Mol. Nutr. Food Res. 2014, 00, 1–17 1 DOI 10.1002/mnfr.201300818 RESEARCH ARTICLE Nicotinamide treatment ameliorates the course of experimental colitis mediated by enhanced neutrophil-specific antibacterial clearance Dominik Bettenworth 1 , Tobias M. Nowacki 1 , Matthias Ross 1 , Pierre Kyme 2 , Daniela Schwammbach 3 , Linda Kerstiens 3 , Gabriela B. Thoennissen 3 , Carsten Bokemeyer 4 , Karin Hengst 1 , Wolfgang E. Berdel 3 , Jan Heidemann 1∗ and Nils H. Thoennissen 3,4∗ 1 Department of Medicine B, University of M ¨ unster, M ¨ unster, Germany 2 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA 3 Department of Medicine A, Hematology, Oncology and Pneumology, University of M ¨ unster, M ¨ unster, Germany 4 Department of Oncology and Hematology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Received: November 6, 2013 Revised: March 19, 2014 Accepted: March 19, 2014 Scope: In previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis. Methods and Results: Colitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil-depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity. Conclusion: Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD). Keywords: Bacterial killing / Colitis / Inflammation / Nicotinamide / Vitamin B 3  Additional supporting information may be found in the online version of this article at the publisher’s web-site Correspondence: Dr. Dominik Bettenworth, Department of Medicine B, University Hospital of Muenster, Albert-Schweitzer- Campus 1, D-48149 M ¨ unster, Germany E-mail: dominik.bettenworth@ukmuenster.de Fax: +49-251-83-47570 Abbreviations: CFU, colony forming units; DSS, dextran sodium sulphate; FBS, fetal bovine serum; HDAC, histone deacetylase; IBD, inflammatory bowel disease; IL, interleukin; i.p., intraperi- toneal; MLN, mesenterial lymph node; NAM, nicotinamide; PMN, polymorphonuclear leucocyte; p.i., post infection; TNBS, trini- trobenzene sulfonate; TNF-, tumor necrosis factor-alpha 1 Introduction Differentiation and functional maturation of hematopoetic and immune cells are regulated on molecular level by central transcriptional mediators including the CCAAT/enhancer binding protein (C/EBP) family. In previous studies, we could prove that deficiency of these transcription factor fam- ily members can lead to severe dysfunction of the innate im- mune system, e.g., impaired cytokine responses, increased predisposition for bacterial infections and development of ∗ Authors contributed equally and share senior authorship. C  2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com