The Gut–Brain Axis in Schizophrenia: A Systems-Level Understanding of Psychiatric Illness

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Comments on the applied microbiology paper

• You said (Alterations in gut microbial composition are now believed to influence brain

 function through immune modulation, neuroinflammatory pathways) What is the difference between immunomodulation and neuroinflammatory pathways? 

 

• You stated that dysbiosis contributes to the possible cause of schizophrenia. I am asking if schizophrenia may be the cause of gut dysbiosis. yes, there is an association, but the cause-and-effect relation is not decisive
• You mentioned that a leaky intestine is responsible for brain injury in schizophrenia. Have you checked for papers testing blood levels of serotonin, fatty acids, and metabolites related to dysbiosis?

Author Response

Dear Editor and Reviewer 1,

Thank you for your thoughtful and constructive feedback on our manuscript, “The Gut–Brain Axis in Schizophrenia: A Systems-Level Understanding of Psychiatric Illness.” We greatly appreciate the opportunity to revise our work and have carefully addressed each of your comments to strengthen the manuscript. Please find them summarized below.

 

Reviewer Comment 1:
“You said, ‘Alterations in gut microbial composition are now believed to influence brain function through immune modulation, neuroinflammatory pathways.’ What is the difference between immunomodulation and neuroinflammatory pathways?”

Response:
Thank you for raising this important distinction. To improve conceptual clarity, we revised the Introduction (Section 1, paragraph 2) to clearly differentiate between these mechanisms. We now clarify that:

“Immune modulation involves systemic immune alterations driven by microbial metabolites such as short-chain fatty acids (SCFAs), whereas neuroinflammatory pathways refer to direct inflammatory processes within the central nervous system (CNS).”

Location: Page 2, Section 1 (Introduction), Paragraph 2, Lines 53–57.

 

Reviewer Comment 2:
“You stated that dysbiosis contributes to the possible cause of schizophrenia. I am asking if schizophrenia may be the cause of gut dysbiosis. Yes, there is an association, but the cause-and-effect relation is not decisive.”

Response:
We fully agree with this point. In response, we revised language throughout the manuscript to avoid implying causality. These changes better reflect the current state of evidence and address the reviewer’s concern.

Location: Throughout the revised manuscript.

Reviewer Comment 3:
“You mentioned that a leaky intestine is responsible for brain injury in schizophrenia. Have you checked for papers testing blood levels of serotonin, fatty acids, and metabolites related to dysbiosis?”

Response:
Thank you for this valuable suggestion. We have expanded Section 4.5 (Metabolite and Biomarker Evidence) to include recent studies, specifically Qi et al. (2024) and Ghorbani et al. (2024) that report altered serum levels of serotonin, dopamine, BDNF, glutamate, and fatty acids in patients with schizophrenia. A thorough discussion is done on their levels in the blood and the significance they may have when considered with the rest of the body. Furthermore, what may be the reasons for their elevation or depletion in the body in schizophrenic patients.

Location: Page 5-6, lines 217-234

 

We believe these revisions significantly improve the clarity, precision, and scientific rigor of the manuscript. For further details regarding changes made according to the suggested edits, please see the yellow highlighted sections in the revised manuscript. We are grateful for your insightful feedback and for the opportunity to revise and resubmit our work. Thank you greatly once again.

Sincerely,
Haadiya Chaudhry
On behalf of all co-authors

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Suggestions for the Authors:

1. Lines 85-86: Please pay attention to how you cite references.
2. Throughout the text, I suggest making a clearer distinction between correlational and causative findings. Sometimes, without enough experimental support, relationships are presented in a way that could be mistaken for causation.
3. In the field, the definition of dysbiosis is still ambiguous. To prevent ambiguity, the manuscript might benefit from a more detailed operational definition or set of criteria.
4. It would be beneficial to provide information about the probiotic strains and dosages utilized in the major clinical trials covered in the section on microbiome-targeted medicines, along with the length of time these interventions lasted.

Questions for the authors:

1. How do the authors understand the significance of Lactobacillus species in schizophrenia, considering the inconsistent findings across studies? Could it be influenced by contextual factors like dietary habits, medication status, or particular bacterial subtypes?
2. Do the authors see a future for personalized microbiome-based therapies (e.g., targeted to symptom clusters, drug resistance, or specific dysbiotic patterns) given the substantial interindividual heterogeneity in microbiome composition and response to treatment?

Author Response

Dear Editors and Reviewer,

We would like to extend our sincere thanks for your detailed and thoughtful feedback on our manuscript titled “The Gut–Brain Axis in Schizophrenia: A Systems-Level Understanding of Psychiatric Illness.” Your insights were immensely helpful in refining and strengthening the manuscript. We have carefully addressed each of your comments, and the revisions have improved the precision, clarity, and scientific rigor of the work.

Below, we provide a point-by-point summary of the changes made in direct response to your suggestions, along with specific locations in the revised manuscript.

 

1. Reviewer Comment: “Lines 85-86: Please pay attention to how you cite references”
   
   

Response: All in-text citations have been revised to comply with the journal’s formatting style. We ensured consistent use of brackets and citation groupings (e.g., “[2,3]” instead of “[Author name, date]”) throughout the manuscript.
Location: Changes are applied globally.

 

2. Reviewer Comment: “Throughout the text, I suggest making a clearer distinction between correlational and causative findings. Sometimes, without enough experimental support, relationships are presented in a way that could be mistaken for causation.”
   
   

Response: We have revised multiple statements to accurately reflect observational data and avoid overstating causality. For instance, we now use phrasing such as “associated with” or “may contribute to” rather than definitive causal language.
Location: Edits made across Sections 2–4 (Lines 115–390), particularly in discussions of SCFAs, neurotransmitter modulation, and microbial composition.

 

3. Reviewer Comment: “In the field, the definition of dysbiosis is still ambiguous. To prevent ambiguity, the manuscript might benefit from a more detailed operational definition or set of criteria.”

Response: A refined definition has been incorporated into Section 3, characterizing dysbiosis as a deviation from an individual’s baseline microbiota profile, marked by reduced SCFA-producing species (e.g., Faecalibacterium, Roseburia) and an increase in pro-inflammatory microbes (e.g., Eggerthella).
Location: Lines 120-123.

 

4. Reviewer Comment: “It would be beneficial to provide information about the probiotic strains and dosages utilized in the major clinical trials covered in the section on microbiome-targeted medicines, along with the length of time these interventions lasted.”

Response: Both the Therapeutic Implications section and Appendix A.2 now contain detailed strain-specific data, including Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB12, with dosage and treatment duration.  
Location: Appendix A.2 and Section 5 (Lines 256–333).

 

5. Reviewer Comment: “How do the authors understand the significance of Lactobacillus species in schizophrenia, considering the inconsistent findings across studies? Could it be influenced by contextual factors like dietary habits, medication status, or particular bacterial subtypes?”
   
   

Response: We expanded our discussion to include nuance around strain-specific effects, noting that Lactobacillus species may exhibit both beneficial and pro-inflammatory properties. Factors such as antipsychotic medication and diet are also considered in the significance of Lactobacillus bacteria in the gut microbiome for individuals with schizophrenia.
Quote from manuscript:

“The role of Lactobacillus species in schizophrenia remains uncertain, with studies showing mixed results. While some of the research reports improvement in inflammation or symptoms, others find minimal or no therapeutic benefit. We think that these inconsistencies may reflect the influence of contextual factors like diet, medication and bacterial strain differences between individuals.”
Location: Lines 491-500

 

6. Reviewer Comment: “Do the authors see a future for personalized microbiome-based therapies (e.g., targeted to symptom clusters, drug resistance, or specific dysbiotic patterns) given the substantial interindividual heterogeneity in microbiome composition and response to treatment?”

Response: We now address this explicitly in Section 5.4 and the Conclusion. We suggest that microbial profiling could be used to stratify patients by symptom domain, inflammation, or treatment response.
Quote from manuscript:

“In the future, therapies should be personalized and microbiome-informed that consider symptom clusters, drug response profiles, and individual dysbiosis patterns. Personalized treatments will enable for healthcare practitioners to predict drug responses in the body. Given up to 30% of patients fail to respond to antipsychotic therapy”
Location: Lines 430-445.

 

We are truly grateful for your careful reading and insightful suggestions, which have strengthened the manuscript significantly. For further information regarding the changes made to manuscript according to your suggestions, please refer to the green highlighted sections in the revised manuscript. We hope the revised version now meets the standards for publication and offers a clearer, more nuanced discussion of microbiome–brain interactions in schizophrenia.

Sincerely,
Haadiya Chaudhry
On behalf of all co-authors

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript's focus on the role of the gut - brain axis in schizophrenia is well-placed and significant. Nevertheless, the manuscript requires considerable improvements before it is suitable for publication.

 

• The manuscript needs citation formatting revisions to comply with MDPI guidelines. Please switch from the current author - year style to a numeric citation  system (e.g. [1], [2]).
• The current reference list format doesn't align with MDPI's
• Ensure, that the references are numbered consecutively, reflecting the order in which they are cited in the manuscript.
• The manuscript would benefit from a broader range of sources, I recommend expanding the reference list to at least 100 sources, prioritizing recent publications from the last 2-3 years.
• The manuscript's readability and clarity could be enhanced by incorporating visual elements, I recommend including figures and tables to illustrate complex relationships and mechanisms. Specifically, consider adding a schematic of the gut - brain axis, a visual representation of microbiome - schizophrenia links, a table comparing microbial composition, and a table summarizing clinical trials.
• While the manuscript covers relevant topics, it needs to go beyond a superficial presentation, The analysis should be deepened, and repetitive concepts should be addressed with more nuance and differentiation across sections.
• The manuscript should provide a more detailed and clear explanation of the specific mechanisms through which microbiome disturbances influence schizophrenia symptoms. This includes a deeper exploration of SCFAs, tryptophan/kynurenine pathways, and neurotransmitter signaling.
• The therapeutic implications and interventions section should be expanded to provide a clearer and more detailed overview of the diverse range of microbiome - based strategies. Please explicitly differentiate between probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation.
• The manuscript requires reorganization to improve the flow of information and reduce redundancy. Each section should build logically on the previous one, creating a clear and cohesive narrative for the reader.

Recommendation
Overall, I recommend a major revision of the manuscript. Addressing the issues discussed above is essential to strengthen the manuscript's clarity, scientific depth, and adherence to journal expectations With thorough revisions, this manuscript could become a valuable addition to the field's literature.

Author Response

Dear Reviewer,

We would like to extend our sincere thanks for your detailed and thoughtful feedback on our manuscript titled “The Gut–Brain Axis in Schizophrenia: A Systems-Level Understanding of Psychiatric Illness.” Your insights were immensely helpful in refining and strengthening the manuscript. We have carefully addressed each of your comments, and the revisions have improved the precision, clarity, and scientific rigor of the work.

Below, we provide a point-by-point summary of the changes made in direct response to your suggestions, along with specific locations in the revised manuscript.

 

1. Comment: “The manuscript needs citation formatting revisions to comply with MDPI guidelines. Please switch from the current author - year style to a numeric citation system (e.g. [1], [2]). The current reference list format doesn't align with MDPI's. Ensure, that the references are numbered consecutively, reflecting the order in which they are cited in the manuscript.

Response: We have revised the manuscript to comply with MDPI’s numeric citation style. All in-text citations have been updated accordingly, and the reference list has been reordered to reflect the new numbering.
Location: Applied throughout the manuscript.

 

2. Comment: “Expand the reference list to at least 100 sources, prioritizing recent publications.”
   
   

Response: We truly value the feedback, and the reference list has been expanded from 24 to 66 sources. We prioritized literature published between 2021 and 2025 to better reflect recent developments in microbiome–schizophrenia research. While we did not reach 100 citations, the expansion substantially by almost three-fold broadened the scope without compromising the perspective article format.

 

3. Comment: The manuscript's readability and clarity could be enhanced by incorporating visual elements, I recommend including figures and tables to illustrate complex relationships and mechanisms. Specifically, consider adding a schematic of the gut - brain axis, a visual representation of microbiome - schizophrenia links, a table comparing microbial composition, and a table summarizing clinical trials.
   
   

Response: We opted not to include schematic figures, as although their inclusion would undoubtedly enhance understanding of the gut-brain axis, we felt they would shift the focus from understanding the gut microbiome’s impact on schizophrenia to the underlying mechanism. Furthermore, the tone of the manuscript may shift towards a review article. We are more than open to further discussion and deliberation on whether to include a schematic should it still be advised upon further review. We have added two detailed tables in the appendix as advised:

• Appendix A.1 summarizes compositional differences in the microbiota of individuals with schizophrenia compared to controls.
• Appendix A.2 provides a structured summary of clinical and preclinical studies involving microbiome-targeted interventions.

Location: Appendix A.1 and A.2 (pages 13–14), referenced in

 

4. Comment: “The manuscript's readability and clarity could be enhanced by incorporating visual elements, I recommend including figures and tables to illustrate complex relationships and mechanisms. Specifically, consider adding a schematic of the gut - brain axis, a visual representation of microbiome - schizophrenia links, a table comparing microbial composition, and a table summarizing clinical trials”
   
   

Response: We revised the manuscript to improve analytical depth and minimize repetition. Specific changes include:

• Expanded analysis of the dual roles of Lactobacillus (page 5)
• Clearer delineation of microbial profiles across psychiatric disorders (pages 13–14)
• Consolidation of overlapping material on SCFAs and their pathways in Sections 4 and 5

Location: Sections 3–6 (pages 5–14), referenced in line 148 and 254 respectively.

 

5. Comment: “The manuscript should provide a more detailed and clear explanation of the specific mechanisms through which microbiome disturbances influence schizophrenia symptoms. This includes a deeper exploration of SCFAs, tryptophan/kynurenine pathways, and neurotransmitter signaling.”
   
   

Response: We significantly expanded Section 4 to clarify the role of microbial metabolites in schizophrenia. Notable additions include:

• The neuroprotective role of valeric and caproic acids (page 4)
• A more detailed explanation of the tryptophan-kynurenine pathway, alongside kynurenine metabolites and their impact on NMDA receptor activity (pages 6–7)
• Integration of microbial influence on GABA, dopamine, and glutamate signaling (pages 7–8)

Location: Section 4, Mechanistic Pathways (pages 4–8)

 

6. Comment: “The therapeutic implications and interventions section should be expanded to provide a clearer and more detailed overview of the diverse range of microbiome - based strategies. Please explicitly differentiate between probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation.”
   
   

Response: Section 5 was expanded and reorganized to offer a clearer breakdown of distinct intervention types:

• Subsections for probiotics, prebiotics, dietary strategies, and fecal microbiota transplantation (pages 6–10)
• Explained the differences between different modalities like probiotics and prebiotics thoroughly using evidence from studies describing their action in the gut microbiome.
• Inclusion of specific strains, treatment durations, clinical outcomes, and proposed mechanisms.
• Clearer differentiation between experimental versus more established approaches

Location: Section 5, Therapeutic Implications (pages 6-10)

 

7. Comment: “The manuscript requires reorganization to improve the flow of information and reduce redundancy. Each section should build logically on the previous one, creating a clear and cohesive narrative for the reader.”
   
   

Response: To improve clarity and narrative coherence, we:

• Streamlined transitions between sections to ensure that contents followed a logical progression of ideas.
• Reduced overlap between mechanistic and therapeutic discussions
• Refined topic sentences and bridging paragraphs to strengthen the conceptual flow

Location: throughout manuscript

We are truly grateful for your careful reading and insightful suggestions, which have strengthened the manuscript significantly. For further details regarding the changes made according to your suggestions, please find the teal highlighted sections in the article manuscript. We hope the revised version now meets the standards for publication and offers a clearer, more nuanced discussion of microbiome–brain interactions in schizophrenia.

Sincerely,
Haadiya Chaudhry
On behalf of all co-authors

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript has been significantly improved, and most of the reviewer’s comments have been addressed. I understand and respect the authors' rationale for not including figures, however, I do not fully agree with this reasoning. Including figures in a perspective article does not necessarily shift its nature toward a review article, and indeed, many excellent perspective articles published in top-tier journals routinely include illustrative figures.

I acknowledge the authors’ concern that adding detailed figures might overly emphasize mechanistic aspects. Therefore, I suggest incorporating a summarizing figure, specifically focusing on the gut microbiome’s impact on schizophrenia, similar in style and scope to a graphical abstract. Such a figure would enhance clarity and accessibility without altering the intended scope of the manuscript.

Nevertheless, in its current form, the manuscript fulfills publication requirements and is significantly closer to being ready for publication.

Author Response

Comment:
“The manuscript has been significantly improved, and most of the reviewer’s comments have been addressed. I understand and respect the authors' rationale for not including figures, however, I do not fully agree with this reasoning. Including figures in a perspective article does not necessarily shift its nature toward a review article, and indeed, many excellent perspective articles published in top-tier journals routinely include illustrative figures.

I acknowledge the authors’ concern that adding detailed figures might overly emphasize mechanistic aspects. Therefore, I suggest incorporating a summarizing figure, specifically focusing on the gut microbiome’s impact on schizophrenia, similar in style and scope to a graphical abstract. Such a figure would enhance clarity and accessibility without altering the intended scope of the manuscript.”

Response:
We sincerely appreciate the reviewer’s continued engagement and their thoughtful recommendation. In response, we have now included a summarizing figure (Figure 1) in the style of a graphical abstract, which visually outlines the key relationships between gut dysbiosis, systemic effects (e.g., neuroinflammation, neurotransmitter disruption), and schizophrenia symptom domains. Our goal was to enhance accessibility and clarity, while preserving the manuscript’s framing as a perspective piece.

We have also updated the manuscript to reference this figure in-text and included an appropriate figure caption to aid reader comprehension, and we remain open to feedback regarding the produced figure, and welcome suggestions to enhance its quality.

Thank you once again for your helpful suggestions and encouragement, 

Haadiya Chaudhry
On behalf of all authors