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We investigate the contribution of interspecies interactions on the antibiotic response of\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    to clinically relevant antibiotics using bottom-up assembly of human gut communities. We identify 2 classes of microbial interactions that alter\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    \u2019s antibiotic susceptibility: interactions resulting in increased ability of\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    to grow at high antibiotic concentrations (rare) and interactions resulting in\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    growth enhancement at low antibiotic concentrations (common). Based on genome-wide transcriptional profiling data, we demonstrate that metal sequestration due to hydrogen sulfide production by the prevalent gut species\n                    <jats:italic>Desulfovibrio piger<\/jats:italic>\n                    increases the minimum inhibitory concentration (MIC) of metronidazole for\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    . Competition with species that display higher sensitivity to the antibiotic than\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    leads to enhanced growth of\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    at low antibiotic concentrations due to competitive release. A dynamic computational model identifies the ecological principles driving this effect. Our results provide a deeper understanding of ecological and molecular principles shaping\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>difficile<\/jats:italic>\n                    \u2019s response to antibiotics, which could inform therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3002100","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T13:21:13Z","timestamp":1683811273000},"page":"e3002100","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Gut microbiota interspecies interactions shape the response of Clostridioides difficile to clinically relevant antibiotics"],"prefix":"10.1371","volume":"21","author":[{"given":"Susan","family":"Hromada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2200-1963","authenticated-orcid":true,"given":"Ophelia S.","family":"Venturelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"pbio.3002100.ref001","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/nri3535","article-title":"Microbiota-mediated colonization resistance against intestinal pathogens","volume":"13","author":"CG Buffie","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"pbio.3002100.ref002","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1128\/AAC.02176-12","article-title":"Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection","volume":"57","author":"KA Brown","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"pbio.3002100.ref003","doi-asserted-by":"crossref","first-page":"hzw007","DOI":"10.1093\/biohorizons\/hzw007","article-title":"Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium difficile infection","volume":"9","author":"C. 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