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

<jats:p> 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 (PPARγ) 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 PPARγ functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of β-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of <jats:italic>Pparγ</jats:italic> mutant animals shows defective killing of several major components of the intestinal microbiota, including <jats:italic>Candida albicans</jats:italic> , <jats:italic>Bacteroides fragilis</jats:italic> , <jats:italic>Enterococcus faecalis</jats:italic> , and <jats:italic>Escherichia coli</jats:italic> . Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARγ-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; <jats:italic>P</jats:italic> = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARγ-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD. </jats:p>