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Although prior studies have found genetic variation between\n                      <jats:italic toggle=\"yes\">S. epidermidis<\/jats:italic>\n                      from infections and commensal strains, prior studies also have found that individual strains can inhabit multiple sites within an individual. None of these studies, however, have considered urogenital isolates. Here, we collected samples from 76 healthy female participants and performed whole-genome sequencing on 114\n                      <jats:italic toggle=\"yes\">S. epidermidis<\/jats:italic>\n                      isolates from the skin, nasal cavity, oral cavity, and urine. Pairwise average nucleotide identity (ANI) revealed instances of identical strains (&gt;99.99% ANI) across multiple body sites within individuals and, in some cases, between individuals. Accessory genome functional profiles showed no clustering by anatomical site, indicating limited niche specialization and a broadly shared accessory gene pool. Intact prophages were shared among isolates, consistent with a fluid, mobile accessory genome. Although multinomial logistic regression using gene-cluster presence\/absence identified site-associated gene enrichment, the model achieved low accuracy in predicting isolation source from publicly available genomes. The absence of strong evidence for niche-specific adaptation among isolates from healthy individuals supports the species\u2019 generalist lifestyle and genetic diversity. This study advances our understanding of\n                      <jats:italic toggle=\"yes\">S. epidermidis<\/jats:italic>\n                      population structure in healthy hosts, including the urinary tract.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        While traditionally considered a benign skin colonizer,\n                        <jats:italic toggle=\"yes\">Staphylococcus epidermidis<\/jats:italic>\n                        is also a resident and transient member of the nasal, oral, gastrointestinal, and urinary microbiota. Strain-level diversity and ecological adaptations in healthy humans remain underexplored. This study reveals that the same\n                        <jats:italic toggle=\"yes\">S. epidermidis<\/jats:italic>\n                        strains can colonize multiple body sites in the same individual, highlighting a generalist colonization strategy. This is further supported by our development of a machine-learning model, which has a relatively low accuracy in predicting the isolation source for strains that are not associated with infections. This study provides a genomic framework for distinguishing commensal adaptation from pathogenic potential.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00114-26","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T12:00:42Z","timestamp":1782129642000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Strain-level genomic analysis of\n                    <i>Staphylococcus epidermidis<\/i>\n                    across multiple body sites in healthy females"],"prefix":"10.1128","volume":"14","author":[{"given":"Sandra","family":"Jablonska","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04b6x2g63","id-type":"ROR","asserted-by":"publisher"}],"name":"Bioinformatics Program, Loyola University Chicago","place":["Chicago, 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NIPS\u201914: Proceedings of the 28th International Conference on Neural Information Processing Systems. , Vol. 1, p 1646\u20131654"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.21105\/joss.03021"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1010"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae979"}],"container-title":["Microbiology Spectrum"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.00114-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.00114-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:40:58Z","timestamp":1786027258000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/spectrum.00114-26"}},"subtitle":[],"editor":[{"given":"Victor","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":78,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,4]]}},"alternative-id":["10.1128\/spectrum.00114-26"],"URL":"https:\/\/doi.org\/10.1128\/spectrum.00114-26","relation":{},"ISSN":["2165-0497"],"issn-type":[{"value":"2165-0497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"assertion":[{"value":"2026-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00114-26"}}