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Phosphorylated lantibiotics (pLANs) are a recently identified class of ribosomally synthesized and post-translationally modified peptides (RiPPs), with dual antimicrobial and pro-immune activities. In this manuscript, we explore the potential of commensals\u2019 pLANs biosynthesis as a mechanism for pathogen suppression and microbiome homeostasis. Subgingival metagenomics revealed that oral health correlates with\n                    <jats:italic>Streptococcus salivarius<\/jats:italic>\n                    enrichment and an increased prevalence of streptococcal RiPP biosynthetic gene clusters. Guided by these associations, we screened 80\n                    <jats:italic>S. salivarius<\/jats:italic>\n                    isolates, identifying a small subset producing pLANs with potent activity against\n                    <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                    , vancomycin-resistant\n                    <jats:italic>Enterococcus faecium<\/jats:italic>\n                    , and multidrug-resistant\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    . A representative lead strain, SALI-10, exhibited robust epithelial adhesion and a sorbitol-driven metabolic adaptation that enhances pLANs expression. In human-derived dysbiotic biofilms, SALI-10 stably engrafted, suppressed periopathogens, reduced antibiotic-resistance genes, and enriched acid-buffering pathways. In a first-in-human feasibility trial, daily oral administration of SALI-10 for one week yielded increased pLANs signals, pathogen depletion, and reduced oral neutrophil counts. Ultimately, pLANs-producing\n                    <jats:italic>S. salivarius<\/jats:italic>\n                    acts as a precision commensal to restore ecological balance, defining a mechanistically grounded and microbiota-mediated strategy to prevent oral and respiratory infections.\n                  <\/jats:p>","DOI":"10.1038\/s41522-026-00976-y","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T13:28:38Z","timestamp":1775222918000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylated lantibiotics-producing commensals integrate into the human oral microbiome to suppress pathogens and promote microbiome homeostasis"],"prefix":"10.1038","volume":"12","author":[{"given":"Abdelahhad","family":"Barbour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehoshua","family":"Bendayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Hei Kelly","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morvarid","family":"Oveisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Callaghan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Zargaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dempsey","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"McLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Mazzulli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Glogauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"976_CR1","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1016\/S0140-6736(24)02811-3","volume":"405","author":"E Bernabe","year":"2025","unstructured":"Bernabe, E. et al. 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They are inventors on patents related to phosphorylated lantibiotics and\n                      S. salivarius\n                      SALI-10 (USA: 18\/837439; Europe: EP23752199.2A). They are also inventors on a provisional patent application related to sorbitol-mediated enhancement of phosphorylated lantibiotic production (United States Provisional Application No. 63\/765,057). Y.B C.M., Y.K.C., and M.C. are employees at Ostia Sciences Inc. All other authors declare they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"101"}}