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However, <jats:italic>Cd<\/jats:italic> can colonize the gut in the absence of disease symptoms. Prevalence of asymptomatic colonization by toxigenic <jats:italic>Cd<\/jats:italic> in healthy populations is high; asymptomatic carriers are at increased risk of infection compared to noncolonized individuals and may be a reservoir for transmission of <jats:italic>Cd<\/jats:italic> infection<jats:sup>2,3<\/jats:sup>. Elucidating the molecular mechanisms by which <jats:italic>Cd<\/jats:italic> persists in the absence of disease is necessary for understanding pathogenesis and developing refined therapeutic strategies. Here, we show with gut microbiome metatranscriptomic analysis that mice recalcitrant to <jats:italic>Cd<\/jats:italic> infection and inflammation exhibit increased community-wide expression of arginine and ornithine metabolic pathways. To query <jats:italic>Cd<\/jats:italic> metabolism specifically, we leverage RNA sequencing in gnotobiotic mice infected with two wild-type strains (630 and R20291) and isogenic toxin-deficient mutants of these strains to differentiate inflammation-dependent versus -independent transcriptional states. A single operon encoding oxidative ornithine degradation is consistently upregulated across non-toxigenic <jats:italic>Cd<\/jats:italic> strains. Combining untargeted and targeted metabolomics with bacterial and host genetics, we demonstrate that both diet- and host-derived sources of ornithine provide a competitive advantage to <jats:italic>Cd<\/jats:italic>, suggesting a mechanism for <jats:italic>Cd<\/jats:italic> persistence within a non-inflammatory, healthy gut.<\/jats:p>","DOI":"10.1038\/s42255-021-00506-4","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T17:03:00Z","timestamp":1641488580000},"page":"19-28","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Oxidative ornithine metabolism supports non-inflammatory C.\u2009difficile colonization"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8619-5886","authenticated-orcid":false,"given":"Kali M.","family":"Pruss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8812-2026","authenticated-orcid":false,"given":"Fatima","family":"Enam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Battaglioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7689-9655","authenticated-orcid":false,"given":"Mary","family":"DeFeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4041-2096","authenticated-orcid":false,"given":"Oscar R.","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven K.","family":"Higginbottom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3386-9813","authenticated-orcid":false,"given":"Curt R.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-6259","authenticated-orcid":false,"given":"Andrew J.","family":"Hryckowian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Van Treuren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6210-6239","authenticated-orcid":false,"given":"Dylan","family":"Dodd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purna","family":"Kashyap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2299-6817","authenticated-orcid":false,"given":"Justin L.","family":"Sonnenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"key":"506_CR1","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1056\/NEJMoa1408913","volume":"372","author":"FC Lessa","year":"2015","unstructured":"Lessa, F. 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