Time-restricted feeding ameliorates type 2 diabetes via gut microbiota–bile acids-liver axis

Time-restricted feeding ameliorates type 2 diabetes via gut microbiota–bile acids-liver axis | 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 Time-restricted feeding ameliorates type 2 diabetes via gut microbiota–bile acids-liver axis Xuebo Liu, Shaobo Ma, Wanjun Gu, Gianmarco Bellucci, Xiaowei Bo, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8605936/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Time-restricted feeding (TRF) improves metabolic health, yet the pathways linking feeding rhythms to host–microbe metabolic integration remain unclear. Using clinical profiling, humanized mouse models, and network analysis, we characterize a liver-driven metabolic axis mediating TRF’s benefits in type 2 diabetes (T2DM). We show that hepatic HNF4α–CYP8B1 pathway dysregulation contributes to T2DM by increasing 12α-hydroxylated bile acids and altering the gut microbial environment, specifically depleting Parabacteroides distasonis . TRF suppresses this hepatic pathway, shifting the bile acid pool toward non-12α-hydroxylated species like ursodeoxycholic acid (UDCA), thereby creating a permissive niche for the restoration of beneficial gut microbes, including P. distasonis . Although supplementation with P. distasonis or UDCA provides partial metabolic improvements, only TRF corrects the upstream hepatic driver, HNF4α. These findings suggest TRF improves T2DM by realigning the liver–bile acid–microbiota axis, highlighting feeding timing as a regulator of host and microbial metabolism. Health sciences/Health care/Nutrition Health sciences/Diseases/Endocrine system and metabolic diseases/Diabetes/Type 2 diabetes Health sciences/Gastroenterology/Gastrointestinal diseases/Dysbiosis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementarytable.pdf Supplementary Tables Supplementaryfigure.pdf Supplementary Figures Cite Share Download PDF Status: Under Review 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. 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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-8605936","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":579487583,"identity":"1aac2a1d-387a-4ec0-b5c8-05dfb0b5654d","order_by":0,"name":"Xuebo 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Using clinical profiling, humanized mouse models, and network analysis, we characterize a liver-driven metabolic axis mediating TRF’s benefits in type 2 diabetes (T2DM). We show that hepatic HNF4α–CYP8B1 pathway dysregulation contributes to T2DM by increasing 12α-hydroxylated bile acids and altering the gut microbial environment, specifically depleting \u003ci\u003eParabacteroides distasonis\u003c/i\u003e. TRF suppresses this hepatic pathway, shifting the bile acid pool toward non-12α-hydroxylated species like ursodeoxycholic acid (UDCA), thereby creating a permissive niche for the restoration of beneficial gut microbes, including \u003ci\u003eP. distasonis\u003c/i\u003e. Although supplementation with \u003ci\u003eP. distasonis\u003c/i\u003e or UDCA provides partial metabolic improvements, only TRF corrects the upstream hepatic driver, HNF4α. 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