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In the human colon, both toxins cause intestinal inflammation and stimulate tumor necrosis factor alpha (TNF-\u03b1) expression via the activation of NF-\u03baB. It is well established that the macrolide antibiotic fidaxomicin is associated with reduced relapses of<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>infection. We showed that fidaxomicin and its primary metabolite OP-1118 significantly inhibited toxin A-mediated intestinal inflammation in mice<jats:italic>in vivo<\/jats:italic>and toxin A-induced cell rounding<jats:italic>in vitro<\/jats:italic>. We aim to determine whether fidaxomicin and OP-1118 possess anti-inflammatory effects against toxin A and toxin B in the human colon and examine the mechanism of this response. We used fresh human colonic explants, NCM460 human colonic epithelial cells, and RAW264.7 mouse macrophages to study the mechanism of the activity of fidaxomicin and OP-1118 against toxin A- and B-mediated cytokine expression and apoptosis. Fidaxomicin and OP-1118 dose-dependently inhibited toxin A- and B-induced TNF-\u03b1 and interleukin-1\u03b2 (IL-1\u03b2) mRNA expression and histological damage in human colonic explants. Fidaxomicin and OP-1118 inhibited toxin A-mediated NF-\u03baB phosphorylation in human and mouse intestinal mucosae. Fidaxomicin and OP-1118 also inhibited toxin A-mediated NF-\u03baB phosphorylation and TNF-\u03b1 expression in macrophages, which was reversed by the NF-\u03baB activator phorbol myristate acetate (PMA). Fidaxomicin and OP-1118 prevented toxin A- and B-mediated apoptosis in NCM460 cells, which was reversed by the addition of PMA. PMA reversed the cytoprotective effect of fidaxomicin and OP-1118 in toxin-exposed human colonic explants. Fidaxomicin and OP-1118 inhibit<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>toxin A- and B-mediated inflammatory responses, NF-\u03baB phosphorylation, and tissue damage in the human colon.<\/jats:p>","DOI":"10.1128\/aac.01513-17","type":"journal-article","created":{"date-parts":[[2017,10,17]],"date-time":"2017-10-17T00:55:24Z","timestamp":1508201724000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Fidaxomicin and OP-1118 Inhibit Clostridium difficile Toxin A- and B-Mediated Inflammatory Responses via Inhibition of NF-\u03baB Activity"],"prefix":"10.1128","volume":"62","author":[{"given":"Hon Wai","family":"Koon","sequence":"first","affiliation":[{"name":"Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, 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