{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:24:52Z","timestamp":1785461092096,"version":"3.56.0"},"reference-count":122,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bio &amp; Medical Technology Development Program of the National Research Foundation","award":["RS-2025-02263193"],"award-info":[{"award-number":["RS-2025-02263193"]}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["RS-2026-25474823"],"award-info":[{"award-number":["RS-2026-25474823"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2026-25474823"],"award-info":[{"award-number":["RS-2026-25474823"]}],"id":[{"id":"https:\/\/ror.org\/01xpa3123","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Major depressive disorder (MDD) is a mental illness with high mortality, suicide, and relapse rates that could become the leading cause of health problems worldwide by 2030. The microbiota\u2013gut\u2013brain axis involves bidirectional communication between the human gut microbiota and the central nervous system (CNS). The gut microbiome is a complex ecosystem of approximately 100 trillion microorganisms, including viruses, bacteria, and fungi. The gut microbiota has recently been recognized for its impact on various diseases and health concerns. Several factors influence the composition and structure of gut microbes, ultimately affecting human physiology, with the nervous system being particularly vulnerable. The gut\u2013brain\u2013microbiota axis influences several important brain functions through numerous pathways, including vagus nerve signaling, gut microbial synthesis of metabolites, and immune-related chemicals. These factors can influence neurotransmitter activity, neuroinflammation, behavior, and mental health. Despite increased interest, the possibility of modifying the gut microbiota as a therapeutic approach remains unclear. Although numerous studies suggest that microbiota play an important role in many illnesses, the precise mechanisms are yet to be elucidated, and there are currently no evidence-based, microbiota-focused treatments for these illnesses. Recent research indicates that gut dysbiosis (GD) causes increased intestinal permeability (leaky gut), initiates systemic inflammation, and contaminates the blood. Opportunistic microbial metabolites cross the blood\u2013brain barrier, triggering a neuroinflammatory cascade and apoptotic pathways while affecting neurogenesis and neurotransmitters, ultimately resulting in the development of MDD and anxiety. This review examined the factors influencing normal gut microbiota and GD-mediated MDD, as well as possible therapeutic options. The study outlines its objectives and methodological approaches, including the screening and filtering of research on GD-induced depression. Furthermore, it explored the daily use of dietary supplements, revealing new paths for clinical and preclinical research.<\/jats:p>","DOI":"10.3390\/cells15110972","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T10:19:52Z","timestamp":1779877192000},"page":"972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gut Dysbiosis-Mediated Major Depressive Disorder: A Review of Pathogenic Mechanisms and Potential Therapeutic Strategies"],"prefix":"10.3390","volume":"15","author":[{"given":"Muhammad Sohail","family":"Khan","sequence":"first","affiliation":[{"name":"College of Korean Medicine, Gachon University, 1342 Seongnam-daero, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Faizan","sequence":"additional","affiliation":[{"name":"Department of Animal Reproduction, Faculty of Veterinary Sciences, The University of Agriculture, Peshawar 25130, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabsik","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Gachon University, 1342 Seongnam-daero, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Sung","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Gachon University, 1342 Seongnam-daero, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","first-page":"e55831","article-title":"Exploring the Effects of Major Depressive Disorder on Daily Occupations and the Impact of Psychotherapy: A Literature Review","volume":"16","author":"Iliou","year":"2024","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Liu, Z., and Kuai, M. (2025). The global burden of depression in adolescents and young adults, 1990\u20132021: Systematic analysis of the global burden of disease study. BMC Psychiatry, 25.","DOI":"10.1186\/s12888-025-07201-8"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1037\/bul0000102","article-title":"Gender differences in depression in representative national samples: Meta-analyses of diagnoses and symptoms","volume":"143","author":"Salk","year":"2017","journal-title":"Psychol. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ferrari, A.J., Charlson, F.J., Norman, R.E., Flaxman, A.D., Patten, S.B., Vos, T., and Whiteford, H.A. (2013). The epidemiological modelling of major depressive disorder: Application for the Global Burden of Disease Study 2010. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069637"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113055","DOI":"10.1016\/j.jep.2020.113055","article-title":"Chinese medicine formula Kai-Xin-San ameliorates depression-like behaviours in chronic unpredictable mild stressed mice by regulating gut microbiota-inflammation-stress system","volume":"261","author":"Cao","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1503\/jpn.150205","article-title":"Why is depression more prevalent in women?","volume":"40","author":"Albert","year":"2015","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ferrari, A.J., Charlson, F.J., Norman, R.E., Patten, S.B., Freedman, G., Murray, C.J., Vos, T., and Whiteford, H.A. (2013). Burden of depressive disorders by country, sex, age, and year: Findings from the global burden of disease study 2010. PLoS Med., 10.","DOI":"10.1371\/journal.pmed.1001547"},{"key":"ref_8","first-page":"167","article-title":"Treatment-resistant depression","volume":"80","author":"Little","year":"2009","journal-title":"Am. Fam. Physician"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4103\/0019-5545.117131","article-title":"Diagnostic and statistical manual of mental disorders 5: A quick glance","volume":"55","author":"Vahia","year":"2013","journal-title":"Indian J. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4103\/jfmpc.jfmpc_248_17","article-title":"Prevalence of depression and anxiety among children in rural and suburban areas of Eastern Uttar Pradesh: A cross-sectional study","volume":"7","author":"Mishra","year":"2018","journal-title":"J. Fam. Med. Prim. Care"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tian, X., Hu, N., Lu, L., Tan, L., and Li, P. (2024). Gender differences in major depressive disorder at different ages: A REST-meta-MDD project-based study. BMC Psychiatry, 24.","DOI":"10.1186\/s12888-024-06021-6"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cai, H., Xie, X.M., Zhang, Q., Cui, X., Lin, J.X., Sim, K., Ungvari, G.S., Zhang, L., and Xiang, Y.T. (2021). Prevalence of Suicidality in Major Depressive Disorder: A Systematic Review and Meta-Analysis of Comparative Studies. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.690130"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hsiao, S.H., Cheng, C.C., Lin, I.J., Yu, C.P., Huang, Y.C., Huang, S.H., Sun, C.A., Fann, L.Y., Sheu, M.Y., and Chien, W.C. (2022). Persistent Depressive Disorder-Related Effect of Sleep Disorder on the Highest Risk of Suicide in Taiwan, 2000\u20132015. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph192013169"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jpsychires.2021.02.053","article-title":"Estimating the risk of suicide associated with mental disorders: A systematic review and meta-regression analysis","volume":"137","author":"Moitra","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.30773\/pi.2025.0211","article-title":"Global Burden of Depressive Disorders, 1990\u20132021, During the COVID-19 Pandemic and Projections to 2050: A Global Burden of Disease Study 2021","volume":"22","author":"Lee","year":"2025","journal-title":"Psychiatry Investig."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, C., Zhang, C., Hong, X., Xiao, Y., Ying, W., and Ma, W. (2025). Cross-national comparison of major depressive disorder burden in China, India, and the United States of America: An age-period-cohort analysis of GBD 2021. Front. Psychiatry, 16.","DOI":"10.3389\/fpsyt.2025.1686919"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9350","DOI":"10.12998\/wjcc.v9.i31.9350","article-title":"Major depressive disorder: Validated treatments and future challenges","volume":"9","author":"Karrouri","year":"2021","journal-title":"World J. Clin. Cases"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"212290","DOI":"10.7573\/dic.212290","article-title":"Antidepressant efficacy and side-effect burden: A quick guide for clinicians","volume":"4","author":"Santarsieri","year":"2015","journal-title":"Drugs Context"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, J., Wan, B., Zhou, L., Qian, X., Wang, F., Gu, S., Ma, X., and Huang, J.H. (2025). Gut microbiota dysbiosis induces neuroinflammation in major depressive disorders: Mechanisms targeting the gut-brain axis. Front. Psychiatry, 16.","DOI":"10.3389\/fpsyt.2025.1629182"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, H., Chen, Y., Zhao, A., Shen, Z., and Zhang, Y. (2025). The role of probiotics in modulation of the gut-brain axis: A prospective therapy for depression and mood disorders. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1709060"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Guo, Y., Xie, J.P., Deng, K., Li, X., Yuan, Y., Xuan, Q., Xie, J., He, X.M., Wang, Q., and Li, J.J. (2019). Prophylactic Effects of Bifidobacterium adolescentis on Anxiety and Depression-Like Phenotypes After Chronic Stress: A Role of the Gut Microbiota-Inflammation Axis. Front. Behav. Neurosci., 13.","DOI":"10.3389\/fnbeh.2019.00126"},{"key":"ref_22","first-page":"369","article-title":"Treatment-resistant depression: Therapeutic trends, challenges, and future directions","volume":"6","year":"2012","journal-title":"Patient Prefer. Adherence"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/17460441.2025.2460674","article-title":"Investigating novel pharmacological strategies for treatment-resistant depression: Focus on new mechanisms and approaches","volume":"20","author":"Toscano","year":"2025","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Elias, E., Zhang, A.Y., and Manners, M.T. (2022). Novel Pharmacological Approaches to the Treatment of Depression. Life, 12.","DOI":"10.3390\/life12020196"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41392-024-01743-1","article-title":"Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases","volume":"9","author":"Loh","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bbi.2015.03.016","article-title":"Altered fecal microbiota composition in patients with major depressive disorder","volume":"48","author":"Jiang","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Karen, C., Shyu, D.J.H., and Rajan, K.E. (2021). Lactobacillus paracasei Supplementation Prevents Early Life Stress-Induced Anxiety and Depressive-Like Behavior in Maternal Separation Model-Possible Involvement of Microbiota-Gut-Brain Axis in Differential Regulation of MicroRNA124a\/132 and Glutamate Receptors. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.719933"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1007\/s12088-025-01447-2","article-title":"Comprehensive Genomic, Mutation, Phylogenetic, and statistical analysis of the Monkeypox virus across multiple countries","volume":"65","author":"Zafar","year":"2025","journal-title":"Indian J. Microbiol."},{"key":"ref_29","unstructured":"Kulkarni, A.J., Siarry, P., Singh, P.K., Abraham, A., Zhang, M., Zomaya, A., and Baki, F. (2022). Big data analytics for health: A comprehensive review of techniques and applications. Big Data Analytics for Healthcare, Elsevier."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117795","DOI":"10.1016\/j.envres.2023.117795","article-title":"Multifunctional role of nanoparticles for the diagnosis and therapeutics of cardiovascular diseases","volume":"242","author":"Arshad","year":"2024","journal-title":"Environ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Newington, L., Wells, M., Adonis, A., Bolton, L., Bolton Saghdaoui, L., Coffey, M., Crow, J., Costa, O.F., Hughes, C., and Savage, M. (2021). A qualitative systematic review and thematic synthesis exploring the impacts of clinical academic activity by healthcare professionals outside medicine. BMC Health Serv. Res., 21.","DOI":"10.1186\/s12913-021-06354-y"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105263","DOI":"10.1016\/j.bspc.2023.105263","article-title":"Reviewing methods of deep learning for intelligent healthcare systems in genomics and biomedicine","volume":"86","author":"Zafar","year":"2023","journal-title":"Biomed. Signal Process. Control"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rayan, R.A., Zafar, I., and Tsagkari, C. (2021). Blockchain technology for healthcare cloud-based data privacy and security. Integration of WSNs into Internet of Things, CRC Press.","DOI":"10.1201\/9781003107521-16"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rayan, R.A., Tsagkaris, C., and Zafar, I. (2021). IoT-integrated robotics in the health sector. Robotic Technologies in Biomedical and Healthcare Engineering, CRC Press.","DOI":"10.1201\/9781003112273-1"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0031-9384(01)00424-3","article-title":"Subchronic mild noise stress increases HRP permeability in rat small intestine in vitro","volume":"73","author":"Bijlsma","year":"2001","journal-title":"Physiol. Behav."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s12974-018-1223-4","article-title":"Effects of chronic noise exposure on the microbiome-gut-brain axis in senescence-accelerated prone mice: Implications for Alzheimer\u2019s disease","volume":"15","author":"Cui","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/0016-5085(89)91678-8","article-title":"Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone levels in dogs","volume":"97","author":"Gue","year":"1989","journal-title":"Gastroenterology"},{"key":"ref_38","first-page":"5","article-title":"Health effects caused by noise: Evidence in the literature from the past 25 years","volume":"6","author":"Ising","year":"2004","journal-title":"Noise Health"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1111\/j.1461-0248.2011.01664.x","article-title":"How and why environmental noise impacts animals: An integrative, mechanistic review","volume":"14","author":"Kight","year":"2011","journal-title":"Ecol. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3748\/wjg.v4.i6.519","article-title":"Experimental study on mechanism and protection of stress ulcer produced by explosive noise","volume":"4","author":"Liu","year":"1998","journal-title":"World J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxlet.2017.07.898","article-title":"Acoustic stress induces long term severe intestinal inflammation in the mouse","volume":"280","author":"Miranda","year":"2017","journal-title":"Toxicol. Lett."},{"key":"ref_42","first-page":"2284","article-title":"Effect of explosive noise on gastrointestinal transit and plasma levels of polypeptide hormones","volume":"12","author":"Mu","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"31027","DOI":"10.1038\/srep31027","article-title":"Oral exposure to environmental pollutant benzo[a]pyrene impacts the intestinal epithelium and induces gut microbial shifts in murine model","volume":"6","author":"Ribiere","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1007\/s11356-012-1283-4","article-title":"Impact of chronic exposure to low doses of chlorpyrifos on the intestinal microbiota in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME\u00ae) and in the rat","volume":"20","author":"Joly","year":"2013","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.jnutbio.2012.04.005","article-title":"Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol","volume":"24","author":"Huderson","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Defois, C., Ratel, J., Denis, S., Batut, B., Beugnot, R., Peyretaillade, E., Engel, E., and Peyret, P. (2017). Environmental Pollutant Benzo[a]Pyrene Impacts the Volatile Metabolome and Transcriptome of the Human Gut Microbiota. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.01562"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1097\/MPG.0b013e3181d1b11e","article-title":"Intestinal microbiota of 6-week-old infants across Europe: Geographic influence beyond delivery mode, breast-feeding, and antibiotics","volume":"51","author":"Fallani","year":"2010","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/ismej.2009.112","article-title":"Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice","volume":"4","author":"Zhang","year":"2010","journal-title":"ISME J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1152\/physrev.00045.2009","article-title":"Gut microbiota in health and disease","volume":"90","author":"Sekirov","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1053\/j.gastro.2009.08.042","article-title":"High-fat diet determines the composition of the murine gut microbiome independently of obesity","volume":"137","author":"Hildebrandt","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1126\/science.1208344","article-title":"Linking long-term dietary patterns with gut microbial enterotypes","volume":"334","author":"Wu","year":"2011","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"417","DOI":"10.3945\/jn.112.166322","article-title":"Habitual dietary intake is associated with stool microbiota composition in monozygotic twins","volume":"143","author":"Simoes","year":"2013","journal-title":"J. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3390\/pathogens3010014","article-title":"Metabolism of cholesterol and bile acids by the gut microbiota","volume":"3","author":"Gerard","year":"2013","journal-title":"Pathogens"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/978-3-642-24716-3_11","article-title":"Intestinal microbiota and obesity","volume":"Volume 209","author":"Blaut","year":"2012","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s11745-017-4253-2","article-title":"Short Term High Fat Diet Induces Obesity-Enhancing Changes in Mouse Gut Microbiota That are Partially Reversed by Cessation of the High Fat Diet","volume":"52","author":"Shang","year":"2017","journal-title":"Lipids"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Li, S., Liu, J., Zhang, X., Gu, Q., Wu, Y., Tao, X., Tian, T., Pan, G., and Chu, M. (2025). The Potential Impact of Antibiotic Exposure on the Microbiome and Human Health. Microorganisms, 13.","DOI":"10.3390\/microorganisms13030602"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e15417","DOI":"10.1016\/j.heliyon.2023.e15417","article-title":"The influence of antibiotic treatment on the behavior and gut microbiome of adult rats neonatally insulted with lipopolysaccharide","volume":"9","author":"Tejkalova","year":"2023","journal-title":"Heliyon"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"43425","DOI":"10.1038\/s41598-025-25645-6","article-title":"Dynamics of the gut microbiome and resistome in response to prophylactic antibiotic treatment in post-surgical giant pandas","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1007\/s10620-021-07000-7","article-title":"Gut Dysbiosis Associated with Antibiotics and Disease Severity and Its Relation to Mortality in Critically Ill Patients","volume":"67","author":"Ojima","year":"2022","journal-title":"Dig. Dis. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Dahiya, D., and Nigam, P.S. (2023). Antibiotic-Therapy-Induced Gut Dysbiosis Affecting Gut Microbiota-Brain Axis and Cognition: Restoration by Intake of Probiotics and Synbiotics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043074"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41398-023-02670-5","article-title":"Gut microbiota composition in depressive disorder: A systematic review, meta-analysis, and meta-regression","volume":"13","author":"Gao","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Yun, Y., An, H., Zhao, W., Ma, T., Wang, Z., and Yang, F. (2021). Gut Microbiome Composition Associated with Major Depressive Disorder and Sleep Quality. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.645045"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e02177","DOI":"10.1002\/brb3.2177","article-title":"Gut microbiota variations in patients diagnosed with major depressive disorder-A systematic review","volume":"11","author":"Knudsen","year":"2021","journal-title":"Brain Behav."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Sejbuk, M., Siebieszuk, A., and Witkowska, A.M. (2024). The Role of Gut Microbiome in Sleep Quality and Health: Dietary Strategies for Microbiota Support. Nutrients, 16.","DOI":"10.3390\/nu16142259"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1159\/000530386","article-title":"Gut Microbiome Composition and Its Association with Sleep in Major Psychiatric Disorders","volume":"82","author":"Mairinger","year":"2023","journal-title":"Neuropsychobiology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"270","DOI":"10.4161\/oxim.2.5.9498","article-title":"Plant polyphenols as dietary antioxidants in human health and disease","volume":"2","author":"Pandey","year":"2009","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Ciupei, D., Coli\u015far, A., Leopold, L., St\u0103nil\u0103, A., and Diaconeasa, Z.M. (2024). Polyphenols: From Classification to Therapeutic Potential and Bioavailability. Foods, 13.","DOI":"10.3390\/foods13244131"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Saad, A.M., Mohammed, D.M., Alkafaas, S.S., Ghosh, S., Negm, S.H., Salem, H.M., Fahmy, M.A., Semary, H.E., Ibrahim, E.H., and AbuQamar, S.F. (2025). Dietary polyphenols and human health: Sources, biological activities, nutritional and immunological aspects, and bioavailability- a comprehensive review. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1653378"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Brglez Mojzer, E., Knez Hrn\u010di\u010d, M., \u0160kerget, M., Knez, \u017d., and Bren, U. (2016). Polyphenols: Extraction Methods, Antioxidative Action, Bioavailability and Anticarcinogenic Effects. Molecules, 21.","DOI":"10.3390\/molecules21070901"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"162750","DOI":"10.1155\/2013\/162750","article-title":"Chemistry and biological activities of flavonoids: An overview","volume":"2013","author":"Kumar","year":"2013","journal-title":"Sci. World J."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Frent, O.D., Stefan, L., Morgovan, C.M., Duteanu, N., Dejeu, I.L., Marian, E., Vica\u0219, L., and Manole, F. (2024). A Systematic Review: Quercetin-Secondary Metabolite of the Flavonol Class, with Multiple Health Benefits and Low Bioavailability. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212091"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e202402461","DOI":"10.1002\/cbdv.202402461","article-title":"A Comprehensive Review of Phytochemistry and Anticancer of the Genus Goniothalamus","volume":"22","author":"Xie","year":"2025","journal-title":"Chem. Biodivers."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Dias, M.C., Pinto, D., and Silva, A.M.S. (2021). Plant Flavonoids: Chemical Characteristics and Biological Activity. Molecules, 26.","DOI":"10.3390\/molecules26175377"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Davani-Davari, D., Negahdaripour, M., Karimzadeh, I., Seifan, M., Mohkam, M., Masoumi, S.J., Berenjian, A., and Ghasemi, Y. (2019). Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods, 8.","DOI":"10.3390\/foods8030092"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"118598","DOI":"10.1016\/j.foodres.2026.118598","article-title":"Interplay of probiotics, prebiotics, synbiotics and postbiotics: A review of their therapeutic potential for gastrointestinal inflammation","volume":"230","author":"Baheti","year":"2026","journal-title":"Food Res. Int."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"110337","DOI":"10.1016\/j.jnutbio.2026.110337","article-title":"Prebiotics partially protect offspring from maternal antibiotic-induced obesity risk by altering maternal milk microbiota and gut colonization in Sprague-Dawley rats","volume":"153","author":"Lowry","year":"2026","journal-title":"J. Nutr. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e70247","DOI":"10.1002\/jcsm.70247","article-title":"Effects of Phenolic-Rich Extra Virgin Olive Oil and Prebiotics on Sarcopenia in Older Adults: FOOP-Sarc Project","volume":"17","author":"Queral","year":"2026","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8273","DOI":"10.1038\/s41598-026-37841-z","article-title":"Yeast prebiotics mitigate lead toxicity in Nile tilapia through physiological and ultrastructural improvements","volume":"16","author":"Dessouki","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Martin-Pelaez, S., Martin-delosReyes, L.M., and Cano-Ibanez, N. (2026). Prebiotics, probiotics, and synbiotics and maternal mental health during pregnancy and postpartum period: A systematic review. Front. Nutr., 13.","DOI":"10.3389\/fnut.2026.1776398"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Bonnard, L.C., Sharpe, G.R., Martin, M., Dodd, G.F., and Williams, N.C. (2026). Prebiotics and Synbiotics in Asthma: An Integrative Review of Human Trials and Murine Meta-Analysis. Nutrients, 18.","DOI":"10.3390\/nu18040683"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Dai, Q., Duan, Z., Fang, C., and Chen, R. (2026). Research progress and controversies in the treatment of functional constipation-related depression with probiotics and prebiotics: A narrative review. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1735614"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ahmed, S., Roberts, K.D., McCormick, T.S., and Ghannoum, M.A. (2026). Improving Growth Dynamics of Faecalibacterium prausnitzii by Exposure to Prebiotics. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27041698"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Yoo, S., Jung, S.C., Kwak, K., and Kim, J.S. (2024). The Role of Prebiotics in Modulating Gut Microbiota: Implications for Human Health. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094834"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"You, S., Ma, Y., Yan, B., Pei, W., Wu, Q., Ding, C., and Huang, C. (2022). The promotion mechanism of prebiotics for probiotics: A review. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.1000517"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2428848","DOI":"10.1080\/19490976.2024.2428848","article-title":"Prebiotics in food and dietary supplements: A roadmap to EU health claims","volume":"16","author":"Tuohy","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Gao, X., Hu, S., Liu, Y., De Alwis, S.A.S.S., Yu, Y., Li, Z., Wang, Z., and Liu, J. (2025). Dietary Fiber as Prebiotics: A Mitigation Strategy for Metabolic Diseases. Foods, 14.","DOI":"10.3390\/foods14152670"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Neyrinck, A.M., Nazare, J.A., Rodriguez, J., Jottard, R., Dib, S., Sothier, M., Berghe, L.V.D., Alligier, M., Alexiou, H., and Maquet, V. (2020). Development of a Repertoire and a Food Frequency Questionnaire for Estimating Dietary Fiber Intake Considering Prebiotics: Input from the FiberTAG Project. Nutrients, 12.","DOI":"10.21203\/rs.3.rs-31912\/v1"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.clnu.2019.03.002","article-title":"Nutritional interest of dietary fiber and prebiotics in obesity: Lessons from the MyNewGut consortium","volume":"39","author":"Delzenne","year":"2020","journal-title":"Clin. Nutr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1080\/19490976.2017.1290756","article-title":"Dietary fiber and prebiotics and the gastrointestinal microbiota","volume":"8","author":"Holscher","year":"2017","journal-title":"Gut Microbes"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3945\/an.115.010546","article-title":"Prebiotics, Fermentable Dietary Fiber, and Health Claims","volume":"7","author":"Delcour","year":"2016","journal-title":"Adv. Nutr."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev-food-081315-032749","article-title":"A Critical Look at Prebiotics Within the Dietary Fiber Concept","volume":"7","author":"Verspreet","year":"2016","journal-title":"Annu. Rev. Food Sci. Technol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1159\/000351483","article-title":"Probiotics, prebiotics, and dietary fiber in the management of functional gastrointestinal disorders","volume":"108","author":"Horvath","year":"2013","journal-title":"World Rev. Nutr. Diet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.gtc.2007.03.001","article-title":"Prebiotics, probiotics, and dietary fiber in gastrointestinal disease","volume":"36","author":"Park","year":"2007","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.biopsych.2016.12.031","article-title":"Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice","volume":"82","author":"Burokas","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"114153","DOI":"10.1016\/j.foodres.2024.114153","article-title":"Prebiotics modulate the microbiota-gut-brain axis and ameliorate anxiety and depression-like behavior in HFD-fed mice","volume":"182","author":"Paiva","year":"2024","journal-title":"Food Res. Int."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Chudzik, A., Orzy\u0142owska, A., Rola, R., and Stanisz, G.J. (2021). Probiotics, Prebiotics and Postbiotics on Mitigation of Depression Symptoms: Modulation of the Brain-Gut-Microbiome Axis. Biomolecules, 11.","DOI":"10.3390\/biom11071000"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e70703","DOI":"10.1002\/cam4.70703","article-title":"The Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression","volume":"14","author":"Lu","year":"2025","journal-title":"Cancer Med."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Banaszkiewicz, J.K., Kukie\u0142ka, A., Kudyk, E., Walczak, \u0141.J., Wicha-Komsta, K., Herbet, M., Pi\u0105tkowska-Chmiel, I., Nowicki, G., Mielnik, C.E., and Kocki, T. (2026). Modulation of the Kynurenine Pathway: A New Approach for Treating Neurodegeneration. Life, 16.","DOI":"10.3390\/life16020266"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"507","DOI":"10.9758\/cpn.2020.18.4.507","article-title":"Kynurenine Pathway of Tryptophan Metabolism in Neuropsychiatric Disorders: Pathophysiologic and Therapeutic Considerations","volume":"18","author":"Muneer","year":"2020","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, Y., Wang, W., Zhang, Y., Dong, X., and Liu, Y. (2025). Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease. Metabolites, 15.","DOI":"10.3390\/metabo15030210"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1178646920928984","DOI":"10.1177\/1178646920928984","article-title":"Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease","volume":"13","author":"Bosi","year":"2020","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/advances\/nmz127","article-title":"Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain","volume":"11","author":"Gao","year":"2020","journal-title":"Adv. Nutr."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Xu, M., Zhou, E.Y., and Shi, H. (2025). Tryptophan and Its Metabolite Serotonin Impact Metabolic and Mental Disorders via the Brain-Gut-Microbiome Axis: A Focus on Sex Differences. Cells, 14.","DOI":"10.3390\/cells14050384"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Kaur, H., Bose, C., and Mande, S.S. (2019). Tryptophan Metabolism by Gut Microbiome and Gut-Brain-Axis: An in silico Analysis. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01365"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Cheng, Y., Zhang, L., Li, Y., Zheng, C., Ma, T., and Sun, Z. (2026). The Gut Microbiota-Tryptophan-Brain Axis in Autism Spectrum Disorder: A New Frontier for Probiotic Intervention. Microorganisms, 14.","DOI":"10.3390\/microorganisms14020312"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Zhu, L., Hu, J., Li, J., Qu, X., Zhou, X., Gan, G., Liu, Y., Liu, S., and Chen, X. (2025). Sini San ameliorates symptoms of depression by modulating gut microbiota structure, Tryptophan metabolism, and short-chain fatty acid levels. BMC Complement. Med. Ther., 26.","DOI":"10.1186\/s12906-025-05190-5"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Blevins, H.M., Xu, Y., Biby, S., and Zhang, S. (2022). The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.879021"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Luo, Y., Long, M., Wu, X., and Zeng, L. (2025). Targeting the NLRP3 inflammasome in kidney disease: Molecular mechanisms, pathogenic roles, and emerging small-molecule therapeutics. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1703560"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Liu, B., and Yu, J. (2021). Anti-NLRP3 Inflammasome Natural Compounds: An Update. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020136"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Kelley, N., Jeltema, D., Duan, Y., and He, Y. (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133328"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1021\/acs.jafc.2c08444","article-title":"Rosmarinic Acid Restores Colonic Mucus Secretion in Colitis Mice by Regulating Gut Microbiota-Derived Metabolites and the Activation of Inflammasomes","volume":"71","author":"Wang","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Chhunchha, B., Kubo, E., Lehri, D., and Singh, D.P. (2025). NLRP3 Inflammasome and Inflammatory Response in Aging Disorders: The Entanglement of Redox Modulation in Different Outcomes. Cells, 14.","DOI":"10.3390\/cells14130994"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"110575","DOI":"10.1016\/j.biopha.2020.110575","article-title":"Lychee seed polyphenol inhibits A\u03b2-induced activation of NLRP3 inflammasome via the LRP1\/AMPK mediated autophagy induction","volume":"130","author":"Qiu","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"S203","DOI":"10.1111\/j.1750-3841.2007.00297.x","article-title":"Preventive antioxidant effects of cocoa polyphenolic extract on free radical production and cognitive performances after heat exposure in Wistar rats","volume":"72","author":"Rozan","year":"2007","journal-title":"J. Food Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s11011-018-0353-9","article-title":"Combined actions of blueberry extract and lithium on neurochemical changes observed in an experimental model of mania: Exploiting possible synergistic effects","volume":"34","author":"Spohr","year":"2019","journal-title":"Metab. Brain Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"129108","DOI":"10.1016\/j.foodchem.2021.129108","article-title":"Evaluation of the inhibition of monoamine oxidase A by bioactive coffee compounds protecting serotonin degradation","volume":"348","author":"Grzelczyk","year":"2021","journal-title":"Food Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.trsl.2016.10.002","article-title":"Feeding the microbiota-gut-brain axis: Diet, microbiome, and neuropsychiatry","volume":"179","author":"Sandhu","year":"2017","journal-title":"Transl. Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.pnpbp.2013.07.009","article-title":"Antidepressant-like effects of curcumin in chronic mild stress of rats: Involvement of its anti-inflammatory action","volume":"47","author":"Jiang","year":"2013","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ejphar.2015.10.026","article-title":"Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB\/BDNF signaling in mice","volume":"768","author":"Ge","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1002\/biof.1533","article-title":"Benefits of curcumin in brain disorders","volume":"45","author":"Bhat","year":"2019","journal-title":"Biofactors"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s10522-017-9696-6","article-title":"Consumption of green tea epigallocatechin-3-gallate enhances systemic immune response, antioxidative capacity and HPA axis functions in aged male swiss albino mice","volume":"18","author":"Sharma","year":"2017","journal-title":"Biogerontology"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Sonali, S., Ray, B., Ahmed Tousif, H., Rathipriya, A.G., Sunanda, T., Mahalakshmi, A.M., Rungratanawanich, W., Essa, M.M., Qoronfleh, M.W., and Chidambaram, S.B. (2022). Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review. 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