Ursodiol and vitamin D help keep bile sterile

[Guest guest]

Gastroenterology [in Press] (2008)

Bile salts control the antimicrobial peptide cathelicidin through

nuclear receptors in the human biliary epithelium.

d'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D,

Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N

Abbreviations : CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic

acid; FXR, farnesoid X receptor; PBC, primary biliary cirrhosis; VDR,

vitamin D receptor.

Correspondence : Nicolas Chignard, Ph.D.; CdR Saint-Antoine, UMR_S

893, 27 rue de Chaligny, 75571 Paris Cedex 12, France; Telephone: 33-

1-40 01 13 56; Fax: 33-1-40 01 13 52; e-mail: nicolas.chignard@...

Backgrounds and Aims : Under normal conditions, the biliary tract is

a microbial-free environment. The absence of microorganism has been

attributed to various defense mechanisms, that include the

physicochemical and signaling actions of bile salts. Here, we

hypothesized that bile salts may stimulate the expression of a major

antimicrobial peptide, cathelicidin, through nuclear receptors in the

biliary epithelium. Methods : The expression of cathelicidin was

analyzed in human liver samples by immunostaining and RT-QPCR. The

regulation of cathelicidin expression by the endogenous bile salt,

chenodeoxycholic acid (CDCA) and by the therapeutic bile salt,

ursodeoxycholic acid (UDCA), was assessed in human biliary epithelial

cells in which endogenous nuclear receptor expression was blunted

by siRNA or dominant negative strategies. Results : In the human

liver, biliary epithelial cells show intense immunoreactivity for

cathelicidin and for the vitamin D receptor. In cultured biliary

epithelial cells, CDCA and UDCA induce cathelicidin expression

through two different nuclear receptors, i.e. the farnesoid X

receptor and the vitamin D receptor, respectively. Importantly,

vitamin D further increases the induction of cathelicidin expression

by both bile salts. In a prototypical inflammatory biliary disease,

i.e. primary biliary cirrhosis, we document that hepatic expressions

of the vitamin D receptor and of cathelicidin significantly increase

upon UDCA therapy. Conclusions : Our results indicate that bile salts

may contribute to biliary tract sterility by controlling epithelial

cell innate immunity. They further suggest that in inflammatory

biliary diseases, which involve bacterial factors, a strategy

systematically combining UDCA with vitamin D would increase

therapeutic efficacy.

Dave

(father of (23); PSC 07/03; UC 08/03)