{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:55:19Z","timestamp":1791298519947,"version":"4.1.0"},"reference-count":57,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100008982","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE-2137424"],"award-info":[{"award-number":["DGE-2137424"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI195616"],"award-info":[{"award-number":["R01 AI195616"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007015","name":"University of Wisconsin-Madison","doi-asserted-by":"publisher","award":["Startup funds"],"award-info":[{"award-number":["Startup funds"]}],"id":[{"id":"10.13039\/100007015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Bacteriol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Clostridioides difficile<\/jats:italic>\n                      is an urgent threat to human health. Current treatments for\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      infections (CDIs) are antibiotics and microbiome restoration therapy (MRT) for recurrent cases. However, antibiotics contribute to antibiotic resistance and recurrent CDIs, and the long-term sustainability and accessibility of MRTs remain to be determined. Since a dysbiotic gut microbiome is the primary risk factor for CDI, a better understanding of the interactions between\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      , the microbiome, and the host will aid development of treatments with improved precision. Emerging evidence supports that butyrate, a prominent end product of gut microbiome metabolism, is a key determinant of\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      pathogenesis. Notably,\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      releases more of its toxins (TcdA and TcdB) in butyrate-rich environments. Here, we demonstrate that butyrate-dependent toxin release is not driven by two previously characterized modes of toxin release (e.g., TcdE-dependent secretion or Cwp19-dependent autolysis). Instead, butyrate enhances the expression of a broadly conserved endolysin (EndD), which is responsible for butyrate-dependent toxin release. We additionally demonstrate that\n                      <jats:italic toggle=\"yes\">endD<\/jats:italic>\n                      -dependent toxin release does not universally occur under all growth conditions, that its expression is dependent on the late-stage sporulation sigma factor SigK, and that\n                      <jats:italic toggle=\"yes\">endD<\/jats:italic>\n                      enhances butyrate-dependent sporulation. Overall, our findings provide deeper insight into butyrate-dependent effects on\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      pathogenesis and set the stage for future work to better understand the molecular and genetic underpinnings of\n                      <jats:italic toggle=\"yes\">endD<\/jats:italic>\n                      regulation.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Clostridioides difficile<\/jats:italic>\n                        is a leading cause of infectious diarrhea. The gut microbiome-derived short-chain fatty acid butyrate triggers\n                        <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                        to release its major virulence factors, toxins TcdA and TcdB. Here, we show that butyrate-dependent toxin release is independent of classical secretion or autolytic pathways and is instead mediated by EndD, an endolysin broadly conserved among\n                        <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                        clinical isolates. We also demonstrate that\n                        <jats:italic toggle=\"yes\">endD<\/jats:italic>\n                        expression is governed by the sporulation factor SigK and enhances sporulation, directly linking transmission and virulence. Uncovering how\n                        <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                        couples metabolic sensing to EndD-mediated toxin release and sporulation advances our understanding of pathogen\u2013microbiome interactions and highlights potential targets for non-antibiotic therapeutics.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00341-26","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:41:11Z","timestamp":1791297671000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["EndD mediates butyrate-dependent toxin release and sporulation in\n                    <i>Clostridioides difficile<\/i>"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1530-4301","authenticated-orcid":true,"given":"Horia 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