AbstractPostoperative delirium is associated with both gut microbiota alterations and Tau phosphorylation; however, how these factors interact and jointly contribute to postoperative delirium remains poorly understood. This prospective observational cohort study screened 491 patients aged ≥65 years undergoing elective laminectomy or hip or knee replacement under general or spinal anesthesia at Massachusetts General Hospital (2016–2020). The study aimed to assess the correlation between plasma Tau protein levels, specific gut microbiota, and the gut microbiota-derived metabolite indole-3-propionic acid (IPA) in participants with and without postoperative delirium. Exclusion criteria included major neurological disease, smoking history, sensory impairment, and recent antibiotic use. Delirium was assessed 24–48 h postoperatively. Out of 491 screened participants, 139 had blood biomarker data, and 86 had gut microbiota data included in the final analysis. Ten percent of the participants experienced postoperative delirium. Co-occurrence network analysis demonstrated that microbial interactions differed between postoperative delirium and non-postoperative delirium groups. Significant associations among gut microbiota, IPA, and Tau biomarkers were observed only in postoperative delirium participants. Additionally, three machine learning classifiers distinguished postoperative delirium cases from non-postoperative delirium cases with Area Under the Curve values above 50%. The results suggest that plasma Tau may interact with gut microbiota, and this interaction is associated with postoperative delirium, suggesting the involvement of a gut–blood-brain axis in postoperative delirium vulnerability. These findings implicate a microbiota–Tau interaction that may represent both a potential pathogenic mechanism and a therapeutic target for postoperative delirium pending confirmative studies. Furthermore, machine learning classifiers utilizing microbiome-derived features demonstrate a potential in distinguishing patients with and without postoperative delirium.This is a preview of subscription content, access via your institutionAccess options Access through your institutionSubscribe to this journalReceive 12 print issues and online access269,00 € per yearonly 22,42 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Study Enrollment Design, Patient Inclusion, and Sample Disposition Flow Chart.Fig. 2: Comparison of Gut Microbial Networks between Postoperative Delirium and Non-Postoperative Delirium Participants.Fig. 3: Correlations Between Gut Microbiota and Plasma Biomarkers between Postoperative Delirium and Non-Postoperative Delirium Participants.Fig. 4: Hypothesis-generating schematic summarizing a conceptual framework linking surgical/perioperative stress, gut microbiota alterations, microbial metabolites, and postoperative delirium.Data availabilityThis study exclusively analyzed previously published datasets. No new data were generated or deposited as part of this work. The gut microbiota data used in this study were originally reported by Zhang et al. [11], and are publicly available in the NCBI Sequence Read Archive (SRA) under BioProject accession number PRJNA967718 (https://www.ncbi.nlm.nih.gov/sra/PRJNA967718). The plasma phosphorylated-Tau data were originally reported by Liang et al. [16], and the indole-3-propionic acid (IPA) data were originally reported by Zhou et al. [21]. Readers should refer to the original articles for dataset access links and associated documentation.ReferencesAbelha FJ, Luís C, Veiga D, Parente D, Fernandes V, Santos P, et al. Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery. Crit Care. 2013;17:R257.Article PubMed PubMed Central Google Scholar Kirfel A, Guttenthaler V, Mayr A, Coburn M, Menzenbach J, Wittmann M. 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J Clin Anesth. 2025;104:111855.Article CAS PubMed PubMed Central Google Scholar Download referencesAcknowledgementsThe authors thank Han Chen from the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital for assistance with part of the Fig. 1 design. The authors also acknowledge support from the Anesthesia Research Center, housed within the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital.FundingY.Z. discloses support for the research of this work from the National Institutes of Health, Bethesda, MD, USA [grant numbers R21AG065606, R21AG081763 and R35GM166431]. Y.Z. also discloses philanthropic gift support from the Tang Family and Sygenis Company. Z.X. discloses support for the research of this work from the National Institutes of Health, Bethesda, MD, USA [grant numbers R01AG062509, RF1AG070761, R01AG041274 and R01AG098122]. S.Sh. discloses support for the research of this work from the National Institutes of Health, Bethesda, MD, USA [grant numbers R01AG082975, R01AG070141 and R01AT013489].Author informationAuthor notesKathryn BaldygaPresent address: Marcus Institute for Aging Research - Hebrew SeniorLife, Roslindale, MA, 02131, USKali StevensPresent address: Orthopedic Hand Surgery Fellowship at Philadelphia Hand to Shoulder Center, Philadelphia, PA, USJúlio Ken MatsubaraPresent address: Department of Medicine, Faculdade de Medicina de Marília, Marília, SP, 17519-030, BrazilThese authors contributed equally: Wenyu Song, Shrishti Singh, Wang Xiang.Authors and AffiliationsDepartment of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USWenyu SongDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USShrishti Singh, Kathryn Baldyga, Kali Stevens, Wei Qi, Júlio Ken Matsubara, Hao Deng, Ji-Eun Kim, Shiqian Shen & Yiying ZhangStem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA, 90033, USWang XiangDepartment of Computer Science and Engineering, University of Minnesota - Twin Cities, Minneapolis, MN, 55455, USChang GeDivisions of General Medicine and Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USEdward R. MarcantonioDepartment of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USZhongcong XieAuthorsWenyu SongView author publicationsSearch author on:PubMed Google ScholarShrishti SinghView author publicationsSearch author on:PubMed Google ScholarWang XiangView author publicationsSearch author on:PubMed Google ScholarKathryn BaldygaView author publicationsSearch author on:PubMed Google ScholarKali StevensView author publicationsSearch author on:PubMed Google ScholarWei QiView author publicationsSearch author on:PubMed Google ScholarJúlio Ken MatsubaraView author publicationsSearch author on:PubMed Google ScholarChang GeView author publicationsSearch author on:PubMed Google ScholarHao DengView author publicationsSearch author on:PubMed Google ScholarJi-Eun KimView author publicationsSearch author on:PubMed Google ScholarEdward R. MarcantonioView author publicationsSearch author on:PubMed Google ScholarShiqian ShenView author publicationsSearch author on:PubMed Google ScholarZhongcong XieView author publicationsSearch author on:PubMed Google ScholarYiying ZhangView author publicationsSearch author on:PubMed Google ScholarContributionsStudy concept and design: ZX, YZ, SQS and ERM Acquisition of data: ZX, SQS, KB, KS, and YZ Analysis and interpretation of data: YZ, WS, WX, HD, CG, SS, JEK and JEK. Drafting of the manuscript: WS, WX, SS, ZX., WQ, WS. and YZ. Critical revision of the manuscript for important intellectual content: HD, CG, ZX, and ERM. Obtained funding: SQS, ZX and YZ Administrative, technical, and material support: WS, SQS, ZX, and YZ Study supervision: ZX, SQS, and YZ All authors approved the manuscript.Corresponding authorsCorrespondence to Zhongcong Xie or Yiying Zhang.Ethics declarationsCompeting interestsThe authors declare no competing or conflicting interests to disclose for the present study. Dr. Zhongcong Xie provided consulting services to Baxter (Deerfield, IL), NanoMosaic (Waltham, MA), Shanghai Fourth, Ninth, and Tenth Hospitals, the Shanghai Mental Health Center affiliated with Shanghai Jiao Tong University School of Medicine (Shanghai, P.R. China), and the journal Anesthesiology and Perioperative Science (Chengdu, P. R. China) within the past 36 months, but is not currently engaged in any of these roles.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationRights and permissionsSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsAbout this article