Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

Abstract

Background: Non-obese gallstone patients exhibit a diminished expression of apical sodium-dependent bile acid transporter (ASBT) in terminal ileum. Crohn’s ileitis demonstrates a significant downregulation of this transporter. Aim: To test whether subclinical ileal inflammation contributes to gallstone disease. Methods: Biopsies from terminal ileum of female subjects with gallstone disease (n = 7), active Crohn’s disease (n = 17) and controls (n = 22) were investigated. mRNA expression of ASBT, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-8, c-jun and c-fos was measured. c-jun and c-fos protein levels were determined and hematoxylin and eosin staining was applied for ileal histology. Results: ASBT expression was comparably low both in gallstone (47% of controls, p = 0.0093) and Crohn’s disease (42% of controls, p = 0.0008). In gallstone disease there was a non-significant trend towards elevated TNF-α and IL-1β, but all cytokines were increased in active Crohn’s disease. c-jun and c-fos were slightly diminished in patients with gallstones. Neither cytokines nor transcription factors correlated significantly with ASBT. The gallstone-associated ileal biopsies exhibited no histological inflammation. Conclusion: Although the expression of ASBT was similarly diminished in both gallstone and Crohn’s disease, subclinical ileal inflammation does not appear to be relevant in gallstone patients. The mechanisms of transcriptional repression of ASBT in both diseases are apparently different.

Bile acid malabsorption in inflammatory bowel disease

“…involvement. This is in agreement with the results of Jung et al 31 and Holzer et al, 32 who reported a diminished expression of SLC10A2, independent of the ileal inflammation in CD patients. Recently, a novel haplotype block, linked to a reduced ileal expression of SLC10A2, was described.…”

A Variant of the SLC10A2 Gene Encoding the Apical Sodium-Dependent Bile Acid Transporter Is a Risk Factor for Gallstone Disease

“…In line with differences in cholesterol metabolism in lean and obese subjects [18], the reduced expression of the transporter was weight-specific and observed in normal weight individuals only [16]. Furthermore, subclinical inflammation was excluded as the molecular pathomechanism of reduced ASBT expression in gallstone patients [19]. The role of this transporter has been suggested to be the major determinant of bile acid pool size [20].…”

Bile acid transporters

“…Indeed, a recent genetic study identifi ed an ASBT haplotype associated with signifi cantly reduced ileal expression of ASBT mRNA and protein ( 191 ). Other disorders associated with intestinal bile acid malabsorption that could potentially involve the ASBT include hypertriglyceridemia ( 192,193 ), idiopathic chronic diarrhea ( 194 ), chronic ileitis ( 195 ), gallstone disease ( 196,197 ), postcholecystectomy diarrhea, Crohn's disease (198)(199)(200)(201)(202), and irritable bowel syndrome ( 203 ).…”