{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:13:16Z","timestamp":1792113196794,"version":"4.4.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJ"],"award-info":[{"award-number":["PJ"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,9]]},"abstract":"<jats:p>\n                    Intestinal bile acids play an essential role in the\n                    <jats:italic>Clostridioides difficile<\/jats:italic>\n                    lifecycle having been shown in\u00a0vitro to modulate various aspects of pathogenesis, including spore germination, vegetative growth, and more recently the action of the primary virulence determinant, TcdB. Here, we investigated whether physiological levels of the total pool of intestinal bile acids in mice and humans protect against TcdB action. Small molecules extracted from the lumenal contents of the small intestine, cecum, colon, and feces were found to inhibit TcdB in accordance with the differential amounts of total bile acids in each compartment. Extracts from antibiotic-treated and germ-free mice, despite harboring dramatically altered bile acid profiles, unexpectedly also prevented TcdB-induced cell rounding to similar extents. We show that protection, however, is surmountable and can be overcome at higher doses of TcdB\u2014typical to those seen during severe\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    infection\u2014suggesting that the protective properties of intestinal bile acids are operant primarily under low to moderate toxin levels. Taken together, these findings demonstrate a role for intestinal bile acids in attenuating virulence, provide insights into asymptomatic carriage of toxigenic\n                    <jats:italic>C. difficile<\/jats:italic>\n                    , and inform strategies to manipulate bile acid levels for therapeutic benefit.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2301252120","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T15:11:27Z","timestamp":1682953887000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Intestinal bile acids provide a surmountable barrier against\n                    <i>C. difficile<\/i>\n                    TcdB-induced disease pathogenesis"],"prefix":"10.1073","volume":"120","author":[{"given":"Simoun","family":"Icho","sequence":"first","affiliation":[{"name":"Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer S.","family":"Ward","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Tam","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry K.","family":"Kociolek","sequence":"additional","affiliation":[{"name":"Ann &amp; Robert H. Lurie, Children\u2019s Hospital of Chicago, Chicago, IL 60611"},{"name":"Department of Pediatrics, Division of Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1895-8941","authenticated-orcid":false,"given":"Casey M.","family":"Theriot","sequence":"additional","affiliation":[{"name":"Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7187-2362","authenticated-orcid":false,"given":"Roman A.","family":"Melnyk","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01765-07"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.anaerobe.2017.12.001"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.20"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit426"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1602615"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01540-16"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","unstructured":"M. J. T. Crobach Understanding clostridium difficile colonization. Clin. Microbiol. Rev. 31 e00021-17 (2018). e00021-17","DOI":"10.1128\/CMR.00021-17"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002103420604"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198901263200402"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00610-0"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/151.2.355"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003356"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.anaerobe.2017.03.004"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.01206"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00045-15"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4114"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00153-22"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","unstructured":"J. A. Winston Ursodeoxycholic acid (UDCA) mitigates the host inflammatory response during clostridioides difficile infection by altering gut bile acids. Infect. Immun. 88 e00045-20 (2020). e00045-20","DOI":"10.1128\/IAI.00045-20"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13828"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916965117"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916965117"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.4161\/gmic.19142"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4114"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01104-10"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.02601-13"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.05.011"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12046"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2014.04.003"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09397"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.56.9.2299-2306.1988"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.2307\/30141083"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2164"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2006.01580.x"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/651706"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.00646"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2014.12.010"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00551-15"},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","unstructured":"A. Di Ciaula Bile acid physiology. Ann. Hepatol. 16 (Suppl. 1) S4\u2013S14 (2017).","DOI":"10.5604\/01.3001.0010.5493"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.11.010"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2014.12.010"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz582"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2301252120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:19:29Z","timestamp":1695287969000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2301252120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5]]},"references-count":41,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2023,5,9]]}},"alternative-id":["10.1073\/pnas.2301252120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2301252120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5]]},"assertion":[{"value":"2023-01-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2301252120"}}