Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis

Abstract

Background and Aims: Many patients with cholesterol gallbladder stones (GBS) have a high percentage of deoxycholic acid (DCA) in gallbladder bile (all of which are in the conjugated form), probably as a result of prolonged large bowel transit times (LBTT). However, whether the prolonged LBTT increases DCA formation, solubilization, or absorption (or all 3) is not known. Methods: In 40 subjects (20 with GBS; age range, 24-74 years), we measured LBTT using radiopaque markers, and intestinal luminal pH by radiotelemetry. We also measured quantitative anaerobic bacteriology and the activities of 2 bile acid-metabolizing enzymes in fresh cecal aspirates obtained during clinically indicated unprepared colonoscopy, and related these results to the percentage of DCA in fasting serum measured by gas chromatography-mass spectrometry. Results: Compared with controls, GBS patients had longer LBTT (mean 23.1 ± SEM 2.8 h vs. 36.5 ± 3.3 h; P < 0.01); more total (2.7 ± 0.6 x 109 vs. 5.9 ± 1.5 x 109 cfu/mL) and Gram-positive (9.5 ± 3.1 x 108 vs. 18.0 ± 4.1 x 108 cfu/mL; P < 0.05) anaerobes; and greater 7α-dehydroxylating (7α-DH) activity (3.39 ± 0.59 vs. 10.37 ± 1.15 x 10-4 U/mg protein) in the cecal aspirates. They also had higher intracolonic pH values (P < 0.02) and increased percentages of DCA in fasting serum (13.4% ± 1.52% vs. 21.8% ± 2.19%; P < 0.005). Results of univariate and multivariate analyses confirmed that LBTT was critical in determining the percentage of DCA in serum and showed that 7α-DH activity and apparent distal colonic pH were also significant independent variables. Conclusions: Slow colonic transit (more time), increased Gram-positive anaerobes (more bacteria), and greater 7α-DH activity (more enzyme) favor enhanced DCA formation; transit-induced increases in distal colonic luminal pH favor enhanced DCA solubilization/bioavailability; and increases in LBTT (more time) again favor DCA absorption.