CARD14 signaling in intestinal epithelial cells induces intestinal inflammation and intestinal transit delay.

CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However, its function in the intestine remains unknown. We demonstrate here that transgenic mice expressing the psoriasis-associated gain-of-function human CARD14(E138A) mutant specifically in IEC show mild intestinal inflammation, without epithelial damage. Moreover, CARD14(E138A)IEC mice show a drastic reduction in intestinal motility, often associated with rectal prolapse. Enteric neuronal survival and functionality are unaffected in CARD14(E138A)IEC mice. Transcriptome analysis of IEC from CARD14(E138A)IEC mice reveals decreased expression of antimicrobial peptides by Paneth cells, accompanied by microbial dysbiosis and increased susceptibility to enteric bacterial infection. Our findings suggest that gain-of-function CARD14 mutations may not only predispose patients to psoriasis but also mild intestinal inflammation, reduced intestinal motility, and increased sensitivity to intestinal infection. CARD14(E138A)IEC mice are also a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.