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Despite its substantial energetic advantages, many modern microbes remain obligate anaerobes, confined to anoxic niches such as the mammalian gut. Why these organisms cannot tolerate oxygen has remained unresolved for more than two centuries. Here, using integrated multi-omics analyses, we identify a network of interlocking vulnerabilities in central metabolism, biosynthetic pathways, and redox homeostasis that together impose an aerobic growth barrier in the obligate anaerobic commensal\n                  <jats:italic>Bacteroides thetaiotaomicron<\/jats:italic>\n                  . Rational repair of these vulnerabilities restores metabolic integrity and progressively enhances oxygen tolerance, yielding engineered strains capable of robust growth at 10% O\n                  <jats:sub>2<\/jats:sub>\n                  and markedly improved resilience in the oxygenated, inflamed gut. These findings define a molecular basis for obligate anaerobiosis and establish a framework for engineering commensal bacteria to function in oxidative environments, expanding their ecological range and therapeutic potential.\n                <\/jats:p>","DOI":"10.64898\/2026.06.05.730451","type":"posted-content","created":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T06:25:12Z","timestamp":1780813512000},"source":"Crossref","is-referenced-by-count":0,"title":["Rational engineering of facultative anaerobiosis enables commensal survival in the oxygenated gut"],"prefix":"10.64898","author":[{"given":"Abigail E.","family":"Rose","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Langford-Butler","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisella","family":"Spiga","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Bak","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Boston College, Chestnut Hill, MA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxwell","family":"Neal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muen","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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