Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology | 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 bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology Federico Rey, Vaibhav Vemuganti, Jea Kang, Qijun Zhang, Sandra Harding, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7077445/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 The gut microbiome influences metabolic, immune, and neuroinflammatory processes that are increasingly implicated in the pathophysiology of Alzheimer’s disease (AD). Alterations in microbial composition have been associated with cognitive decline, systemic inflammation, and disruptions in the gut-brain axis observed in AD. Despite a growing number of studies linking gut dysbiosis to AD-related brain changes, the underlying mechanisms remain poorly understood. The bacterial metabolite imidazole propionate (ImP) has been previously associated with dementia risk factors, including type 2 diabetes and cardiovascular disease, however, the impact of ImP on brain remains relatively unknown. Here, we show that elevated plasma ImP levels are associated with lower cognitive performance and biomarkers of AD pathology in a large cohort of cognitively unimpaired individuals (>1,100). Furthermore, high plasma ImP levels predicted accelerated progression of AD-related pathology. Metagenomic profiling of stool samples identified gut bacteria encoding predicted orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Supporting the human observations, chronic ImP administration in AD mouse model activated neurodegenerative pathways, exacerbated AD pathology, and increased blood-brain barrier (BBB) permeability. Finally, in vitro studies showed that ImP compromised the integrity of human brain endothelial cells. Together, these findings implicate ImP in AD progression and position it as a potential target for early intervention. Health sciences/Diseases/Neurological disorders/Dementia/Alzheimer's disease Health sciences/Medical research/Biomarkers/Predictive markers Full Text Additional Declarations Yes there is potential Competing Interest. KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sunbird Bio, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of MicThera (outside submitted work). 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-7077445","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":489220905,"identity":"eef841a8-e327-4555-8640-5eb63845e06e","order_by":0,"name":"Federico 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potential Competing Interest.\nKB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sunbird Bio, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp \u0026 Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of MicThera (outside submitted work).","formattedTitle":"Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-7077445/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7077445/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The gut microbiome influences metabolic, immune, and neuroinflammatory processes that are increasingly implicated in the pathophysiology of Alzheimer’s disease (AD). Alterations in microbial composition have been associated with cognitive decline, systemic inflammation, and disruptions in the gut-brain axis observed in AD. Despite a growing number of studies linking gut dysbiosis to AD-related brain changes, the underlying mechanisms remain poorly understood. The bacterial metabolite imidazole propionate (ImP) has been previously associated with dementia risk factors, including type 2 diabetes and cardiovascular disease, however, the impact of ImP on brain remains relatively unknown. Here, we show that elevated plasma ImP levels are associated with lower cognitive performance and biomarkers of AD pathology in a large cohort of cognitively unimpaired individuals (\u003e1,100). Furthermore, high plasma ImP levels predicted accelerated progression of AD-related pathology. Metagenomic profiling of stool samples identified gut bacteria encoding predicted orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Supporting the human observations, chronic ImP administration in AD mouse model activated neurodegenerative pathways, exacerbated AD pathology, and increased blood-brain barrier (BBB) permeability. Finally, in vitro studies showed that ImP compromised the integrity of human brain endothelial cells. 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