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 (PPARγ) is essential for intestinal homeostasis in response to both dietaryand 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 Pparγ 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 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; 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 PPARγ-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.β-defensin 1 | Crohn's disease | microbiota | nutrition | PPAR-γ

High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine

“…PPAR-γ acts as a main lipid sensor in the SI. It has previously been shown to be a major regulator of mucosal defenses (58,59). We observed that HF diet down-regulated Ppar-γ gene expression by 1.84-fold (Fig.…”

“…Taken together, these data indicate an association between PPAR-γ and the mucus formation in the ileum. It has also been described that PPAR-γ is a direct regulator of β-defensin expression in the human and mouse colons but not in the mouse ileum (58). However, in the current HF diet model, down-regulation of Ppar-γ was concomitant to down-regulation of major AMP, such as defensins, in the ileum, and when Ppar-γ expression was increased by rosiglitazone, AMP gene expression was also restored.…”

Innate immune dysfunction in inflammatory bowel disease

“…It is interesting that HBD1 expression seems to be maintained by the peroxisome proliferator-activated receptor gamma (PPARgamma) acting as an antimicrobial factor [55]. In line with this, the colonic mucosa of PPAR-gamma mutant mice showed a reduced killing capacity against Candida albicans, B. fragilis, Enterococcus faecalis and E. coli as compared to wild-type littermates [55].…”

PPARγ ligand attenuates portal inflammation in the MRL-lpr mouse: a new strategy to restrain cholangiopathy in primary biliary cirrhosis

“…12 In addition to the biliary epithelial cells of PBC, a reduction of PPARγ expression in the colonic epithelial mucosa is reportedly associated with the pathogenesis of inflammatory bowel diseases (IBD). [13][14][15][16] Furthermore, the expression of PPARγ is affected by the commensal intestinal flora and ligands (agonists) for PPARγ can attenuate colitis in IBD-model mice, supporting the notion that PPARγ ligands may have salutary effects on IBD. 14,[16][17][18] As for anti-inflammatory activities, the activation of PPARγ by its ligands is shown to inhibit the expression of pro-inflammatory cytokines, the induction of which is mediated via NF-κB and mitogen activated protein kinase (MAPK).…”