Bidirectional Causality in IBD and Periodontitis: Insights from Mendelian Randomization and Bioinformatics

Bidirectional Causality in IBD and Periodontitis: Insights from Mendelian Randomization and Bioinformatics | 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 Research Article Bidirectional Causality in IBD and Periodontitis: Insights from Mendelian Randomization and Bioinformatics Zhijun Feng, Zhongyi Gu, Aichao Gao, Xiang Ma, Xiaotong Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5966082/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Background The causal relationship between inflammatory bowel disease (IBD) and periodontitis remains a topic of debate. This study aimed to assess the causal relationship between the two. Methods This study employed a bidirectional Mendelian randomization (MR) analysis combined with integrated bioinformatics. On one hand, it explored the causal relationship between IBD and periodontitis using bidirectional MR analysis, with inverse variance weighting (IVW) as the judgment basis and conducted sensitivity analysis. On the other hand, it utilized RNA sequencing data to mine the co-expressed differential genes between the two diseases, to explore the common inflammatory molecules and potential molecular signaling pathways between them. Results The study found a bidirectional causal link between IBD and periodontitis ( P 0.05). The results of the MR analysis further confirmed the causal relationship between them. The integrated bioinformatics analysis indicated that immune-related factors, represented by IL1B and CXCR4, and signaling pathways, notably TNF and IL17, may play an important role in the progression of both diseases. Conclusion This study, through Mendelian Randomization analysis, established a mutual causal relationship between IBD and periodontitis. The transcriptome sequencing data analysis revealed the common pathological mechanisms and the role of key immune regulatory factors in these diseases. These findings provide important scientific basis for the diagnosis and treatment of IBD and periodontitis, emphasizing the importance of a deep understanding of the interaction between these diseases. Epigenetics & Genomics causal relationship inflammatory bowel disease IBD periodontitis Mendelian randomization integrated bioinformatics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-5966082","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":581226747,"identity":"cd4a467b-0d90-4124-ba49-a3506ca89f52","order_by":0,"name":"Zhijun Feng","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhijun","middleName":"","lastName":"Feng","suffix":""},{"id":581226748,"identity":"fc2f7eca-98b5-4301-a79d-4e6e8974638b","order_by":1,"name":"Zhongyi Gu","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhongyi","middleName":"","lastName":"Gu","suffix":""},{"id":581226749,"identity":"3a059ad5-aefa-43fa-b65f-d0d2d704b143","order_by":2,"name":"Aichao Gao","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Aichao","middleName":"","lastName":"Gao","suffix":""},{"id":581226750,"identity":"bbc2021e-7532-401d-b233-3bb98bc2e902","order_by":3,"name":"Xiang Ma","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Ma","suffix":""},{"id":581226751,"identity":"ea1c9755-0816-4511-adeb-fc49e05f5a72","order_by":4,"name":"Xiaotong Wang","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaotong","middleName":"","lastName":"Wang","suffix":""},{"id":581226752,"identity":"c880f145-1499-423f-a8bf-8d336d6608db","order_by":5,"name":"Caiqing Qiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYLCCCgaGejb2xsbHUL4BYS1nGBgS+HgOHzYmTYuchFuaNFFaDG4kP3twoOJOHpsEj1l1wZ9t8gzszdskGGru4NGSZm5w4MyzYjbpHrPbM3huGzbwHCuTYDj2DI+WBDPpj22HGdtkzpjd5pG4ncAgkWMmwdhwGI+W9G8SB/8BtQBVFvMYALXIvyGkBWjmwYbDiW0SaWnMPAkgW3jwa5E886ZM4sCxw8ZswECWnnHgtmEbT1qxRcIx3Fr4jqdvkzhQc1hOvr2x8XPBn9vy/OyHN974UINbi8IBdBE2EJGAUwMDg3wDHslRMApGwSgYBWAAACVPWZGJ5/tQAAAAAElFTkSuQmCC","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Caiqing","middleName":"","lastName":"Qiu","suffix":""},{"id":581226753,"identity":"bbb648ec-0008-47dc-9719-1ad800eb4fce","order_by":6,"name":"Shupeng Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYBACfmbmgw8SDGzk+CF8ZsJaJNvbkg0+VKQZSzYQq8XgzBkzyRlnDiVuOECsFoYbCQbSvG0HGDefP50mwVBhndjAfvYAXh2MMxISjHnb7jCb3cjdJsFwJj2xgScvAa8WZomEA8m8bc/YzG7wbpNgbDuc2CDBY4BXC5tEYsNh3rbDPMb9Z4Fa/hGhhYfnMGPjjDOHJQwYgA5jbCBCiwR7GzMDMJANJG7kbrZIOJZu3MaTg1+L/WH+7z+AUVnf3392440PNday/exn8GtBBQkg35GgfhSMglEwCkYBDgAAA2hI7fBnYeMAAAAASUVORK5CYII=","orcid":"","institution":"Southern Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shupeng","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-02-05 13:23:32","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5966082/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-5966082/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102069950,"identity":"370eedd3-9efa-46d7-8b1d-733caadc9c61","added_by":"auto","created_at":"2026-02-06 19:19:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":112620,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis workflow and the details of the datasets\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2/49e58d325646814180ab2d42.png"},{"id":102069956,"identity":"2c39e927-c29f-48b4-8488-afdbf57e2693","added_by":"auto","created_at":"2026-02-06 19:19:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":590493,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot for Mendelian randomization (MR) results. 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The vertical line at coordinate 0 is the reference line.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2/15313f23c984f661d870448d.png"},{"id":102069952,"identity":"24c192d4-740b-4e42-bd75-a38f842f5903","added_by":"auto","created_at":"2026-02-06 19:19:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":130440,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plots for effects of genetic liability to exposure on outcomes in this bidirectional MR analysis. Each point represents an included SNP, and the color of the lines corresponds to the methods described in the legend.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2/416d868e505f8199e8393d5d.png"},{"id":102295782,"identity":"2ef1f5bf-c87c-495b-aadb-32da9697c94e","added_by":"auto","created_at":"2026-02-10 10:15:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":192085,"visible":true,"origin":"","legend":"\u003cp\u003eLeave-one-out tests were conducted to evaluate the effects of excluding individual SNP on the results of MR analysis.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2/14d678e613f250a70ebb7bfb.png"},{"id":102295698,"identity":"6a2cf652-b053-42bd-ad16-3ae047e682e7","added_by":"auto","created_at":"2026-02-10 10:14:03","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":283184,"visible":true,"origin":"","legend":"\u003cp\u003eDifferential gene expression in patients with IBD (A, C) and periodontitis (B, D). PD, chronic periodontitis; down, down-regulated genes, up, up-regulated genes; stable, genes whose expression with no significance between disease and healthy tissues.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2/623765997d8403b92286dbe3.png"},{"id":102295946,"identity":"724fe4b2-7e93-4932-afc9-83c0ab1d3891","added_by":"auto","created_at":"2026-02-10 10:16:20","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":463141,"visible":true,"origin":"","legend":"\u003cp\u003eThe results of enrichment analysis and PPI network of Co-DEGs.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2/4d52a2f51c309f29db8f527f.png"},{"id":102299001,"identity":"952b2ed0-01f7-467f-bd0e-b126c4327a98","added_by":"auto","created_at":"2026-02-10 11:02:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1754162,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5966082/v2_covered_08660fe0-89f9-4e97-b874-c322c41f999f.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Bidirectional Causality in IBD and Periodontitis: Insights from Mendelian Randomization and Bioinformatics","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"causal relationship, inflammatory bowel disease, IBD, periodontitis, Mendelian randomization, integrated bioinformatics","lastPublishedDoi":"10.21203/rs.3.rs-5966082/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5966082/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe causal relationship between inflammatory bowel disease (IBD) and periodontitis remains a topic of debate. This study aimed to assess the causal relationship between the two.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study employed a bidirectional Mendelian randomization (MR) analysis combined with integrated bioinformatics. On one hand, it explored the causal relationship between IBD and periodontitis using bidirectional MR analysis, with inverse variance weighting (IVW) as the judgment basis and conducted sensitivity analysis. On the other hand, it utilized RNA sequencing data to mine the co-expressed differential genes between the two diseases, to explore the common inflammatory molecules and potential molecular signaling pathways between them.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study found a bidirectional causal link between IBD and periodontitis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with the sensitivity analysis showing consistency and no significant heterogeneity or pleiotropy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The results of the MR analysis further confirmed the causal relationship between them. The integrated bioinformatics analysis indicated that immune-related factors, represented by IL1B and CXCR4, and signaling pathways, notably TNF and IL17, may play an important role in the progression of both diseases.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study, through Mendelian Randomization analysis, established a mutual causal relationship between IBD and periodontitis. The transcriptome sequencing data analysis revealed the common pathological mechanisms and the role of key immune regulatory factors in these diseases. These findings provide important scientific basis for the diagnosis and treatment of IBD and periodontitis, emphasizing the importance of a deep understanding of the interaction between these diseases.\u003c/p\u003e","manuscriptTitle":"Bidirectional Causality in IBD and Periodontitis: Insights from Mendelian Randomization and Bioinformatics","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-02-06 19:19:38","doi":"10.21203/rs.3.rs-5966082/v2","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}},{"code":1,"date":"2025-02-10 12:12:38","doi":"10.21203/rs.3.rs-5966082/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":"257c2c93-f897-424d-b810-7863cbf0ff5c","owner":[],"postedDate":"February 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61833668,"name":"Epigenetics \u0026 Genomics"}],"tags":[],"updatedAt":"2025-02-10T13:54:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-06 19:19:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-5966082","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5966082","identity":"rs-5966082","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}