Eggerthella lenta evades bacteriophage through reversible megabase-scale inversions of capsular polysaccharide gene clusters

Eggerthella lenta evades bacteriophage through reversible megabase-scale inversions of capsular polysaccharide gene clusters | 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 Eggerthella lenta evades bacteriophage through reversible megabase-scale inversions of capsular polysaccharide gene clusters Peter Turnbaugh, Shenwei Zhang, Colin Buttimer, Kai Trepka, Kathy Lam, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9488777/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 Bacteriophages are a promising tool for microbiome editing, yet their development has been constrained by limited insights into bacteriophage-host interactions within their shared mammalian body habitat. We isolated a lytic phage ΦKL11 that efficiently targets a disease-associated member of the human gut microbiota, Eggerthella lenta , during in vitro growth. However, ΦKL11 selects for a pre-existing and reversible bacteriophage-resistant sub-population in mice. Long-read sequencing revealed a massive genomic inversion event, representing >50% of the E. lenta genome, enriched in response to bacteriophage infection. Transcriptomics linked this inversion to the altered expression of three capsular polysaccharide synthesis (CPS) gene clusters and transmission electron microscopy confirmed differential capsule production. Finally, we show that ΦKL11 has a broad host range attributable to CPS and other strain-variable genes. These findings suggest a previously unrecognized strategy for phage evasion in the gut, involving megabase-scale genomic inversions and reversible capsule variation driving phage resistance. Biological sciences/Microbiology/Microbial communities/Microbiome Biological sciences/Microbiology/Virology/Phage biology microbiome editing human gut microbiome phage-host interaction Eggerthella lenta bacteriophage genomic structural variation chromosomal inversion capsular polysaccharide phage resistance phase variation Full Text Additional Declarations Yes there is potential Competing Interest. P.J.T. is on the scientific advisory boards of Pendulum and SNIPRbiome. All other authors declare no competing interests. Supplementary Files LentaphageNatMicroSupplTables.xlsx Supplementary Tables 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. 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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-9488777","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":634329208,"identity":"7ef20540-3a41-46d8-8d74-fa808f9c6857","order_by":0,"name":"Peter 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