Peripheral Surgical Interventions and Psychiatric Outcomes: A Systematic Review of Gut-Brain-Immune Axis Mechanisms

Peripheral Surgical Interventions and Psychiatric Outcomes: A Systematic Review of Gut-Brain-Immune Axis Mechanisms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Peripheral Surgical Interventions and Psychiatric Outcomes: A Systematic Review of Gut-Brain-Immune Axis Mechanisms Ishan Abbasi, Yousra Iftequar, Aryan Shailesh Nainani, Sharvari Vikram Joshi, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7818982/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The gut-brain-immune axis has emerged as a potential mediator in the development of psychiatric disorders. This systematic review examines associations between peripheral surgical interventions and psychiatric outcomes, with emphasis on potential underlying mechanisms involving microbiota, immune function, and neural signaling. Methods We conducted a systematic review following PRISMA guidelines, searching PubMed, EMBASE, and Cochrane databases from inception to May 2024. Studies examining associations between peripheral surgical procedures (appendectomy, vagotomy, tonsillectomy) and psychiatric outcomes were included. Risk of bias was assessed using appropriate tools for each study design. Results Eleven studies met inclusion criteria, including two large population-based cohort studies, one randomized controlled trial, and several mechanistic studies. Childhood appendectomy was associated with increased risk of mood disorders (adjusted hazard ratio [aHR] 1.19, 95% CI: 1.15–1.23) and anxiety disorders (aHR 1.20, 95% CI: 1.16–1.24), but not schizophrenia or obsessive-compulsive disorder. Truncal vagotomy was associated with mental health disorders (hazard ratio 1.22, 95% CI: 1.08–1.38), while selective vagotomy was not. Mechanistic studies identified alterations in inflammatory markers (TNF-α, IL-6), gut barrier function, and vagal signaling as potential mediators. Conclusions Limited evidence suggests that peripheral surgical interventions may be associated with increased risk of certain psychiatric disorders, possibly through gut-brain-immune axis mechanisms. However, the observational nature of most studies precludes causal inferences. The evidence base remains insufficient for clinical recommendations, particularly regarding obsessive-compulsive disorder and schizophrenia. Future research should focus on prospective studies with standardized biomarker assessments and longer follow-up periods. Surgery gut-brain axis appendectomy vagotomy psychiatric disorders microbiome neuroinflammation Figures Figure 1 Figure 2 Figure 3 1. INTRODUCTION Mental health disorders represent a significant global health burden, affecting approximately one billion people worldwide and contributing substantially to disability-adjusted life years (DALYs)¹. Among these, schizophrenia affects approximately 1% of the global population and ranks among the leading causes of disability worldwide². Obsessive-compulsive disorder (OCD), with lifetime prevalence estimates between 1–3%, causes significant functional impairment through persistent intrusive thoughts and compulsive behaviors³. Traditionally, psychiatric disorders have been understood primarily in terms of central nervous system dysfunction. However, emerging research has highlighted the importance of peripheral factors, particularly the gut-brain-immune axis, in mental health regulation⁴. This bidirectional communication network involves neural, hormonal, and immune pathways connecting the gastrointestinal tract with the central nervous system⁵. The gut microbiota, comprising trillions of microorganisms residing in the gastrointestinal tract, plays crucial roles in host physiology, including immune system modulation, neurotransmitter synthesis, and inflammation regulation⁶. Disruptions to this ecosystem, termed dysbiosis, have been implicated in various psychiatric conditions⁷. Recent evidence suggests alterations in gut and oral microbiomes in schizophrenia, particularly during neurodevelopment⁸. Similarly, preliminary studies in OCD have identified potential microbial contributions to disorder pathogenesis⁹. These findings have generated interest in understanding how peripheral interventions, including surgical procedures affecting gut physiology, might influence psychiatric outcomes. Surgical procedures such as appendectomy and vagotomy directly impact gut-associated lymphoid tissue and neural signaling pathways, respectively¹⁰. The appendix contains substantial gut-associated lymphoid tissue and serves as a reservoir for beneficial bacteria¹¹. Vagotomy disrupts the vagus nerve, a key component of gut-brain communication¹². Understanding whether these interventions influence long-term psychiatric risk could have important clinical implications. This systematic review aims to synthesize current evidence examining associations between peripheral surgical interventions and psychiatric outcomes, with particular attention to potential mechanisms involving the gut-brain-immune axis. 2. METHODS 2.1 Protocol This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹³.. 2.2 Search Strategy We conducted comprehensive searches of PubMed, EMBASE, Cochrane Library, and Web of Science databases. Search strategies were developed using Medical Subject Headings (MeSH) and keywords related to surgical interventions, psychiatric outcomes, and gut-brain axis mechanisms. 2.3 Eligibility Criteria Inclusion criteria : Studies examining associations between peripheral surgical interventions (appendectomy, vagotomy, tonsillectomy, or other gut-related procedures) and psychiatric outcomes. Human observational studies (cohort, case-control, cross-sectional) and experimental studies. Studies reporting quantitative measures of association or biological markers. Peer-reviewed publications in English. Studies published from 2010 onwards to capture recent advances in gut-brain axis research. Exclusion criteria : Studies not reporting psychiatric outcomes as primary or secondary endpoints. Case reports, editorials, commentaries, or conference abstracts. Studies examining only surgical complications or short-term postoperative outcomes. Animal studies (included separately for mechanistic insights but not in primary analysis). 2.4 Study Selection Two reviewers independently screened titles and abstracts, followed by full-text review of potentially eligible articles. Disagreements were resolved through discussion with a third reviewer. 2.5 Data Extraction Data were extracted using standardized forms including: Study characteristics (design, setting, sample size, follow-up duration) Population demographics Surgical intervention details Psychiatric outcomes and measurement methods Effect estimates with confidence intervals Biological markers and mechanistic data Risk of bias indicators 2.6 Risk of Bias Assessment Study quality was assessed using appropriate tools: Newcastle-Ottawa Scale for observational studies¹⁴ Cochrane Risk of Bias tool for randomized controlled trials¹⁵ 2.7 Data Synthesis Due to anticipated heterogeneity in study designs, populations, and outcomes, we planned narrative synthesis rather than meta-analysis. Studies were grouped by intervention type and outcome, with mechanistic studies analyzed separately. 3. RESULTS 3.1 Study Selection The search strategy identified 145 records after removing duplicates. Following title and abstract screening, 22 studies underwent full-text review. Eleven studies met the final inclusion criteria. The study selection process is shown in Fig. 1 . 3.2 Study Characteristics The included studies comprised: Two large population-based cohort studies¹⁶˒¹⁷ One randomized controlled trial (RCT)¹⁸ Two case-control studies¹⁹˒²⁰ One cross-sectional study²¹ Five mechanistic studies examining biological pathways²²⁻²⁶ Studies were conducted across eight countries, with sample sizes ranging from 44 to over 500,000 participants. Follow-up periods in longitudinal studies ranged from 6 weeks to 20 years. Table 1 Characteristics of Included Studies Study Design Country Population Sample Size Intervention Primary Outcomes Follow-up Ekström et al. ( 2020 )¹⁶ Population cohort Sweden General population 508,147 Childhood appendectomy Depression, anxiety, bipolar disorder 20 years Bunyoz et al. (2021)¹⁷ Population cohort Denmark Peptic ulcer patients 113,086 Vagotomy subtypes Any mental disorder 11.5–18 years Pinto-Sanchez et al. ( 2017 )¹⁸ RCT Canada IBS patients 44 Probiotic intervention Depression scores, brain activity 10 weeks Maes et al. ( 2021 )¹⁹ Case-control Thailand Schizophrenia patients 119 — Immune markers, gut permeability Cross-sectional Cui et al. ( 2021 )²¹ Cross-sectional China Schizophrenia spectrum 125 — Metabolomic profiles Cross-sectional IBS: Irritable bowel syndrome; RCT: randomized controlled trial 3.3 Risk of Bias Assessment The two large population-based cohort studies demonstrated high methodological quality with low risk of bias across most domains. The randomized controlled trial showed adequate randomization and blinding. Case-control and cross-sectional studies showed moderate risk of bias, primarily due to potential selection bias and confounding. A detailed quality assessment is provided in Supplementary Table S1 . 3.4 Associations Between Surgical Interventions and Psychiatric Outcomes Appendectomy The largest study, by Ekström et al. ( 2020 ), examined 508,147 individuals from Swedish national registers, comparing those who underwent appendectomy before age 14 with matched controls¹⁶. Over a mean follow-up of 20 years, childhood appendectomy was associated with increased risk of several psychiatric disorders: Depression : aHR 1.19 (95% CI: 1.15–1.23) Anxiety disorders : aHR 1.20 (95% CI: 1.16–1.24) Bipolar disorder : aHR 1.27 (95% CI: 1.18–1.37) No statistically significant associations were observed with: Schizophrenia: aHR 1.08 (95% CI: 0.96–1.21) Obsessive-compulsive disorder: aHR 1.12 (95% CI: 0.98–1.28) The study controlled for multiple confounders, including family history, socioeconomic factors, and comorbidities. Vagotomy Bunyoz et al. (2021) analyzed the Danish National Patient Register, following 113,086 individuals who underwent different types of vagotomy¹⁷. The analysis revealed differential effects by surgical technique: Truncal vagotomy : HR 1.22 (95% CI: 1.08–1.38) for any mental disorder Selective vagotomy : HR 0.98 (95% CI: 0.89–1.08) – no significant association Highly selective vagotomy : HR 1.10 (95% CI: 0.95–1.27) – no significant association The association with truncal vagotomy remained significant after adjusting for comorbidities and medication use. 3.5 Biological Mechanisms Inflammatory Pathways Maes et al. ( 2021 ) identified differential inflammatory profiles in schizophrenia patients¹⁹: First-episode schizophrenia : Elevated IgA responses to gut barrier proteins (E-cadherin, β-catenin) Increased IgA against Klebsiella pneumoniae Reduced paraoxonase 1 (PON1) antioxidant activity Multiple-episode schizophrenia : Elevated pro-inflammatory cytokines: TNF-α (p < 0.001), IL-6 (p < 0.01) Increased oxidative stress markers Enhanced complement activation (C1q immune complexes) Metabolomic Alterations Cui et al. ( 2021 ) performed salivary metabolomic analysis in individuals at clinical high risk for psychosis and first-episode schizophrenia²¹. Key findings included: Disrupted aromatic amino acid metabolism Altered nucleotide and glutamine pathways Changes in tricarboxylic acid (TCA) cycle activity Discriminatory metabolite panels with high diagnostic accuracy (AUC > 0.80) Vagus Nerve-Mediated Signaling Ma et al. ( 2024 ) demonstrated that bacterial extracellular vesicles from depression patients induced neuroinflammation and behavioral changes in mice through vagus nerve-dependent mechanisms²⁶. Vagotomy attenuated both neuroinflammatory responses and depressive-like behaviors. Therapeutic Interventions The RCT by Pinto-Sanchez et al. ( 2017 ) provided proof-of-concept evidence for gut-targeted interventions¹⁸. Treatment with Bifidobacterium longum NCC3001 for 6 weeks in patients with irritable bowel syndrome and comorbid depression resulted in: Significant reduction in depression scores (p = 0.04) Decreased amygdala reactivity to negative emotional stimuli Altered functional connectivity in emotion-processing networks Changes in urinary metabolite profiles, despite minimal alterations in overall gut microbiota composition 4. DISCUSSION 4.1 Summary of Evidence This systematic review identified limited but suggestive evidence for associations between specific peripheral surgical interventions and psychiatric outcomes. The most robust evidence comes from large population-based studies showing increased risk of mood and anxiety disorders following childhood appendectomy and truncal vagotomy. These associations were not observed for schizophrenia or OCD, suggesting disorder-specific mechanisms. 4.2 Potential Mechanisms The reviewed studies support several mechanistic pathways linking peripheral surgery to psychiatric outcomes: Gut-Associated Lymphoid Tissue Disruption : Appendectomy removes a significant component of gut-associated lymphoid tissue, potentially altering immune homeostasis and microbial colonization patterns¹⁶. Vagus Nerve Signaling : Truncal vagotomy disrupts bidirectional gut-brain communication, potentially affecting neurotransmitter balance and anti-inflammatory signaling¹⁷˒²⁶. Inflammatory Activation : Elevated pro-inflammatory cytokines and oxidative stress markers have been identified in psychiatric conditions, suggesting shared inflammatory pathways¹⁹˒²¹. Microbiota-Mediated Effects : Evidence from intervention studies suggests that modulating gut microbiota can influence brain function and mood, supporting the therapeutic relevance of the gut-brain axis¹⁸. 4.3 Limitations and Confounding Several limitations affect interpretation of these findings: Confounding by Indication : Conditions requiring surgery (e.g., appendicitis, peptic ulcer disease) may independently increase psychiatric risk through inflammatory or stress-related mechanisms. Observational Study Design : Most evidence comes from observational studies that cannot establish causality. Despite large sample sizes and long follow-up periods, unmeasured confounding remains possible. Limited Disorder-Specific Evidence : Evidence for schizophrenia and OCD remains sparse; most OCD-related findings come from studies of broader psychiatric populations. Mechanistic Disconnect : Mechanistic studies typically lack long-term psychiatric outcome data, while large cohort studies rarely include biological markers, limiting integration of pathways with outcomes. 4.4 Clinical Implications The current evidence base is insufficient for specific clinical recommendations. Nonetheless, several implications emerge: Awareness of Potential Risk : Clinicians should be aware of possible long-term psychiatric risks following gut-altering surgeries, particularly in vulnerable populations. Enhanced Monitoring : Patients undergoing procedures such as truncal vagotomy or childhood appendectomy may benefit from enhanced psychiatric screening during follow-up care. Research Priorities : The gut-brain-immune axis represents a promising therapeutic target, but more rigorous research is needed before translation into clinical practice. 4.5 Future Research Directions Future research should prioritize: Prospective Studies with Biological Markers : Large-scale prospective studies with standardized biomarker panels to clarify causal relationships and mechanisms. Disorder-Specific Research : Dedicated studies on OCD and schizophrenia, given the limited current evidence. Intervention Studies : Randomized controlled trials of gut-targeted interventions in high-risk populations. Mechanistic Validation : Studies validating proposed biological pathways in human populations to guide therapeutic development. 5. CONCLUSIONS This systematic review provides preliminary evidence suggesting potential associations between specific peripheral surgical interventions and certain psychiatric disorders, possibly mediated through gut-brain-immune axis mechanisms. However, the observational nature of most studies, the potential for confounding by indication, and limited disorder-specific data preclude definitive conclusions or clinical recommendations. These findings highlight an emerging area of research at the intersection of surgery, psychiatry, and microbiology that warrants further investigation. Future research should prioritize prospective studies with integrated biological assessments, focus on psychiatric conditions with limited current evidence, and explore therapeutic interventions targeting the gut-brain axis. Clinicians should remain aware of potential psychiatric implications of gut-altering surgeries while recognizing that current evidence is insufficient for changes to clinical practice. The gut-brain-immune axis represents a promising frontier for understanding psychiatric disorder development and treatment, but substantial research investment is needed to translate these early findings into clinical applications. 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The vagus nerve: an old but new player in brain-body communication. Brain Behav Immun. 2025;124:28-39. Kakinuma Y. Significance of vagus nerve function in terms of pathogenesis of psychosocial disorders. Neurochem Int. 2021;143:104934. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7818982","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":527200633,"identity":"9542c445-1d50-4b93-a4cc-54e07e1e44c3","order_by":0,"name":"Ishan Abbasi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ishan","middleName":"","lastName":"Abbasi","suffix":""},{"id":527200634,"identity":"8ffa5347-2938-4df1-8f38-bd1adecc30bd","order_by":1,"name":"Yousra 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1","display":"","copyAsset":false,"role":"figure","size":206797,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePRISMA flow diagram showing systematic review study selection process\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7818982/v1/ff88d701e99bf290e0e46763.png"},{"id":93343857,"identity":"8e1b345d-7e02-42f2-8920-772fa9ca9c0f","added_by":"auto","created_at":"2025-10-12 14:53:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101586,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eForest plot of hazard ratios (95% CI) for psychiatric outcomes following peripheral surgical interventions\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7818982/v1/f1e1c846615aef09d43157ec.png"},{"id":93343022,"identity":"c09ee2b5-249d-407a-9279-197d7235f874","added_by":"auto","created_at":"2025-10-12 14:45:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":165706,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eProposed mechanistic pathways linking peripheral surgical interventions to psychiatric outcomes via the gut-brain-immune axis\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7818982/v1/b84b10c875a1182f3bed350e.png"},{"id":93344058,"identity":"d9bc73d1-f69f-4b7d-b252-9382f3da8289","added_by":"auto","created_at":"2025-10-12 15:01:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1461421,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7818982/v1/79888d06-19bf-4a83-9306-8398a5900bdf.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003ePeripheral Surgical Interventions and Psychiatric Outcomes: A Systematic Review of Gut-Brain-Immune Axis Mechanisms\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eMental health disorders represent a significant global health burden, affecting approximately one billion people worldwide and contributing substantially to disability-adjusted life years (DALYs)\u0026sup1;. Among these, schizophrenia affects approximately 1% of the global population and ranks among the leading causes of disability worldwide\u0026sup2;. Obsessive-compulsive disorder (OCD), with lifetime prevalence estimates between 1\u0026ndash;3%, causes significant functional impairment through persistent intrusive thoughts and compulsive behaviors\u0026sup3;.\u003c/p\u003e\u003cp\u003eTraditionally, psychiatric disorders have been understood primarily in terms of central nervous system dysfunction. However, emerging research has highlighted the importance of peripheral factors, particularly the gut-brain-immune axis, in mental health regulation⁴. This bidirectional communication network involves neural, hormonal, and immune pathways connecting the gastrointestinal tract with the central nervous system⁵.\u003c/p\u003e\u003cp\u003eThe gut microbiota, comprising trillions of microorganisms residing in the gastrointestinal tract, plays crucial roles in host physiology, including immune system modulation, neurotransmitter synthesis, and inflammation regulation⁶. Disruptions to this ecosystem, termed dysbiosis, have been implicated in various psychiatric conditions⁷.\u003c/p\u003e\u003cp\u003eRecent evidence suggests alterations in gut and oral microbiomes in schizophrenia, particularly during neurodevelopment⁸. Similarly, preliminary studies in OCD have identified potential microbial contributions to disorder pathogenesis⁹. These findings have generated interest in understanding how peripheral interventions, including surgical procedures affecting gut physiology, might influence psychiatric outcomes.\u003c/p\u003e\u003cp\u003eSurgical procedures such as appendectomy and vagotomy directly impact gut-associated lymphoid tissue and neural signaling pathways, respectively\u0026sup1;⁰. The appendix contains substantial gut-associated lymphoid tissue and serves as a reservoir for beneficial bacteria\u0026sup1;\u0026sup1;. Vagotomy disrupts the vagus nerve, a key component of gut-brain communication\u0026sup1;\u0026sup2;. Understanding whether these interventions influence long-term psychiatric risk could have important clinical implications.\u003c/p\u003e\u003cp\u003eThis systematic review aims to synthesize current evidence examining associations between peripheral surgical interventions and psychiatric outcomes, with particular attention to potential mechanisms involving the gut-brain-immune axis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Protocol\u003c/h2\u003e\u003cp\u003eThis systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines\u0026sup1;\u0026sup3;..\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Search Strategy\u003c/h2\u003e\u003cp\u003eWe conducted comprehensive searches of PubMed, EMBASE, Cochrane Library, and Web of Science databases. Search strategies were developed using Medical Subject Headings (MeSH) and keywords related to surgical interventions, psychiatric outcomes, and gut-brain axis mechanisms.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Eligibility Criteria\u003c/h2\u003e\u003cp\u003e\u003cb\u003eInclusion criteria\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eStudies examining associations between peripheral surgical interventions (appendectomy, vagotomy, tonsillectomy, or other gut-related procedures) and psychiatric outcomes.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eHuman observational studies (cohort, case-control, cross-sectional) and experimental studies.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies reporting quantitative measures of association or biological markers.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePeer-reviewed publications in English.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies published from 2010 onwards to capture recent advances in gut-brain axis research.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eExclusion criteria\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eStudies not reporting psychiatric outcomes as primary or secondary endpoints.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eCase reports, editorials, commentaries, or conference abstracts.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies examining only surgical complications or short-term postoperative outcomes.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAnimal studies (included separately for mechanistic insights but not in primary analysis).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Study Selection\u003c/h2\u003e\u003cp\u003eTwo reviewers independently screened titles and abstracts, followed by full-text review of potentially eligible articles. Disagreements were resolved through discussion with a third reviewer.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Data Extraction\u003c/h2\u003e\u003cp\u003eData were extracted using standardized forms including:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eStudy characteristics (design, setting, sample size, follow-up duration)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePopulation demographics\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSurgical intervention details\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePsychiatric outcomes and measurement methods\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eEffect estimates with confidence intervals\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eBiological markers and mechanistic data\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eRisk of bias indicators\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Risk of Bias Assessment\u003c/h2\u003e\u003cp\u003eStudy quality was assessed using appropriate tools:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eNewcastle-Ottawa Scale for observational studies\u0026sup1;⁴\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eCochrane Risk of Bias tool for randomized controlled trials\u0026sup1;⁵\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.7 Data Synthesis\u003c/h2\u003e\u003cp\u003eDue to anticipated heterogeneity in study designs, populations, and outcomes, we planned narrative synthesis rather than meta-analysis. Studies were grouped by intervention type and outcome, with mechanistic studies analyzed separately.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Study Selection\u003c/h2\u003e\u003cp\u003eThe search strategy identified 145 records after removing duplicates. Following title and abstract screening, 22 studies underwent full-text review. Eleven studies met the final inclusion criteria. The study selection process is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Study Characteristics\u003c/h2\u003e\u003cp\u003eThe included studies comprised:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eTwo large population-based cohort studies\u0026sup1;⁶˒\u0026sup1;⁷\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOne randomized controlled trial (RCT)\u0026sup1;⁸\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eTwo case-control studies\u0026sup1;⁹˒\u0026sup2;⁰\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOne cross-sectional study\u0026sup2;\u0026sup1;\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFive mechanistic studies examining biological pathways\u0026sup2;\u0026sup2;⁻\u0026sup2;⁶\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eStudies were conducted across eight countries, with sample sizes ranging from 44 to over 500,000 participants. Follow-up periods in longitudinal studies ranged from 6 weeks to 20 years.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of Included Studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePopulation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSample Size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePrimary Outcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEkstr\u0026ouml;m et al. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2020\u003c/span\u003e)\u0026sup1;⁶\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePopulation cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSweden\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGeneral population\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e508,147\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eChildhood appendectomy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDepression, anxiety, bipolar disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20 years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBunyoz et al. (2021)\u0026sup1;⁷\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePopulation cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDenmark\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePeptic ulcer patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e113,086\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVagotomy subtypes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAny mental disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e11.5\u0026ndash;18 years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePinto-Sanchez et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2017\u003c/span\u003e)\u0026sup1;⁸\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIBS patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eProbiotic intervention\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDepression scores, brain activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e10 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaes et al. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u0026sup1;⁹\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThailand\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSchizophrenia patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eImmune markers, gut permeability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCui et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u0026sup2;\u0026sup1;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSchizophrenia spectrum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMetabolomic profiles\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cem\u003eIBS: Irritable bowel syndrome; RCT: randomized controlled trial\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Risk of Bias Assessment\u003c/h2\u003e\u003cp\u003eThe two large population-based cohort studies demonstrated high methodological quality with low risk of bias across most domains. The randomized controlled trial showed adequate randomization and blinding. Case-control and cross-sectional studies showed moderate risk of bias, primarily due to potential selection bias and confounding. A detailed quality assessment is provided in \u003cem\u003eSupplementary Table S1\u003c/em\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Associations Between Surgical Interventions and Psychiatric Outcomes\u003c/h2\u003e\u003cp\u003e\u003cb\u003eAppendectomy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe largest study, by Ekstr\u0026ouml;m et al. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), examined 508,147 individuals from Swedish national registers, comparing those who underwent appendectomy before age 14 with matched controls\u0026sup1;⁶. Over a mean follow-up of 20 years, childhood appendectomy was associated with increased risk of several psychiatric disorders:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eDepression\u003c/b\u003e: aHR 1.19 (95% CI: 1.15\u0026ndash;1.23)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAnxiety disorders\u003c/b\u003e: aHR 1.20 (95% CI: 1.16\u0026ndash;1.24)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eBipolar disorder\u003c/b\u003e: aHR 1.27 (95% CI: 1.18\u0026ndash;1.37)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eNo statistically significant associations were observed with:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSchizophrenia: aHR 1.08 (95% CI: 0.96\u0026ndash;1.21)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eObsessive-compulsive disorder: aHR 1.12 (95% CI: 0.98\u0026ndash;1.28)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThe study controlled for multiple confounders, including family history, socioeconomic factors, and comorbidities.\u003c/p\u003e\u003cp\u003e\u003cb\u003eVagotomy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBunyoz et al. (2021) analyzed the Danish National Patient Register, following 113,086 individuals who underwent different types of vagotomy\u0026sup1;⁷. The analysis revealed differential effects by surgical technique:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eTruncal vagotomy\u003c/b\u003e: HR 1.22 (95% CI: 1.08\u0026ndash;1.38) for any mental disorder\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSelective vagotomy\u003c/b\u003e: HR 0.98 (95% CI: 0.89\u0026ndash;1.08) \u0026ndash; no significant association\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eHighly selective vagotomy\u003c/b\u003e: HR 1.10 (95% CI: 0.95\u0026ndash;1.27) \u0026ndash; no significant association\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThe association with truncal vagotomy remained significant after adjusting for comorbidities and medication use.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Biological Mechanisms\u003c/h2\u003e\u003cp\u003e\u003cb\u003eInflammatory Pathways\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMaes et al. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) identified differential inflammatory profiles in schizophrenia patients\u0026sup1;⁹:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eFirst-episode schizophrenia\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eElevated IgA responses to gut barrier proteins (E-cadherin, β-catenin)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIncreased IgA against \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eReduced paraoxonase 1 (PON1) antioxidant activity\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eMultiple-episode schizophrenia\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eElevated pro-inflammatory cytokines: TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), IL-6 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIncreased oxidative stress markers\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eEnhanced complement activation (C1q immune complexes)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eMetabolomic Alterations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCui et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) performed salivary metabolomic analysis in individuals at clinical high risk for psychosis and first-episode schizophrenia\u0026sup2;\u0026sup1;. Key findings included:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eDisrupted aromatic amino acid metabolism\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAltered nucleotide and glutamine pathways\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eChanges in tricarboxylic acid (TCA) cycle activity\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDiscriminatory metabolite panels with high diagnostic accuracy (AUC\u0026thinsp;\u0026gt;\u0026thinsp;0.80)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eVagus Nerve-Mediated Signaling\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMa et al. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) demonstrated that bacterial extracellular vesicles from depression patients induced neuroinflammation and behavioral changes in mice through vagus nerve-dependent mechanisms\u0026sup2;⁶. Vagotomy attenuated both neuroinflammatory responses and depressive-like behaviors.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTherapeutic Interventions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe RCT by Pinto-Sanchez et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) provided proof-of-concept evidence for gut-targeted interventions\u0026sup1;⁸. Treatment with \u003cem\u003eBifidobacterium longum\u003c/em\u003e NCC3001 for 6 weeks in patients with irritable bowel syndrome and comorbid depression resulted in:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSignificant reduction in depression scores (p\u0026thinsp;=\u0026thinsp;0.04)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDecreased amygdala reactivity to negative emotional stimuli\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAltered functional connectivity in emotion-processing networks\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eChanges in urinary metabolite profiles, despite minimal alterations in overall gut microbiota composition\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Summary of Evidence\u003c/h2\u003e\u003cp\u003eThis systematic review identified limited but suggestive evidence for associations between specific peripheral surgical interventions and psychiatric outcomes. The most robust evidence comes from large population-based studies showing increased risk of mood and anxiety disorders following childhood appendectomy and truncal vagotomy. These associations were not observed for schizophrenia or OCD, suggesting disorder-specific mechanisms.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Potential Mechanisms\u003c/h2\u003e\u003cp\u003eThe reviewed studies support several mechanistic pathways linking peripheral surgery to psychiatric outcomes:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eGut-Associated Lymphoid Tissue Disruption\u003c/b\u003e: Appendectomy removes a significant component of gut-associated lymphoid tissue, potentially altering immune homeostasis and microbial colonization patterns\u0026sup1;⁶.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eVagus Nerve Signaling\u003c/b\u003e: Truncal vagotomy disrupts bidirectional gut-brain communication, potentially affecting neurotransmitter balance and anti-inflammatory signaling\u0026sup1;⁷˒\u0026sup2;⁶.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eInflammatory Activation\u003c/b\u003e: Elevated pro-inflammatory cytokines and oxidative stress markers have been identified in psychiatric conditions, suggesting shared inflammatory pathways\u0026sup1;⁹˒\u0026sup2;\u0026sup1;.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eMicrobiota-Mediated Effects\u003c/b\u003e: Evidence from intervention studies suggests that modulating gut microbiota can influence brain function and mood, supporting the therapeutic relevance of the gut-brain axis\u0026sup1;⁸.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Limitations and Confounding\u003c/h2\u003e\u003cp\u003eSeveral limitations affect interpretation of these findings:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eConfounding by Indication\u003c/b\u003e: Conditions requiring surgery (e.g., appendicitis, peptic ulcer disease) may independently increase psychiatric risk through inflammatory or stress-related mechanisms.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eObservational Study Design\u003c/b\u003e: Most evidence comes from observational studies that cannot establish causality. Despite large sample sizes and long follow-up periods, unmeasured confounding remains possible.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eLimited Disorder-Specific Evidence\u003c/b\u003e: Evidence for schizophrenia and OCD remains sparse; most OCD-related findings come from studies of broader psychiatric populations.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eMechanistic Disconnect\u003c/b\u003e: Mechanistic studies typically lack long-term psychiatric outcome data, while large cohort studies rarely include biological markers, limiting integration of pathways with outcomes.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e4.4 Clinical Implications\u003c/h2\u003e\u003cp\u003eThe current evidence base is insufficient for specific clinical recommendations. Nonetheless, several implications emerge:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAwareness of Potential Risk\u003c/b\u003e: Clinicians should be aware of possible long-term psychiatric risks following gut-altering surgeries, particularly in vulnerable populations.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eEnhanced Monitoring\u003c/b\u003e: Patients undergoing procedures such as truncal vagotomy or childhood appendectomy may benefit from enhanced psychiatric screening during follow-up care.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eResearch Priorities\u003c/b\u003e: The gut-brain-immune axis represents a promising therapeutic target, but more rigorous research is needed before translation into clinical practice.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e4.5 Future Research Directions\u003c/h2\u003e\u003cp\u003eFuture research should prioritize:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eProspective Studies with Biological Markers\u003c/b\u003e: Large-scale prospective studies with standardized biomarker panels to clarify causal relationships and mechanisms.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eDisorder-Specific Research\u003c/b\u003e: Dedicated studies on OCD and schizophrenia, given the limited current evidence.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eIntervention Studies\u003c/b\u003e: Randomized controlled trials of gut-targeted interventions in high-risk populations.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eMechanistic Validation\u003c/b\u003e: Studies validating proposed biological pathways in human populations to guide therapeutic development.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"5. CONCLUSIONS","content":"\u003cp\u003eThis systematic review provides preliminary evidence suggesting potential associations between specific peripheral surgical interventions and certain psychiatric disorders, possibly mediated through gut-brain-immune axis mechanisms. However, the observational nature of most studies, the potential for confounding by indication, and limited disorder-specific data preclude definitive conclusions or clinical recommendations.\u003c/p\u003e\u003cp\u003eThese findings highlight an emerging area of research at the intersection of surgery, psychiatry, and microbiology that warrants further investigation. Future research should prioritize prospective studies with integrated biological assessments, focus on psychiatric conditions with limited current evidence, and explore therapeutic interventions targeting the gut-brain axis.\u003c/p\u003e\u003cp\u003eClinicians should remain aware of potential psychiatric implications of gut-altering surgeries while recognizing that current evidence is insufficient for changes to clinical practice. The gut-brain-immune axis represents a promising frontier for understanding psychiatric disorder development and treatment, but substantial research investment is needed to translate these early findings into clinical applications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFUNDING\u003c/h2\u003e\u003cp\u003eThis research received no specific funding.\u003c/p\u003e\u003cp\u003eCONFLICTS OF INTEREST\u003c/p\u003e\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003eWorld Health Organization. Mental disorders. Geneva: WHO; 2022.\u003c/li\u003e\n\u003cli\u003eCharlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia: findings from the Global Burden of Disease Study 2016. Schizophr Bull. 2018;44(6):1195-1203.\u003c/li\u003e\n\u003cli\u003eRuscio AM, Stein DJ, Chiu WT, Kessler RC. 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Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology. 2017;153(2):448-459.\u003c/li\u003e\n\u003cli\u003eMaes M, Vojdani A, Sirivichayakul S, et al. Inflammatory and oxidative pathways are new drug targets in multiple episode schizophrenia and leaky gut, Klebsiella pneumoniae, and C1q immune complexes are additional drug targets in first episode schizophrenia. Mol Neurobiol. 2021;58(7):3319-3334.\u003c/li\u003e\n\u003cli\u003eMa X, Park HS, Shin YJ, et al. The extracellular vesicle of depressive patient-derived Escherichia fergusonii induces vagus nerve-mediated neuroinflammation in mice. J Neuroinflammation. 2024;21(1):224.\u003c/li\u003e\n\u003cli\u003eCui G, Qing Y, Li M, et al. Salivary metabolomics reveals that metabolic alterations precede the onset of schizophrenia. J Proteome Res. 2021;20(11):5010-5023.\u003c/li\u003e\n\u003cli\u003eChang L, Wei Y, Hashimoto K. 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Neurochem Int. 2021;143:104934.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Medical College and Hospital, Kolkata","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"gut-brain axis, appendectomy, vagotomy, psychiatric disorders, microbiome, neuroinflammation","lastPublishedDoi":"10.21203/rs.3.rs-7818982/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7818982/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe gut-brain-immune axis has emerged as a potential mediator in the development of psychiatric disorders. This systematic review examines associations between peripheral surgical interventions and psychiatric outcomes, with emphasis on potential underlying mechanisms involving microbiota, immune function, and neural signaling.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a systematic review following PRISMA guidelines, searching PubMed, EMBASE, and Cochrane databases from inception to May 2024. Studies examining associations between peripheral surgical procedures (appendectomy, vagotomy, tonsillectomy) and psychiatric outcomes were included. Risk of bias was assessed using appropriate tools for each study design.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eEleven studies met inclusion criteria, including two large population-based cohort studies, one randomized controlled trial, and several mechanistic studies. Childhood appendectomy was associated with increased risk of mood disorders (adjusted hazard ratio [aHR] 1.19, 95% CI: 1.15\u0026ndash;1.23) and anxiety disorders (aHR 1.20, 95% CI: 1.16\u0026ndash;1.24), but not schizophrenia or obsessive-compulsive disorder. Truncal vagotomy was associated with mental health disorders (hazard ratio 1.22, 95% CI: 1.08\u0026ndash;1.38), while selective vagotomy was not. Mechanistic studies identified alterations in inflammatory markers (TNF-α, IL-6), gut barrier function, and vagal signaling as potential mediators.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eLimited evidence suggests that peripheral surgical interventions may be associated with increased risk of certain psychiatric disorders, possibly through gut-brain-immune axis mechanisms. However, the observational nature of most studies precludes causal inferences. The evidence base remains insufficient for clinical recommendations, particularly regarding obsessive-compulsive disorder and schizophrenia. Future research should focus on prospective studies with standardized biomarker assessments and longer follow-up periods.\u003c/p\u003e","manuscriptTitle":"Peripheral Surgical Interventions and Psychiatric Outcomes: A Systematic Review of Gut-Brain-Immune Axis Mechanisms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-12 14:45:48","doi":"10.21203/rs.3.rs-7818982/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e7837c88-608d-422a-9121-973475189a25","owner":[],"postedDate":"October 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56039593,"name":"Surgery"}],"tags":[],"updatedAt":"2025-10-12T14:45:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-12 14:45:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7818982","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7818982","identity":"rs-7818982","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}