{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:05:20Z","timestamp":1791511520137,"version":"4.3.4"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The interplay between Clostridium difficile and the host\u2019s metabolome is believed to influence the severity of infection. However, the mechanism for this phenomenon remains unclear. In this study, we model one of these metabolic pathways by focusing on tryptophan metabolism in the host. We found that inhibition of tryptophan catabolism in IDO1-knockout mice led to increased mucosal destruction, cecal hemorrhage, and increased production of IFN-\u03b3 in response to C. difficile infection, but no significant change in mucosal effector or regulatory T cell numbers or IL-10 mRNA expression. The increased immunopathology in infected IDO1-knockout mice was associated with a lower C. difficile burden and an increased percentage of IFN-\u03b3\u2013expressing neutrophils. We further demonstrated the ability of kynurenine to induce apoptosis in bone marrow\u2013derived neutrophils, whereas the presence of tryptophan reversed this effect, providing a possible mechanism for the increased neutrophil accumulation in IDO1\u2212\/\u2212 mice. We conclude that C. difficile induces tryptophan catabolism in cecal lamina propria cells, which restricts C. difficile\u2013associated immunopathology and the accumulation of IFN-\u03b3\u2013expressing neutrophils. This might represent a self-regulatory mechanism for neutrophils, via the IFN-\u03b3\u2013IDO1 pathway, to restrict their own accumulation during infection. These findings have important clinical implications because IDO inhibitors are used to treat cancer in clinical trials (in patients particularly susceptible to getting C. difficile infection), and treatment with IDO1 inhibitors may exacerbate the severity of C. difficile colitis.<\/jats:p>","DOI":"10.4049\/jimmunol.1302913","type":"journal-article","created":{"date-parts":[[2014,6,17]],"date-time":"2014-06-17T02:54:25Z","timestamp":1402973665000},"page":"807-816","source":"Crossref","is-referenced-by-count":71,"title":["Tryptophan Catabolism Restricts IFN-\u03b3\u2013Expressing Neutrophils and <i>Clostridium difficile<\/i> Immunopathology"],"prefix":"10.1093","volume":"193","author":[{"given":"Mohamad","family":"El-Zaatari","sequence":"first","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ming","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Franz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Shreiner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"McDermott","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koenraad F","family":"van der Sluijs","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center , 1105 AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Respiratory Medicine, Academic Medical Center , 1105 AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Lutter","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Academic Medical Center , 1105 AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Experimental Immunology, Academic Medical Center , 1105 AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Grasberger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Kamada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent B","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary B","family":"Huffnagle","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Y","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Gastroenterology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,7,15]]},"reference":[{"key":"2025030707231191500_r1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.tim.2012.04.001","article-title":"Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance","volume":"20","author":"Britton","year":"2012","journal-title":"Trends Microbiol."},{"key":"2025030707231191500_r2","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1097\/01.qco.0000433318.82618.c6","article-title":"Recent insights into Clostridium difficile pathogenesis","volume":"26","author":"Peniche","year":"2013","journal-title":"Curr. 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