Dear Dr. Ullah,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Academic Editor:

Please review the comments by the reviewers carefully, please include their entire review in your "response to reviewers," and please address their comments in a point-by-point fashion.  I have carefully read your manuscript, their reviews, and I think that addressing their points will improve your study.

Additionally, on my review I found multiple points that should be addressed on the revision.

1) Ideally, all animal research should conform to ARRIVE guidelines (https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000410) Please incorporate these guidelines in your manuscript and I would strongly suggest attaching a completed guideline checklist as supplemental material.

2) How did you control for bias in your experimentations?  Was blinding used?  If so, please indicate when and where.  If not, please also detail this.

3) You seem to have exclusively used male animals.  Why is that?  At a minimum, the title should reflect this and you should state this in your study limitations.

4) Your discussion has no study limitations.  Traditionally, this would be the paragraph just before the conclusion where you outline all of the limitations to your study.  Please include this.

5) How did you control for confounders?  Please outline this in the methods.

6) In the results section, for comparisons, please list the F statistic for the group, and please list any p value for any comparison that you make.

7) In your figures, you compare the sham group to the TBI-control group, and you compare the TBI-control group to the TBI+multisensory stim group.  Please also show the comparisons between the sham group and the TBI+multisensory stim group.

8) At several points, you use the verb "expression" or the phrase "expression levels" in relation to mRNA.  This is confusing.  Protein is generally described as having expression levels.  For mRNA, please remove the term "expression."

==============================

Please submit your revised manuscript by Jan 09 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Eric Anthony Sribnick, MD, PhD, FAANS

Academic Editor

PLOS ONE

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Additional Editor Comments:

Academic Editor:

Please review the comments by the reviewers carefully, please include their entire review in your "response to reviewers," and please address their comments in a point-by-point fashion. I have carefully read your manuscript, their reviews, and I think that addressing their points will improve your study.

Additionally, on my review I found multiple points that should be addressed on the revision.

1) Ideally, all animal research should conform to ARRIVE guidelines (https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000410) Please incorporate these guidelines in your manuscript and I would strongly suggest attaching a completed guideline checklist as supplemental material.

2) How did you control for bias in your experimentations? Was blinding used? If so, please indicate when and where. If not, please also detail this.

3) You seem to have exclusively used male animals. Why is that? At a minimum, the title should reflect this and you should state this in your study limitations.

4) Your discussion has no study limitations. Traditionally, this would be the paragraph just before the conclusion where you outline all of the limitations to your study. Please include this.

5) How did you control for confounders? Please outline this in the methods.

6) In the results section, for comparisons, please list the F statistic for the group, and please list any p value for any comparison that you make.

7) In your figures, you compare the sham group to the TBI-control group, and you compare the TBI-control group to the TBI+multisensory stim group. Please also show the comparisons between the sham group and the TBI+multisensory stim group.

8) At several points, you use the verb "expression" or the phrase "expression levels" in relation to mRNA. This is confusing. Protein is generally described as having expression levels. For mRNA, please remove the term "expression."

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: This is an interesting and well-elaborated study investigating how food-based multisensory stimulation (visual, olfactory, and gustatory cues) modulates gut and brain inflammation following mTBI in rats. The work is original and methodologically solid, combining behavioral analysis, histopathology, microbiome profiling, and in vitro microglial assays. The concept — targeting the gut–brain axis (GBA) through sensory and nutritional stimulation — is novel and aligns with the growing interest in neurogastroenterology and predictive, preventive, and personalized medicine (PPPM).

However, some mechanistic links remain associative, and the translational dimension could be better developed. The manuscript would benefit from (1) clarifying causation versus correlation, (2) expanding on microbiome–brain mechanisms, including probiotic and prebiotic strategies, and (3) connecting experimental findings with clinical markers and evaluation methods of GBA dysfunction and visceral pain.

Major Comments

1. Causation versus correlation

The study convincingly shows that multisensory stimulation alters the intestinal microbiota, increases butyrate levels, and improves neurological and inflammatory outcomes.

However, causality between microbiome modulation and neuroinflammation reduction is not established. The language should be adjusted to avoid overinterpretation (“associated with” rather than “caused by”).

Recommendations:

Discuss or, if possible, perform experiments to test causality:

- Antibiotic depletion or fecal microbiota transfer (FMT) to determine if behavioral benefits depend on microbiota.

- Butyrate pathway perturbation (e.g., receptor antagonism or HDAC inhibition) to confirm mechanistic relevance.

- Time-course analysis to determine whether microbiome or SCFA changes precede neural improvements.

Include an explicit paragraph in the Discussion acknowledging these limitations and outlining future directions.

2. Clarification of mechanisms and butyrate relevance

The in vitro evidence showing butyrate’s anti-inflammatory effect on microglia is valuable but needs quantitative context.

Please:

Report absolute serum butyrate concentrations (µM) and compare them to the 5 mM concentration used in vitro.

Add information about SCFA quantification (LLOQ, sample stability).

Clarify that in vitro butyrate concentrations may exceed physiological levels.

3. Microbiome characterization

Microbiota analyses are limited to the genus level and lack functional insight.

Recommendations:

Provide an ASV/OTU-level differential table (with effect size and p-value) as Supplementary Data.

Add functional predictions (PICRUSt2 or similar) to infer butyrate-synthesis capacity.

Discuss specific taxa known to produce butyrate (e.g., Ruminococcus, Roseburia, Faecalibacterium) and their potential role.

4. Translational implications — personalized microbiome modulation

The translational potential is strong but underdeveloped. Authors should integrate evidence on strain-specific and personalized probiotic or prebiotic use.

Add a short subsection: “Translational implications: microbiome modulation.”

Suggested discussion points:

Strain-specific effects (e.g., Lactobacillus vs. Bifidobacterium spp.) and safety aspects (adhesion, resistance, fermentation patterns).

Personalized selection of probiotics/prebiotics based on host phenotype and microbiome composition.

- References to PPPM studies and consensus papers, for example:

Gibson GR et al., Nat Rev Gastroenterol Hepatol (2017). DOI: 10.1038/nrgastro.2017.75.

Reid G et al., Benef Microbes (2017). DOI: 10.3920/BM2016.0222.Bubnov R., Spivak M. (2023). Pathophysiology-Based Individualized Use of Probiotics and Prebiotics for Metabolic Syndrome. In Microbiome in 3P Medicine Strategies (Springer).

EPMA J (2018). https://pmc.ncbi.nlm.nih.gov/articles/PMC5972142/

These sources outline mechanisms for distant-site probiotic activity (gut–liver, gut–brain) and provide a framework for personalized microbiome therapies.

5. Integration of distant axes (gut–liver–brain and systemic effects)

The Discussion focuses on intestinal and brain findings but omits the gut–liver axis and systemic metabolic intermediates.

Please expand on how liver metabolism, vagal signaling, and systemic immune modulation may mediate brain protection.

6. Translational markers and clinical evaluation of the GBA

To bridge to clinical settings, authors should refer to measurable biomarkers and diagnostic tools used to evaluate GBA integrity and dysfunction.

Recommend adding:

Circulating and fecal SCFAs (butyrate, propionate, acetate).

Systemic inflammation and permeability markers (IL-6, TNF-α, CRP, LPS, zonulin).

CSF biomarkers (YKL-40, NfL, sTREM2) and autonomic indices (heart rate variability).

Visceral pain assessment methods (rectal/colonic barostat, validated visceral pain scales).

Possible myofascial and postural correlations in GBA disorders (constipation–motility–trigger point linkage, as in  [https://onlinelibrary.wiley.com/doi/10.1111/nmo.13671#nmo13671-sec-0439-title]).

Consider the role of central sensitization and CSF flow changes (e.g., Effects on Spinal Fluid Dynamics and Gut-Brain Axis Modulation in Migraine Patients with Central Sensitization Cephalalgia 2024, https://doi.org/10.1177/03331024241280496#sec-206).

These perspectives make the work more relevant to clinical neurology, gastroenterology, and rehabilitation.

Minor Comments

Revise figures to show time-course trends of SCFAs and inflammatory markers alongside behavioral recovery.

Report sample sizes and power calculation for behavioral and molecular endpoints.

Provide details of the multisensory environment (odorant composition, decibel level, exposure duration) to ensure reproducibility.

Deposit raw sequencing data (FASTQ) and GC–MS files in a public repository with accession numbers.

Ensure consistent terminology: “gut–brain axis” (GBA) throughout.

Conclusion and Recommendation

The manuscript presents valuable and innovative research connecting sensory stimulation, microbiome modulation, and neuroinflammation.

However, to reach publication standard in PLOS ONE, the authors should address the mechanistic and translational limitations detailed above.

I recommend major revision with the following priorities:

Clarify causation and avoid overinterpretation.

Expand mechanistic discussion of SCFA and microbiome functions.

Include a translational section on probiotics/prebiotics and personalized strategies.

Discuss clinical and physiological markers of gut–brain axis function.

Once these revisions are implemented, the study will provide an important contribution to the growing field of microbiome–neuroinflammation interaction and personalized therapeutic strategies.

Reviewer #2: This manuscript presents a promising approach to treating cognitive impairment after mild traumatic brain injury using food-based multisensory stimulation. The in vivo work is generally well-executed with comprehensive behavioral, microbiome, and histological analyses that convincingly demonstrate therapeutic benefits. However, the study suffers from several critical weaknesses.

1. The planning of the cognitive experiments (Morris water and nort) in the early post-TBI days may be confounded by sensorimotor impairments and neurological severity, making it difficult to accurately assess cognitive function. The authors should clarify how they accounted for this potential confound.

2. The introduction should be revised to clearly and concisely address the gut–brain connection in mTBI, the associated cognitive impairments, and the rationale for exploring food-based interventions in TBI (PMID: 36481824, 39751900).

3. What was the exact timeline for all the experiments in sequence? A study design figure depicting the time should be made.

4. For the estimation of NSE and S-100β, the same animals were used for different timepoints or different animals, and this should be clearly stated in the methods section.

5. Interventions commenced immediately post-injury and continued for seven days, operating around the clock. But there is no rationale for why 7 days were chosen. No citation of previous multisensory stimulation studies using this duration. No pilot data mentioned. No dose-finding or optimization experiments. The choice appears arbitrary.

6. Also 7 days captures only the acute phase, Gut microbiome remodeling typically takes 2-4 weeks to stabilize

7. The idea of this work revolves around the food based multisensory stimulation. So, was the amount of food consumed by each animal noted throughout the study plan, and what about the weight of the animals data?

8. In the relative mRNA expression results, what is ACTB?

9. The Nissl-positive area has significantly improved in the food-based multisensory group in the CTX and CA3 regions, but not in the CA1 region. What could be the reason?

10. Was an established protocol followed for conducting the behavioral experiments? The method used for calculating the Discrimination Index appears to be adapted from previously published protocols, and therefore, relevant literature should be referenced (e.g., PMID: 38423243).

11. Please clarify how the food items (pet biscuits, chicken jerky) were selected and provide their nutritional composition. Also specify whether the scents were standardized, the concentrations used, and the volume/intensity of the chewing sounds. Indicate whether rats had physical access to the food or only sensory exposure. A brief, detailed protocol describing all stimulus parameters (duration, concentration, intensity) and a simple methods figure of the setup would improve clarity.

12. While the in vitro data (Fig. 4O) shows anti-inflammatory effects of butyrate, it does not establish that butyrate mediates the in vivo cognitive benefits of sensory stimulation; the authors should either include a butyrate-only or butyrate-blockade group, or clearly acknowledge this limitation in the discussion.

13. With numerous outcome measures across multiple timepoints and tissue types, correction for multiple comparisons should be applied or justified if not applied

14. A sensory stimulation + sham injury group would help determine if the intervention affects healthy animals or is specific to mTBI pathology. Either add this control group or explicitly discuss this limitation and its implications for interpreting the specificity of the intervention.

15. The correlation between specific taxa and SCFAs is interesting, but doesn't prove causality. Consider softening language.

16. The differential effects across brain regions (cortex and CA3 protected, CA1 not protected) are intriguing but underexplored. Discuss potential mechanisms for regional specificity. Could it relate to differential expression of SCFA receptors (GPR41, GPR43) or regional vulnerability to the injury model?

17. Abstract: "may be associated" and "possibly promoting" are appropriately cautious but could be stronger given your data. Consider removing some hedging language where data directly support conclusions

18. Methods section numbering is inconsistent (2.4 appears twice)

19. What was the microglial cell source, primary cells? (from rats? mice?) or Cell line? (BV2? N9? …..)

20. Consider discussing the acute (7-day) vs. chronic nature of the intervention and whether effects would persist after cessation

21. In Figure 3, HE staining images need scale bars. Quantification of villus height, crypt depth, or villi to crypt ratio and goblet cell density would strengthen conclusions.

22. Figure 4 is dense with information, consider splitting it into two figures. The correlation heatmap needs clearer labeling

23. Could isoflurane exposure affect gut microbiota? Did sham animals receive equivalent anesthesia duration?

24. How were fecal samples collected to avoid environmental contamination? Were samples from individual pellets or the cage floor?

25. Only male rats were used. Justify this choice and discuss how results might differ in females, given known sex differences in TBI outcomes and microbiome composition.

26. Were animals group housed or single housed? This significantly affects the microbiome.

27. The sample size for each experiment and each group should be indicated in the figure legends to ensure transparency, rigor, and reproducibility of the data.

28. Consider revisiting the manuscript to avoid typos and grammatical errors.

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Reviewer #1: Yes: Rostyslav Bubnov

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Comments PONE-D-25-51866.docx

Dear Dr. Ullah,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Mar 13 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Eric Anthony Sribnick, MD, PhD, FAANS

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Additional Editor Comments:

Academic Editor:

Thank you for diligently answering the reviewers' questions. Please see additional concerns from me: please my review in your "response to reviewers," and please address these comments in a point-by-point fashion. I have carefully read your manuscript, their reviews, and I think that addressing their points will improve your study.

1) I still don't see the filled out ARRIVE guidelines sheet. I see only the supplementary figures and the raw data as supplementary material.

2) In regards to the request: "In the results section, for comparisons, please list the F statistic for the group, and

please list any p value for any comparison that you make." You responded regarding concerns for space/word limitation. As PLOSone is only online, there is no specific word limit. Again, please list the F statistic for the group, and please list any p value for any comparison that you make. Thank you.

3) In your figures, you compare the sham group to the TBI-control group, and you compare the TBI-control group to the TBI+multisensory stim group. Please also show the comparisons between the sham group and the TBI+multisensory stim group. When using multiple groups for an experiment, you cannot arbitrarily decide which groups to use for multiple comparisons. Please include this analysis as requested.

Best regards,

Eric Sribnick, MD, PhD

Academic Editor

PLOS One

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Food-Based Multisensory Stimulation Ameliorates Cognitive Impairment After Mild Traumatic Brain Injury in Male Rats by Modulating Intestinal and Brain Inflammation

PONE-D-25-51866R2

Dear Dr. Ullah,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Eric Anthony Sribnick, MD, PhD, FAANS

Academic Editor

PLOS One

Additional Editor Comments (optional):

Authors have made the requested revisions.

Reviewers' comments: