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The disruption of normal gut microbiota by the use of broad-spectrum antimicrobial agents enables\n                    <jats:italic>C. difficile<\/jats:italic>\n                    to proliferate in the colon. The emergence and prevalence of hypervirulent\n                    <jats:italic>C. difficile<\/jats:italic>\n                    strains result in increased morbidity, mortality, and high recurrence rates of CDI, thus creating a pressing need for novel therapeutics. The multi-domain toxins TcdA and TcdB are the primary determinants of CDI pathogenesis, rendering them ideal drug targets in the anti-virulence paradigm. In this study, we identified caffeic acid and its derivatives from natural compounds library as active inhibitors of TcdB via a cell-based high-throughput phenotypic screening. Further mechanistic investigations revealed that caffeic acid phenethyl ester (CAPE) could directly bind to TcdB, thus suppressing InsP\n                    <jats:sub>6<\/jats:sub>\n                    -induced autoproteolysis and inhibiting glucosyltransferase activity. CAPE treatment remarkably reduces the pathology of CDI in a murine infection model in terms of alleviated diarrhea symptoms, decreased bacterial colonization, and relieved histopathological lesions. Moreover, CAPE treatment of\n                    <jats:italic>C. difficile<\/jats:italic>\n                    -challenged mice induces a remarkable increase in the diversity and composition of the gut microbiota and alterations of gut metabolites (e.g., adenosine, D-proline, and melatonin), which might partially contribute to the therapeutic outcomes of CAPE against CDI. Our results reveal the potential of CAPE as a therapeutic for the management of CDI, or CAPE might serve as a lead compound for the development of antivirulence drugs targeting TcdB.\n                  <\/jats:p>","DOI":"10.7554\/elife.101757","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T10:25:59Z","timestamp":1733307959000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.101757","source":"Crossref","is-referenced-by-count":0,"title":["Caffeic acid phenethyl ester protects Clostridioides difficile infection by toxin inhibition and microbiota modulation"],"prefix":"10.7554","volume":"13","author":[{"given":"Yan","family":"Guo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00js3aw79","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, 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