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The transformation into a spore is a complex developmental process that is regulated in response to conditions within the host, most notably nutrient limitation. Nutrient availability is sensed by\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      through transcriptional regulators, such as CodY. CodY is a global nutritional gene regulator that controls gene expression in response to branched-chain amino acids (BCAAs) and guanosine-triphosphate (GTP). It was previously observed that CodY represses\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      sporulation, but the impact of CodY on sporulation has differed considerably by strain. Here, we investigated the effects of CodY on gene expression during sporulation in the two common research strains 630\n                      <jats:italic toggle=\"yes\">\u2206erm<\/jats:italic>\n                      (ribotype 012) and UK1 (ribotype 027). We confirmed that CodY suppressed premature spore formation in both strains through time-elapsed sporulation assays with\n                      <jats:italic toggle=\"yes\">codY<\/jats:italic>\n                      mutants. Through transcriptional analyses of\n                      <jats:italic toggle=\"yes\">codY<\/jats:italic>\n                      mutant sporulation, we defined the similarities and differences in the CodY-dependent gene expression between strains. We also identified differences in putative CodY sites within the 630 and UK1 genomes that may influence CodY regulation. Finally, we performed CRISPRi knockdowns to examine the effects of selected CodY-regulated genes, demonstrating the impact of multiple CodY-dependent factors on sporulation.\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                        spore formation is crucial for transmission and survival of the bacterium. Spore formation is triggered by the availability of crucial nutrients, which CodY and other regulators sense. However, the mechanism by which CodY represses sporulation in\n                        <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                        is poorly understood. In this study, we identified several CodY-regulated factors that could play a role in sporulation both in 630\n                        <jats:italic toggle=\"yes\">\u2206erm<\/jats:italic>\n                        and UK1 strains. Our results show that many factors under the regulation of CodY can impact sporulation.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01706-25","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T13:00:16Z","timestamp":1763384416000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Deciphering strain differences in codY regulation of\n                    <i>Clostridioides difficile<\/i>\n                    s sporulation"],"prefix":"10.1128","volume":"14","author":[{"given":"Marcos P.","family":"Monteiro","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gars961","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Emory Antibiotic Resistance Center","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2503-3787","authenticated-orcid":true,"given":"Adrianne N.","family":"Edwards","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05a0ya142","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute of MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"DiCandia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05a0ya142","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute of MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6221-714X","authenticated-orcid":true,"given":"Shonna M.","family":"McBride","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gars961","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Emory Antibiotic Resistance Center","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","unstructured":"CDC. 2019. Antibiotic resistance threats in the United States."},{"key":"e_1_3_3_3_2","unstructured":"CDC. 2023. Emerging infections program healthcare-associated infections\u2013community interface report Clostridioides difficile infection surveillance."},{"key":"e_1_3_3_4_2","unstructured":"CDC. 2013. Antibiotic resistance threats in the United States."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2018.09.004"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.18.4.1017-1019.1983"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01765-07"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","unstructured":"Lee CD Rizvi A Carter ZA Edwards AN McBride SM. 2025. The Pxp Complex Detoxifies 5-Oxoproline and Promotes the Growth of Clostridioides difficile. 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