title: Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U795, F-59037 Lille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.forename: Julia
authors.initials: J
authors.lastname: Beisner
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.forename: Sabine
authors.initials: S
authors.lastname: Nuding
authors.forename: Sajit Thottathil
authors.initials: ST
authors.lastname: Oommen
authors.forename: Denise
authors.initials: D
authors.lastname: Kelly
authors.forename: Erika
authors.initials: E
authors.lastname: Parmentier-Decrucq
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Dessein
authors.forename: Emilie
authors.initials: E
authors.lastname: Merour
authors.forename: Philipe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Teddy
authors.initials: T
authors.lastname: Grandjean
authors.forename: Aude
authors.initials: A
authors.lastname: Bressenot
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology*; D002460:Cell Line; D003106:Colon / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology; D005658:Fungi / Q000276:immunology*; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007082:Ileum / Q000276:immunology / Q000382:microbiology; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D047495:PPAR gamma / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: C406407:DEFB1 protein, human; D047495:PPAR gamma; D023083:beta-Defensins