Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis.
OBJECTIVE
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 10(9) vs. 5.9 +/- 1.5 x 10(9) cfu/mL) and Gram-positive (9.5 +/- 3.1 x 10(8) vs. 18.0 +/- 4.1 x 10(8) cfu/mL; P < 0.05) anaerobes; and greater 7alpha-dehydroxylating (7alpha-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 7alpha-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 7alpha-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.
Thomas
L A
LA
Gastroenterology Unit, Division of Medicine, Guys Hospital Campus, United Medical and Dental School of Guy's and St. Thomas' Hospital, London, England.
Veysey
M J
MJ
Bathgate
T
T
King
A
A
French
G
G
Smeeton
N C
NC
Murphy
G M
GM
Dowling
R H
RH
D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000378:metabolism; D001421:Bacteria, Anaerobic / Q000302:isolation & purification; D001647:Bile Acids and Salts / Q000378:metabolism; D002769:Cholelithiasis / Q000378:metabolism / Q000503:physiopathology*; D002784:Cholesterol / Q000378:metabolism*; D003106:Colon / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology; D003840:Deoxycholic Acid / Q000096:biosynthesis* / Q000097:blood; D005215:Fasting / Q000097:blood; D005772:Gastrointestinal Transit / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006913:Hydroxysteroid Dehydrogenases; D007420:Intestine, Large / Q000503:physiopathology; D008875:Middle Aged; D010088:Oxidoreductases; D013250:Steroid Hydroxylases / Q000378:metabolism
D001647:Bile Acids and Salts; D003840:Deoxycholic Acid; D002784:Cholesterol; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; C025376:7 alpha-hydroxysteroid dehydrogenase; D013250:Steroid Hydroxylases; D000581:Amidohydrolases; C023154:choloylglycine hydrolase