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Adv."],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">Clostridioides difficile<\/jats:italic>\n                    is a major cause of antibiotic-associated diarrhea. This pathogen produces toxins essential for disease and flagella that promote intestinal colonization. Flagella and toxins are coregulated in an ON\/OFF manner leading to a heterogeneous population of toxigenic, flagellated cells (\n                    <jats:italic toggle=\"yes\">flg<\/jats:italic>\n                    -ON) and aflagellate cells with attenuated toxin production (\n                    <jats:italic toggle=\"yes\">flg<\/jats:italic>\n                    -OFF). How selective pressures affect ON\/OFF switching dynamics and overall population composition is unknown. Here, we use a mouse model of disease to evaluate the ON\/OFF makeup of the\n                    <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                    population in vivo. Two key results emerged: (i) Directional inversion of the\n                    <jats:italic toggle=\"yes\">flg<\/jats:italic>\n                    switch to the \u201cON\u201d orientation occurs during spore germination, and (ii) toxin-induced inflammation enriches for a\n                    <jats:italic toggle=\"yes\">flg<\/jats:italic>\n                    -OFF population during infection. These findings reveal a cycle in which predominantly\n                    <jats:italic toggle=\"yes\">flg<\/jats:italic>\n                    -OFF spores are disseminated into the environment, and spore germination in the next host resets\n                    <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                    to a virulent population of motile, toxigenic cells at infection onset.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg1542","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:01:07Z","timestamp":1786557667000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A programmed reset mechanism primes\n                    <i>Clostridioides difficile<\/i>\n                    virulence at the onset of infection"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7493-8136","authenticated-orcid":true,"given":"Nicole C.","family":"Gadda","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilarie A.","family":"Santos-Santiago","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-4675","authenticated-orcid":true,"given":"Rani S.","family":"Sellers","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3745-3316","authenticated-orcid":true,"given":"Rita","family":"Tamayo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 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