PubMed. Additionally, it would be helpful to specify the time range of the literature search.
Line 126: A brief introduction to the BBB (blood–brain barrier) should be provided.
Lines 250–252: Regarding obesity-induced gut microbiota alterations, the authors should specify which key bacterial taxa exhibit changes in abundance, as well as which strains are responsible for short-chain fatty acid production. This information needs to be supplemented.
Line 266: For "Gram-negative bacteria," relevant bacterial species should be listed as examples.
Table 2: The descriptions under "Antioxidant mechanism" can be simplified. Table 3: The descriptions under "Effects on microbiota, oxidative stress, and neuroinflammation" should also be presented more concisely.
Line 360: In Figure 1, the terms "obesity" and "high-fat diet" appear somewhat redundant. The authors may consider adding other possible causes of dysbiosis.
It is recommended that the authors add a section on future research perspectives before the Conclusions.
Section 4.3 Combined Antioxidant and Probiotic Strategies: The authors are encouraged to include additional findings from animal experiments in this section.

Author Response

RESPONSE: We sincerely appreciate your valuable comments and suggestions, which undoubtedly helped improve the clarity and overall quality of our manuscript.

1. Methodology: The authors should provide the URLs of the resources such as PubMed. Additionally, it would be helpful to specify the time range of the literature search.

RESPONSE: We have added the URLs and specified the time range of the literature search, as suggested.

2. Line 126: A brief introduction to the BBB (blood–brain barrier) should be provided.

RESPONSE: We have added a brief introduction to the blood‒brain barrier (BBB), as requested.

3. Lines 250–252: Regarding obesity-induced gut microbiota alterations, the authors should specify which key bacterial taxa exhibit changes in abundance, as well as which strains are responsible for short-chain fatty acid production. This information needs to be supplemented.

RESPONSE: We appreciate your suggestion and have incorporated the requested information regarding the key bacterial taxa with altered abundance, as well as those involved in short-chain fatty acid production.

4. Line 266: For "gram-negative bacteria," relevant bacterial species should be listed as examples.

RESPONSE: We have added representative examples of gram-negative bacterial species, as requested.

5. Table 2: The descriptions under "Antioxidant mechanism" can be simplified. Table 3: The descriptions under "Effects on microbiota, oxidative stress, and neuroinflammation" should also be presented more concisely.

RESPONSE: We have simplified the information in Table 2 and clarified the information in Table 3, as suggested.

6. Line 360: In Figure 1, the terms "obesity" and "high-fat diet" appear somewhat redundant. The authors may consider adding other possible causes of dysbiosis.

RESPONSE: We have implemented the suggested changes. Specifically, we have included additional potential causes of intestinal dysbiosis and clarified in the text that relevant alterations occur in the bacterial population.

7. The authors should add a section on future research perspectives before the Conclusions.

RESPONSE: We have added a section on future research perspectives before the conclusions, as suggested.

8. Section 4.3 Combined Antioxidant and Probiotic Strategies: The authors are encouraged to include additional findings from animal experiments in this section.

RESPONSE: We have added additional relevant findings from animal experiments in this section, as suggested.

We sincerely appreciate your valuable comments and constructive observations, which have greatly contributed to improving the clarity and overall quality of our manuscript.

Author Response File: Author Response.docx

Reviewer 2 Report

This paper focuses on the role of the 'microbiota-gut-brain axis' in neuroinflammation associated with metabolic diseases and explores the potential of antioxidants as an intervention strategy. The topic is cutting-edge and aligns with current research hotspots at the intersection of metabolic and neurodegenerative diseases. The article covers a broad scope, integrating mechanistic research with potential interventions, demonstrating a degree of systematic coherence and referential value.

The article also has several shortcomings, some of which are listed below:

Section 3 (Pathophysiological mechanisms) is overly lengthy, and some paragraphs overlap with Section 4 (Antioxidant strategies). For instance, the mechanism of the ROS and inflammation cycle is repeatedly addressed across multiple paragraphs.
On page 23, reference [113] lists the year as '2026,' which contradicts the earlier statement that 'searches were conducted up to May 2025.' Please verify the search date.
After its initial definition, the term 'microbiota-gut-brain axis' continues to be used interchangeably with 'MGB axis.'
Section 4.3 (Combined Antioxidant and Probiotic Strategies) could be expanded upon.
The conclusion is rather general and does not clearly specify future research directions or current research gaps."

Author Response

This paper focuses on the role of the microbiota–gut–brain axis in neuroinflammation associated with metabolic diseases and explores the potential of antioxidants as an intervention strategy. The topic is cutting-edge and aligns with current research hotspots at the intersection of metabolic and neurodegenerative diseases. The article covers a broad scope, integrating mechanistic research with potential interventions, demonstrating a degree of systematic coherence and referential value.

RESPONSE: We sincerely appreciate your positive comments and valuable suggestions. We believe it is important to identify accessible strategies for managing comorbidities associated with metabolic diseases, such as gliosis or neuroinflammation, particularly in countries such as ours, where a high prevalence of abdominal obesity is observed and effective preventive strategies are not consistently implemented in primary care.

The article also has several shortcomings, some of which are listed below:

1. Section 3 (Pathophysiological mechanisms) is overly lengthy, and some paragraphs overlap with Section 4 (Antioxidant strategies). For instance, the mechanism of the ROS and inflammation cycle is repeatedly addressed across multiple paragraphs.

RESPONSE: We have revised the manuscript to address this issue, reducing redundancy and minimizing overlap between Sections 3 and 4, particularly regarding the discussion of the ROS and inflammation cycle, as suggested.

2. On page 23, reference [113] lists the year as '2026,' which contradicts the earlier statement that 'searches were conducted up to May 2025.' Please verify the search date.

RESPONSE: We have verified and corrected the time range corresponding to our literature search and data retrieval, as suggested.

3. After its initial definition, the term 'microbiota-gut-brain axis' continues to be used interchangeably with the 'MGB axis.

RESPONSE: We have revised the manuscript to ensure consistent use of the term “microbiota–gut–brain axis” throughout.

4. Section 4.3 (Combined Antioxidant and Probiotic Strategies) could be expanded upon.

RESPONSE: We have expanded Section 4.3 as suggested and agree on the relevance of this section.

5. The conclusion is rather general and does not clearly specify future research directions or current research gaps."

RESPONSE: We have revised the Conclusions section to address this concern, incorporating current research gaps and future research directions, as suggested.

Finally, we sincerely thank you for your time and valuable comments, which have helped improve the quality of our manuscript.

Author Response File: Author Response.docx

Reviewer 3 Report

Carro-Rodríguez et al. reviewed the interplay among gut dysbiosis, oxidative stress, neuroinflammation, and the microbiota–gut–brain axis in metabolic diseases, with additional discussion of antioxidant-based therapeutic strategies. The topic is of potential interest, as growing evidence suggests that microbiota-related inflammatory and redox pathways may contribute to metabolic and neurological complications. The review also brings together a considerable number of studies concerning obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. However, despite its broad scope, the manuscript in its current form remains conceptually insufficient for publication. In particular, the review lacks a clear and coherent mechanistic framework, does not adequately distinguish association from causation, and frequently mixes evidence derived from different disease contexts and experimental models without sufficient critical evaluation. These issues substantially weaken the focus, rigor, and overall scholarly value of the manuscript.

It is recommended that the Introduction include a brief overview of antioxidants and their clinical or experimental applications.
If this manuscript is intended as a systematic review, the authors should provide a PRISMA-compliant search strategy.
In Section 3.1, the descriptions of obesity and metabolic syndrome are somewhat repetitive and should be streamlined.
In Section 3.2, the basic introduction to the microbiota–gut–brain (MGB) axis would be more appropriately placed in the Introduction rather than in the main results/discussion section.
The mechanistic sequence of “gut dysbiosis → increased LPS / decreased SCFAs → intestinal barrier disruption → inflammation/ROS elevation → BBB impairment → microglial activation → neuroinflammation” is repeated several times throughout the manuscript, making the presentation redundant, loose, and insufficiently concise.
The discussion of dyslipidemia is relatively limited and should be expanded.
Although the manuscript covers a broad range of topics, it lacks a clear central mechanistic framework. Overall, it reads more like a compilation of related studies and pathways than a critically integrated review, with additional concerns including repetitive content, mixed levels of evidence, and an unclear distinction between association and causation.

Author Response

Although the manuscript covers a broad range of topics, it lacks a clear central mechanistic framework. The manuscript reads more like a compilation of related studies and pathways than a critically integrated review

RESPONSE: We appreciate your valuable feedback. We acknowledge that our approach is complex, and in response to your comment, we have revised the manuscript to improve the integration of the discussed mechanisms.

Carro-Rodríguez et al. reviewed the interplay among gut dysbiosis, oxidative stress, neuroinflammation, and the microbiota–gut–brain axis in metabolic diseases, with additional discussion of antioxidant-based therapeutic strategies. The topic is of potential interest, as growing evidence suggests that microbiota-related inflammatory and redox pathways may contribute to metabolic and neurological complications. The review also brings together a considerable number of studies concerning obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. However, despite its broad scope, the manuscript in its current form remains conceptually insufficient for publication. In particular, the review lacks a clear and coherent mechanistic framework, does not adequately distinguish association from causation and frequently mixes evidence derived from different disease contexts and experimental models without sufficient critical evaluation. These issues substantially weaken the focus, rigor, and overall scholarly value of the manuscript.

RESPONSE: We appreciate your thorough and constructive evaluation. In response to your comments, we have revised the manuscript to address the points raised, with particular emphasis on developing a clear and coherent mechanistic framework, strengthening the distinction between association and causation, and improving the critical integration of evidence from different disease contexts and experimental models. We hope that this revised version represents a substantial improvement over the previous manuscript, particularly with regard to the methodological aspects you highlighted.

It is recommended that the Introduction include a brief overview of antioxidants and their clinical or experimental applications.

RESPONSE: We have added a brief overview of antioxidants and their clinical and experimental applications in the Introduction, as suggested.

2. If this manuscript is intended as a systematic review, the authors should provide a PRISMA-compliant search strategy.

RESPONSE: We would like to clarify that this manuscript was conceived as a narrative review rather than a systematic review. The primary objective of this study is to integrate current evidence on the microbiota-gut-brain axis, neuroinflammation, and the potential role of antioxidant strategies, as well as to propose a conceptual framework linking these processes within the context of metabolic diseases. We appreciate your valuable feedback, which has helped us improve and clarify Section 2 (Methodology).

3. In Section 3.1, the descriptions of obesity and metabolic syndrome are somewhat repetitive and should be streamlined.

RESPONSE: We appreciate your suggestion and have revised the wording to reduce repetition, as noted.

4. In Section 3.2, the basic introduction to the microbiota–gut–brain (MGB) axis would be more appropriately placed in the Introduction rather than in the main results/discussion section. ya

RESPONSE: We have implemented the suggested change by relocating the introductory description of the microbiota–gut–brain (MGB) axis to the Introduction section.

5. The mechanistic sequence of “gut dysbiosis → increased LPS/decreased SCFAs → intestinal barrier disruption → inflammation/ROS elevation → BBB impairment → microglial activation → neuroinflammation” is repeated several times throughout the manuscript, making the presentation redundant, loose, and insufficiently concise.

RESPONSE: We have revised the manuscript to address this issue by reducing redundancy and streamlining the presentation of the mechanistic sequence, as suggested.

6.The discussion of dyslipidemia is relatively limited and should be expanded.

RESPONSE: We have expanded the discussion on dyslipidemia by incorporating additional relevant information, as suggested.

7. Although the manuscript covers a broad range of topics, it lacks a clear central mechanistic framework. Overall, it reads more like a compilation of related studies and pathways than a critically integrated review, with additional concerns including repetitive content, mixed levels of evidence, and an unclear distinction between association and causation.

RESPONSE: We sincerely appreciate your valuable and insightful comments, which enabled us to identify and address a fundamental limitation of the manuscript. In response, we have strengthened the conceptual cohesion by incorporating a clearer and more explicit description of the central mechanistic framework we propose, namely, oxidative stress. We have also improved the organization of the manuscript to avoid the impression of a mere compilation of isolated studies, enhancing the critical integration of the available evidence and eliminating redundant content.

Furthermore, we have clarified our conceptual proposal and provided additional support to better justify the novelty of the manuscript. We have incorporated information that contextualizes oxidative stress within metabolic diseases, dysbiosis, and neuroinflammation, establishing a more coherent and logical sequence that supports the potential role of antioxidant interventions. In cases where direct evidence is limited, we have carefully integrated findings from related pathological contexts to maintain conceptual consistency.

With these modifications, we believe the manuscript now presents a more coherent, structured, and analytical narrative, aligned with the objectives of a critical review. We acknowledge that integrating complex and multifactorial mechanisms remains challenging; however, we hope that this revised version contributes meaningfully to the understanding of these interconnected processes.

We are grateful for your insightful comments and thoughtful suggestions, which have helped us enhance the clarity and scientific quality of our manuscript.

Author Response File: Author Response.docx

Reviewer 4 Report

The manuscript requires modifications to improve its quality:

In the introduction section, the authors should explain why a review on this topic is necessary, given that similar reviews have already been published. What is the novelty and scientific relevance of this review compared to others already published? (e.g., J Adv Res. 2021 Sep 17;38:223-244; Cell Mol Life Sci. 2024 Dec 5;81(1):480; Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016 Dec;160(4):461-466; Oxid Med Cell Longev. 2018 Dec 9;2018:2406594; among others). Please include this information in the final version of the manuscript.
In section 3 of the manuscript, the authors must specify the metabolic diseases on which the review focused and explain why these diseases were chosen over others. This information is crucial and must be included in the final version of the manuscript.
Oxidative stress is one of the molecular processes involved in neuroinflammation, but it is not the only one. The authors should indicate whether other processes, such as changes in cytokines/chemokines, changes in extracellular ion levels, and changes in the levels of other chemical mediators, influence neuroinflammation, and whether these changes are affected by gastrointestinal microbiota dysbiosis in metabolic diseases. This relevant information should be included in section 3 of the manuscript.
In section 3.1, the authors should elaborate on how chemical mediators generated by metabolic disease (specify disease and chemical mediator) influence the stability of the blood-brain barrier. Establishing this relationship is essential for this review. Include this information in the final version of the manuscript.
In section 3.1, the authors should also explain how gliosis compromises the stability of the blood-brain barrier. Include this information in the final version of the manuscript.
What is the mechanism by which adipokines and cytokines released by visceral adipose tissue trigger blood-brain barrier instability? The authors should provide scientific evidence for this and explain the mechanisms involved in detail.
Why is the hypothalamus sensitive to adipokines/cytokines from visceral adipose tissue? Authors should include scientific evidence that these adipokines/cytokines from visceral adipose tissue influence the physiology of hypothalamic neurons.
The authors provide evidence for the effects of high-lipid diets, but not for adipokines/cytokines released by visceral adipose tissue. The effects of diets cannot be extrapolated to the effects of adipose tissue on the hypothalamus. What is the level of pro-inflammatory mediators generated in animals that have consumed high-fat diets, compared to control animals? Which of these inflammatory mediators generated by high-fat diets cause BBB instability, and does this affect neurons in the CNS? All of this information is relevant and should be included in the final version of the manuscript.
When authors discuss growth factors that induce neural plasticity, they should specify under what metabolic disease conditions these growth factor changes occur, and in which areas of the nervous system the plastic changes caused by these growth factors take place. They should also clarify whether the plastic changes are structural, functional, or both.
Are the intracellular pathways initiated by the authors in the manuscript activated or repressed in metabolic diseases? This information is relevant and should be discussed in relation to the stability of the blood-brain barrier, neural plasticity, and the influence of the gastrointestinal microbiota on these molecular changes.
Regarding diabetes mellitus, it remains unclear which cellular elements are responsible for the release of inflammatory mediators as a consequence of insulin resistance. This information is relevant and should be included in the final version of the manuscript. Furthermore, it should be indicated whether the described molecular changes correspond to the same cellular elements that exhibit insulin resistance, and how the gastrointestinal microbiota influences this insulin resistance and, indirectly, the aforementioned neural changes. More scientific evidence is needed to support this point.
What is the mechanism by which dyslipidemia generates the appearance of inflammatory mediators? What are these mediators generated by dyslipidemia? Is adipose tissue the main organ releasing these mediators in dyslipidemia? Please include this relevant information in the final version of the manuscript.
Section 3.1 lacks relevant information on the role of oxidative stress in different pathologies and on neuroinflammation. Evidence demonstrating the involvement of the gastrointestinal microbiota in these processes is also lacking.
Section 3.2 should indicate which alterations in the gastrointestinal microbiota population change with metabolic diseases, whether Firmicutes or Bacteroidetes increase or decrease, which chemical mediators secreted by this microbiota are modified in metabolic diseases, and how this influences the inflammatory process and oxidative stress. All this information is highly relevant, and the authors do not provide any scientific evidence.
In this section 3.2, the relationships between metabolic diseases, changes in gastrointestinal microbiota populations, and changes in the mediators generated by the microbiota (e.g., SCFAs) are lacking. In the second and subsequent paragraphs, the authors have attempted to provide information on this topic, but it is very superficial. More information, and in greater depth, is needed.
At the end of this section 3, a summary paragraph with the main evidence could be included.
Section 4 on antioxidant strategies seems correct to me, both in content and length.
It is difficult to understand why the authors include various nervous syndromes or degenerative diseases throughout the manuscript and link them to oxidative stress and neuroinflammation, but without associating them with potential changes induced by mediators secreted by the gastrointestinal microbiota, or with antioxidant treatments. Please provide more scientific evidence to support these associations.

See major comments

Author Response

The manuscript requires modifications to improve its quality:

In the introduction section, the authors should explain why a review on this topic is necessary, given that similar reviews have already been published. What is the novelty and scientific relevance of this review compared to others already published? (e.g., J Adv Res. 2021 Sep 17;38:223-244; Cell Mol Life Sci. 2024 Dec 5;81(1):480; Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016 Dec;160(4):461-466; Oxid Med Cell Longev. 2018 Dec 9;2018:2406594; among others). Please include this information in the final version of the manuscript.

RESPONSE: We sincerely appreciate the relevant references you have provided. Our manuscript was conceived to address a specific gap that is not fully integrated in the cited literature. In particular, the referenced reviews primarily focus on aspects such as the interaction between microbiota and oxidative stress in neurodegeneration and neuroprotection, the role of microbiota in renal fibrosis, or the influence of diet and dysbiosis in inflammatory bowel disease. While these studies provide important background, they do not centrally address oxidative stress as a common pathophysiological axis linking metabolic diseases, dysbiosis, and neuroinflammation, nor do they integrate antioxidant strategies within a unified mechanistic and therapeutic framework.

The novelty of our manuscript lies in the integration of two key components into a single conceptual framework: (1) oxidative stress as a shared mechanistic axis underlying metabolic diseases—including obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome—microbiota–gut–brain axis dysfunction, and neuroinflammation; and (2) the analysis of antioxidant interventions with potential therapeutic relevance. Furthermore, rather than merely describing associations, our review organizes the evidence around specific molecular mechanisms, including LPS/TLR4, NF-κB, NLRP3, ROS, NOX4, SCFAs and the Keap1-Nrf2 pathway, with particular emphasis on their roles in metabolic pathophysiology and their relevance as potential targets for intervention, including both antioxidant compounds and beneficial microorganisms.

2. In Section 3 of the manuscript, the authors must specify the metabolic diseases on which the review focused and explain why these diseases were chosen over others. This information is crucial and must be included in the final version of the manuscript.

RESPONSE: The selection of these metabolic diseases is justified by their high prevalence, frequent coexistence, and the fact that they share key pathophysiological mechanisms, including low-grade chronic inflammation, oxidative stress, endothelial dysfunction, and alterations in the gut microbiota. These shared features make them particularly relevant for the study of the microbiota–gut–brain axis and neuroinflammation. In response to your valuable comment, we have incorporated this information into the Introduction section.

3. Oxidative stress is one of the molecular processes involved in neuroinflammation, but it is not the only one. The authors should indicate whether other processes, such as changes in cytokines/chemokines, changes in extracellular ion levels, and changes in the levels of other chemical mediators, influence neuroinflammation, and whether these changes are affected by gastrointestinal microbiota dysbiosis in metabolic diseases. This relevant information should be included in Section 3 of the manuscript.

RESPONSE: We appreciate your valuable suggestion and have incorporated the requested information into Section 3, including additional mechanisms involved in neuroinflammation, such as alterations in cytokines and chemokines, extracellular ion balance, and other chemical mediators. In addition, their potential modulation by gut microbiota dysbiosis in metabolic diseases was investigated.

4. In Section 3.1, the authors should elaborate on how chemical mediators generated by metabolic disease (specify disease and chemical mediator) influence the stability of the blood‒brain barrier. Establishing this relationship is essential for this review. Include this information in the final version of the manuscript.

RESPONSE: Section 3.1 has been expanded to provide a more detailed explanation of how specific chemical mediators associated with each metabolic disease influence the stability of the blood–brain barrier, as suggested.

5. In Section 3.1, the authors should also explain how gliosis compromises the stability of the blood‒brain barrier. Include this information in the final version of the manuscript.

RESPONSE: We have expanded Section 3.1 to clarify that gliosis not only results from blood–brain barrier (BBB) dysfunction but also contributes to its destabilization. Specifically, we have shown that persistent activation of microglia and astrocytes amplifies local inflammatory signaling and oxidative stress within the neurovascular unit, thereby reinforcing endothelial dysfunction and further compromising BBB integrity.

6. What is the mechanism by which adipokines and cytokines released by visceral adipose tissue trigger blood‒brain barrier instability? The authors should provide scientific evidence for this and explain the mechanisms involved in detail.

RESPONSE: We have expanded the obesity subsection in Section 3.1 to provide a more detailed explanation of how adipokines and cytokines released by visceral adipose tissue contribute to blood–brain barrier instability, supported by relevant scientific evidence, as suggested.

7. Why is the hypothalamus sensitive to adipokines/cytokines from visceral adipose tissue? Authors should include scientific evidence that these adipokines/cytokines from visceral adipose tissue influence the physiology of hypothalamic neurons.

RESPONSE: We explain this mechanism in Section 3. In summary, the hypothalamus is sensitive to adipokines due to its exposure to blood circulation and the abundant presence of receptors for pro-inflammatory adipokines such as leptin, acting through specialized neurons that regulate appetite and satiety. We appreciate your feedback, as this aspect was not explained in detail in the initial version and is important for understanding the manuscript.

8. The authors provide evidence for the effects of high-lipid diets, but not for adipokines/cytokines released by visceral adipose tissue. The effects of diets cannot be extrapolated to the effects of adipose tissue on the hypothalamus. What is the level of pro-inflammatory mediators generated in animals that have consumed high-fat diets, compared to control animals? Which of these inflammatory mediators generated by high-fat diets cause BBB instability, and does this affect neurons in the CNS? All of this information is relevant and should be included in the final version of the manuscript.

RESPONSE: We thank you for this important observation. In the revised manuscript, we have expanded Section 3.1 to clearly differentiate between the endocrine role of visceral adipose tissue and the experimental evidence derived from high-fat diet (HFD) models.

9. When authors discuss growth factors that induce neural plasticity, they should specify under what metabolic disease conditions these growth factor changes occur, and in which areas of the nervous system the plastic changes caused by these growth factors take place. They should also clarify whether the plastic changes are structural, functional, or both.

RESPONSE: We have addressed this important point by specifying the metabolic disease conditions under which these growth factor changes occur, as well as the regions of the nervous system involved, and clarifying whether the resulting plastic changes are structural, functional, or both, as suggested.

10. Are the intracellular pathways initiated by the authors in the manuscript activated or repressed in metabolic diseases? This information is relevant and should be discussed in relation to the stability of the blood‒brain barrier, neural plasticity, and the influence of the gastrointestinal microbiota on these molecular changes.

RESPONSE: In metabolic diseases such as obesity, diabetes mellitus, and dyslipidemia, neuroinflammation-related mechanisms are activated, and the brain’s response mechanisms to limit inflammation are diminished, as neuroprotective and immunomodulatory strategies are not usually implemented. Neuroinflammation accompanies the patient as the disease progresses and can only be slowed down through lifestyle changes, supplementation, reduction of visceral fat, and improvement of the gut microbiota.

11. Regarding diabetes mellitus, it remains unclear which cellular elements are responsible for the release of inflammatory mediators as a consequence of insulin resistance. This information is relevant and should be included in the final version of the manuscript. Furthermore, it should be indicated whether the described molecular changes correspond to the same cellular elements that exhibit insulin resistance, how the gastrointestinal microbiota influences this insulin resistance and, indirectly, the aforementioned neural changes. More scientific evidence is needed to support this point.

RESPONSE: We appreciate your comment. As you indicate, it is important to clarify these associations, as they underpin not only this review but also its potential to promote further research and to identify possible therapeutic targets, particularly in the context of the increasing global prevalence of diabetes mellitus.

12. What is the mechanism by which dyslipidemia generates the appearance of inflammatory mediators? What are these mediators generated by dyslipidemia? Is adipose tissue the main organ releasing these mediators in dyslipidemia? Please include this relevant information in the final version of the manuscript.

RESPONSE: We have expanded the dyslipidemia subsection in Section 3.1 to explain the mechanisms by which dyslipidemia promotes the generation of inflammatory mediators, as suggested.

13. Section 3.1 lacks relevant information on the role of oxidative stress in different pathologies and on neuroinflammation. Evidence demonstrating the involvement of the gastrointestinal microbiota in these processes is also lacking.

RESPONSE: We thank you for this comment and agree that the link between oxidative stress, microbiota, and neuroinflammation is central to this work. Although this information is discussed in detail in Section 3.2 and illustrated in Figure 1, we have inserted a connecting paragraph in Section 3.2.

14. Section 3.2 should indicate which alterations in the gastrointestinal microbiota population change with metabolic diseases, whether Firmicutes or Bacteroidetes increase or decrease, which chemical mediators secreted by this microbiota are modified in metabolic diseases, and how this influences the inflammatory process and oxidative stress. All this information is highly relevant, and the authors do not provide any scientific evidence.

RESPONSE: We appreciate your valuable feedback and have incorporated the requested information into Section 3.2, as suggested.

15. In this Section 3.2, the relationships between metabolic diseases, changes in gastrointestinal microbiota populations, and changes in the mediators generated by the microbiota (e.g., SCFAs) are lacking. In the second and subsequent paragraphs, the authors have attempted to provide information on this topic, but it is very superficial. More information and in greater depth is needed.

RESPONSE: As mentioned earlier, Section 3.2 has been restructured to provide a more in-depth discussion of changes in microbial populations and their relationship to obesity, as suggested.

16. At the end of this Section 3, a summary paragraph with the main evidence could be included.

RESPONSE: We have added a summary paragraph at the end of Section 3 to highlight the main evidence, as suggested.

17. Section 4 on antioxidant strategies seems correct to me, both in content and length.

RESPONSE: We appreciate your positive feedback. However, we have added additional information to Section 4.3 in response to the suggestions of Reviewers 1 and 3.

18. It is difficult to understand why the authors include various nervous syndromes or degenerative diseases throughout the manuscript and link them to oxidative stress and neuroinflammation, but without associating them with potential changes induced by mediators secreted by the gastrointestinal microbiota, or with antioxidant treatments. Please provide more scientific evidence to support these associations.

RESPONSE: In response to your feedback, Section 3 has been restructured to include only the essential information necessary to understand the relationship between oxidative stress and neuroinflammation, avoiding extensive descriptions of neurological syndromes that do not directly contribute to the objective of the manuscript. This approach was adopted because the strongest evidence linking oxidative stress, neuroinflammation, and potential therapeutic interventions primarily derives from studies in neurodegenerative diseases. Therefore, these contexts were used to support the mechanisms discussed and to demonstrate the plausibility of the proposed antioxidant strategies. This rationale has also been clarified at the beginning of Section 4.3.

Additionally, the connection with the gut–brain axis has been strengthened by incorporating evidence linking microbiota-derived mediators to inflammatory and oxidative processes in the nervous system. This provides a clearer justification for the potential use of antioxidant therapies, including both bioactive compounds and bacteria with antioxidant capacity.

We thank you for your careful evaluation and valuable feedback, which have been instrumental in improving the quality and coherence of our manuscript.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

I have reviewed the revised version of your manuscript. I am pleased to say that you have thoroughly addressed all the comments and suggestions I raised in my previous review. I have no further technical or editorial concerns. Therefore, I am happy to recommend acceptance of your manuscript in its current form.

The revisions have significantly improved the clarity, depth, and balance of the review. In particular, the expanded mechanistic discussion on the interplay between dysbiosis, oxidative stress, and neuroinflammation, as well as the more critical evaluation of antioxidant and probiotic interventions, now make the manuscript suitable for publication.

Reviewer 3 Report

The author has already made excellent revisions to all the issues. I have no further questions.

None

Reviewer 4 Report

The authors have significantly improved the manuscript, as they have added relevant information.