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Among this population,\n                      <jats:italic toggle=\"yes\">Enterococcus faecalis<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Ef<\/jats:italic>\n                      ) represents a common member of intestinal microbiota, colonizing humans early in life but also capable of opportunistically infecting its host. Despite its importance in human health, investigations of its physiological adaptation to the mucosal environment remain limited. Building on recent advances in tissue engineering, we here leverage human colonic organoids (colonoids) to investigate the\n                      <jats:italic toggle=\"yes\">Ef<\/jats:italic>\n                      \u2019s mechanisms of mucosal surface colonization across space and time. Using high-resolution microscopy, we visualized\n                      <jats:italic toggle=\"yes\">Ef<\/jats:italic>\n                      growth within the natively formed colonic mucus layer in colonoids. Leveraging a custom perfusion chamber, we tracked\n                      <jats:italic toggle=\"yes\">Ef<\/jats:italic>\n                      growth within the mucus of live colonoids over time under flow, which revealed specific colonization strategies, including biofilm-like microcolony formation. To identify\n                      <jats:italic toggle=\"yes\">Ef<\/jats:italic>\n                      fitness determinants in this niche, we implemented transposon insertion sequencing (Tn-seq) in the natively formed mucus of live colonoids. This approach revealed a large fitness rearrangement compared to typical liquid culture, mainly involving metabolic activity and regulatory response during mucosal colonization, as well as factors that may contribute to colony formation at the mucosal surface. Altogether, our results show important physiological and biophysical adaptation of\n                      <jats:italic toggle=\"yes\">Ef<\/jats:italic>\n                      to the mucosal surface that are not captured by\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      conditions and that cannot be revealed\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      at high resolution.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Gut microbiota interactions with mucus during early intestinal colonization are critical for establishing stable communities and influencing host health. Using human colonic organoids combined with Tn-seq and live imaging, this study reveals how\n                      <jats:italic toggle=\"yes\">Enterococcus faecalis<\/jats:italic>\n                      adapts to the mucosal surface by forming microcolonies and reprogramming its metabolism. This integrative approach provides a powerful platform to study other microbiota members in the native-like environment of the large intestine and evaluate potential therapeutic interventions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.01304-25","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T13:00:17Z","timestamp":1773147617000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Adaptation of\n                    <i>Enterococcus faecalis<\/i>\n                    to intestinal mucus revealed by a human colonic organoid model"],"prefix":"10.1128","volume":"11","author":[{"given":"Sofya","family":"Mikhaleva","sequence":"first","affiliation":[{"name":"School of Life Sciences, Global Health Institute, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL)","place":["Lausanne, Switzerland"]},{"name":"School of Life Sciences, Institute of Bioengineering, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5270-7386","authenticated-orcid":false,"given":"Po-Long","family":"Hsiao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Global Health Institute, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL)","place":["Lausanne, Switzerland"]},{"name":"School of Life Sciences, Institute of Bioengineering, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanzhol","family":"Kurmashev","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering, ETH Z\u00fcrich","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3395-7805","authenticated-orcid":true,"given":"Caleb M.","family":"Anderson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01swzsf04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Colomer-Winter","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01swzsf04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A.","family":"Boos","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering, ETH Z\u00fcrich","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei Yi","family":"Choo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02e7b5302","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0524-8289","authenticated-orcid":true,"given":"Julia L. 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KC Kahnwald M Barbiero S de Medeiros G Suppinger S Kalck V Meylan LC Smallwood SA Stadler MB Liberali P. 2023. 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