Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

Laurent Peyrin-Biroulet, Julia Beisner, Guoxing Wang, Sabine Nuding, Sajit Thottathil Oommen, Denise Kelly, Erika Parmentier-Decrucq, Rodrigue Dessein, Emilie Merour, Philipe Chavatte, Teddy Grandjean, Aude Bressenot, Pierre Desreumaux, Jean-Frédéric Colombel, Béatrice Desvergne, Eduard F Stange, Jan Wehkamp, Mathias Chamaillard

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Abstract

Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.
Original languageEnglish
Pages (from-to)8772-8777
Number of pages6
JournalPNAS
Volume107
Issue number19
Early online date26 Apr 2010
DOIs
Publication statusPublished - 11 May 2010

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Keywords

  • beta-defensin 1
  • Crohn's disease
  • microbiota
  • nutrition
  • PPAR-gamma

Cite this

Peyrin-Biroulet, L., Beisner, J., Wang, G., Nuding, S., Oommen, S. T., Kelly, D., Parmentier-Decrucq, E., Dessein, R., Merour, E., Chavatte, P., Grandjean, T., Bressenot, A., Desreumaux, P., Colombel, J-F., Desvergne, B., Stange, E. F., Wehkamp, J., & Chamaillard, M. (2010). Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. PNAS, 107(19), 8772-8777. https://doi.org/10.1073/pnas.0905745107