Gut microbiota characteristics and its immunoregulatory role in inflammatory depression: joint clinical and animal data

Gut microbiota characteristics and its immunoregulatory role in inflammatory depression: joint clinical and animal data | 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 Article Gut microbiota characteristics and its immunoregulatory role in inflammatory depression: joint clinical and animal data Kerang Zhang, Penghong Liu, Zhifen Liu, Jizhi Wang, Junyan Wang, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3154268/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Apr, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Previous studies have reported that inflammatory depression is a treatment-resistant depression subtype and that disturbed gut microbiota may be the source of low-grade inflammation. But the gut microbiota’s features and its role of immunoregulation in this subtype of depression remains uncertain. We propose that Toll-like receptor 4 (TLR-4)/nuclear factor kappa-B (NF-κB) and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway activated by disordered gut microbiota could contribute to intestinal and central inflammation in inflammatory depression. To test this hypothesis, we performed studies in both humans and mice. Gut microbiota composition in stool, inflammation factor and short chain fatty acid (SCFAs) in plasma, inflammatory and permeability marker in intestinal mucosa were analyzed in inflammatory depression patients. Then we performed fecal microbiota transplantation (FMT) and probiotic supplement to determine whether the behavioral phenotypes were linked with disturbed gut microbiota in inflammatory depression. Compared with non-inflammatory depression and HCs, the relative abundance of Bacteroides was significantly higher, and Clostridium was lower in inflammatory depression patients. Further, we found that SCFA-producing species increased with abnormal butanoate metabolism in the inflammatory depression patients following shotgun metagenomic sequencing. After FMT, gut microbiota in inflammatory depression increased inflammatory factors, those including as hs-CRP, TLR-4, NF-κB, NLRP3, Caspase-1, Interleukin-1β (IL-1β), and iba-1. We also found that intestinal mucosal permeability increased in recipient mice with depressive and anxiety-like behaviors. Clostridium butyricum treatment can normalize the gut microbiota, repair “gut leak,” decrease peripheral and central inflammatory factors, and have an antidepressant-like effect in the mouse model inflammatory depression. Together, our study findings indicate that inflammatory depression patients have increased pro-inflammatory genera and decreased SCFA-producing genera. Gut microbiota-derived inflammatory processes mediated by TLR-4/NF-κB–NLRP3 inflammasome signaling pathway are involved in neuroinflammation in inflammatory depression. Health sciences/Diseases/Psychiatric disorders/Depression Health sciences/Medical research/Biomarkers/Diagnostic markers Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementalmaterialandmethods.doc Dataset all Cite Share Download PDF Status: Published Journal Publication published 08 Apr, 2024 Read the published version in Nature Communications → 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. 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data\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3154268/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3154268/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePrevious studies have reported that inflammatory depression is a treatment-resistant depression subtype and that disturbed gut microbiota may be the source of low-grade inflammation. But the gut microbiota’s features and its role of immunoregulation in this subtype of depression remains uncertain. We propose that Toll-like receptor 4 (TLR-4)/nuclear factor kappa-B (NF-κB) and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway activated by disordered gut microbiota could contribute to intestinal and central inflammation in inflammatory depression. To test this hypothesis, we performed studies in both humans and mice. Gut microbiota composition in stool, inflammation factor and short chain fatty acid (SCFAs) in plasma, inflammatory and permeability marker in intestinal mucosa were analyzed in inflammatory depression patients. Then we performed fecal microbiota transplantation (FMT) and probiotic supplement to determine whether the behavioral phenotypes were linked with disturbed gut microbiota in inflammatory depression. Compared with non-inflammatory depression and HCs, the relative abundance of \u003cem\u003eBacteroides \u003c/em\u003ewas significantly higher, and \u003cem\u003eClostridium \u003c/em\u003ewas lower in inflammatory depression patients. Further, we found that SCFA-producing species increased with abnormal butanoate metabolism in the inflammatory depression patients following shotgun metagenomic sequencing. After FMT, gut microbiota in inflammatory depression increased inflammatory factors, those including as hs-CRP, TLR-4, NF-κB, NLRP3, Caspase-1, Interleukin-1β (IL-1β), and iba-1. We also found that intestinal mucosal permeability increased in recipient mice with depressive and anxiety-like behaviors. Clostridium butyricum treatment can normalize the gut microbiota, repair “gut leak,” decrease peripheral and central inflammatory factors, and have an antidepressant-like effect in the mouse model inflammatory depression. Together, our study findings indicate that inflammatory depression patients have increased pro-inflammatory genera and decreased SCFA-producing genera. 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