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Antimicrobial host response in the gastrointestinal tract

Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and Gram-positive bacteria, fungi, viruses and protozoa. In the gastrointestinal tract, defensins help regulate the composition and number of colonizing microbes, and protect the host from food-borne and water-borne pathogens. In health, the normal host relationship with the commensal luminal microbiota is beneficial, but the same commensal bacteria could have a pathogenic role in inflammatory diseases. A disturbance in antimicrobial defense, as provided by Paneth cells of the small intestine, seems to be a critical factor in the pathogenesis of ileal Crohn's disease, an inflammatory disease of the intestinal tract. The disruption of the critical balance between antimicrobial peptides and luminal bacteria might also explain other gastrointestinal infections and diseases. Elucidating the underlying mechanisms involved in the regulation and biology of defensins could open up new therapeutic avenues.
Major Projects
  • Understanding Inflammatory bowel diseases
  • Functional role of endogenous antimicrobial peptides
  • Mechanisms and regulation of Paneth and other epithelial cell protective host immunity
  • Role of epithelial stem cell differentiation/WNT signaling in Inflammatory bowel diseases
  • Identification of drug targets to bolster innate barrier function
PD Dr. med. Jan Wehkamp

phone: ++49-711-8101 5700

Selected References
  • Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, Buchner J, Schaller M, Stange EF, Wehkamp J. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 2011, 469(7330):419-23.
  • Peyrin-Biroulet L, Beisner J, Wang G, Nuding S, Oommen ST, Kelly D, Parmentier-Decrucq E, Dessein R, Merour E, Chavatte P, Grandjean T, Bressenot A, Desreumaux P, Colombel JF, Desvergne B, Stange EF, Wehkamp J°, Chamaillard M°. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci U S A. 2010 Apr 26. [Epub ahead of print] °share senior authorship
  • Möndel M, Schroeder BO, Zimmermann K, Huber H, Nuding S, Beisner J, Fellermann K, Stange EF, Wehkamp J: Probiotic E. coli treatment mediates antimicrobial human ß-defensin synthesis and fecal excretion in humans. Mucosal Immunology 2009; 2:166-72.
  • Koslowski MJ, Kübler I, Chamaillard M, Schaeffeler E, Reinisch W, Wang G, Beisner J, Teml A, Peyrin-Biroulet L, Winter S, Herrlinger KR, Rutgeerts P, Vermeire S, Cooney R, Fellermann K, Jewell D, Bevins CL, Schwab M, Stange EF and Wehkamp J: Genetic variants of Wnt transcription factor Tcf-4 (Tcf7L2) putative promoter region are associated with small intestinal Crohn´s disease. Public library of Science (PLOS) one 2009; 4:e4496.
  • J. Wehkamp, N.H. Salzman, E. Porter, S. Nuding, M. Weichenthal, R. E. Petras, B. Shen, E. Schaeffeler, M. Schwab, R. Linzmeier, R. W. Feathers, H. Chu, H. Lima, Jr., K. Fellermann, T. Ganz, E. F. Stange, C. L. Bevins; Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18129-34.
  • J. Wehkamp, J. Harder, M. Weichenthal, M. Schwab, E. Schäffeler, M. Schlee, K.R. Herrlinger, A. Stallmach, F. Noack, P. Fritz, J.M. Schröder, C.L. Bevins, K. Fellermann, E.F. Stange. NOD2 (CARD15) mutations in Crohn´s disease are associated with diminished mucosal a-defensin expression. Gut, 2004 Nov;53(11):1658-64.
  • J. Wehkamp, J. Harder, K. Wehkamp, B. Wehkamp-von Meissner, M. Schlee, C. Enders, U. Sonnenborn, S. Nuding, K. Fellermann, J.M. Schröder and E.F. Stange. NF-kappaB and AP-1 mediated induction of human beta defensin-2 in intestinal epithelial cells by E. coli Nissle 1917: a novel effect of a probiotic bacterium. Infection and Immunity, 2004 Oct;72(10):5750-8.
  • J. Wehkamp, J. Harder, M. Weichenthal, O. Müller, K.R. Herrlinger, K. Fellermann, J.M. Schröder, E.F. Stange. Inducible and constitutive beta-defensins are differentially expressed in Crohn´s disease and ulcerative colitis. Inflammatory Bowel Diseases 9(4): 215-223, 2003.
  • J. Wehkamp, G. Wang, I. Kübler, S.Nuding, A.Gregorieff, A.Schnabel, R.J. Kays, K.Fellermann, O.Burk, M. Schwab, H. Clevers, C.L. Bevins, E.F. Stange; The Paneth Cell a-Defensin Deficiency of Ileal Crohn´s Disease is Linked to Wnt/Tcf-4; Journal of Immunology, 2007 Sep 1;179(5):3109-18
  • Kotarsky K, Sitnik KM, Stenstad H, Kotarsky H, Schmidtchen A, Koslowski M, Wehkamp J, Agace WW: A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. Mucosal Immunol 2010; 3:40-8. Epub 2009 Oct 7
  • J. Wehkamp, Michael Schmid and Eduard F. Stange; Defensins and other antimicrobial peptides in inflammatory bowel diseases, Curr Opin Gastroenterol. 2007, Jul;23(4):370-8.
  • J Wehkamp und Eduard F. Stange. NOD2 mutation and mice: no Crohn's disease but many lessons to learn. Trends Mol Med. 2005 Jul;11(7):307-9.
Major Networks and Collaborations
  • Charles L. Bevins, UC Davis, USA
  • Jens Schröder and Jürgen Harder, Kiel Germany
  • Lauren Peyrin-Biroulet, Mathias Chamaillard, France
  • Reiner Wiest, Universtity of Regensburg
Extramural Funding
  • Deutsche Forschungsgemeinschaft (Emmy Noether cluster of excellence program)
  • Deutsche Forschungsgemeinschaft (Sonderforschungsbereich Immunotherapy)
  • Ernst Jung Stiftung, Hamburg

Curriculum Vitae Jan Wehkamp, MD

Affiliation
Group Leader
Emmy Noether Cluster of Excellence Principal Investigator of the Deutsche Forschungsgemeinschaft

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Auerbachstrasse 112
70376 Stuttgart, Germany
Phone: ++49-711-8101 5700
Fax: ++49-711-859295
e-mail: jan.wehkamp@ikp-stuttgart.de
Education and Professional Career
 1994/95-2001 Study of Medicine at the Medical University of Lübeck, Germany
  1998 Scholarship: "Junge Wissenschaft" of the Boehringer Ingelheim Foundation
  08/1997-06/2001 Researcher as a Medical Student, Medical University of Lübeck, Germany, Department of Internal Medicine
  07/1998-10/1998 Visiting Student Scientist, University of Chicago, Inflammatory Bowel Disease Center, Prof. Chang
  06/2001-12/2001 Resident at the Department of Dermatology, Christian Albrecht University Kiel (Prof. Schroeder)
  2002 Thesis (MD): Department of Internal Medicine (Gastroenterology), Medical University of Lübeck. Title: “The role of antimicrobial defensins in inflammatory bowel diseases” (Prof. Stange)
  12/2001-06/2003 Resident at the Department of Internal Medicine (Gastroenterology), Robert Bosch Hospital and the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
  2003 Scholarship of the Robert Bosch Foundation
  06/2003-09/2003 Post-Doctoral Fellow, Cleveland Clinic Foundation, Department of Immunology, USA (Prof. Bevins)
  09/2003-11/2004 Post-Doctoral Fellow, University of California, Davis School of Medicine, Department of Medical Microbiology and Immunology (Prof. Bevins)
  11/2004-11/2005 Junior Faculty member and Project Scientist, University of California, Davis School of Medicine, Department of Medical Microbiology and Immunology
  2005-present Resident at the Department of Internal Medicine (Gastroenterology), Robert Bosch Hospital and the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
  2006 Career Support Award of Medicine of the Ernst Jung Foundation, Hamburg (180.000Euro)
  2006 Ludwig Demling Award of the DCCV (German Crohn´s disease and ulcverative colitis patient organization)
  2007 Emmy Noether Cluster of Excellence Scholarship of the Deutsche Forschungs-gemeinschaft
  2007-present Group Leader and Emmy Noether Cluster of Excellence Principal Investigator of the Deutsche Forschungsgemeinschaft (DFG) at the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
  2008 “Rising star” of European Gastroenterology (UEGW)
  2009 Thannhauser Prize of DGVS (Deutsche Gesellschaft für Verdauung und Stoffwechselstörungen)
Professional Memberships
2009-2011: European Crohn´s and colitis organisation/ Young European Crohn´s and colitis organisation (ECCO/ YECCO) YECCO Co-chair
Deutsche Gesellschaft für Verdauungs und Stoffwechselstörungen (DGVS)
Deutsche Gesellschaft für Innere Medizin
Deutsche Arbeitsgemeinschaft für chronisch entzündliche Darmerkrankungen (DACED), Chair 2011
Scientific Journal Editorial Board Memberships
Journal of Crohn´s colitis (JCC)