Slow Intestinal Transit: A Motor Disorder Contributing to Cholesterol Gallstone Formation in the Ground Squirrel

Abstract

Impaired gallbladder motility is an established factor stone disease may initially represent a metabolic liver in cholesterol gallstone formation. We assessed whether disorder but can be modulated by the enterohepatic altered small intestinal smooth muscle contractility with circulation of bile salts.2,9-14 The gallbladder (by filling slow transit might potentiate gallstone formation by fur-and emptying) and the small intestine (by governing ther impeding enterohepatic cycling of bile acids. transit time) are the rate-limiting steps that control Ground squirrels were fed a 1% or a trace (controls) cho-the enterohepatic cycling frequency of bile salts and lesterol diet. Small intestinal transit was evaluated from their flux through the liver. [9][10]14,15 Enterohepatic cy- size calculated by isotope dilution. Gas-liquid chromaProlonged small intestinal transit, like impaired tography (GLC) assessed bile salt profile. In animals on gallbladder emptying, should hinder enterohepatic cythe 1% cholesterol diet, aboral transit was significantly cling and lower the bile salt secretion rate, thus predisdelayed, the maximal contractile response to betha-posing to the formation of gallbladder bile saturated nechol was markedly increased (P õ .05) with no change with cholesterol.9,10,14 Recent studies of cholesterol gallin median effective concentration in either circular or stone pathogenesis in nonobese subjects and in acromelongitudinal muscle strips from both the jejunum and galic patients treated with the long-acting somatoileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. statin analog, octreotide, support and advance this Cholesterol saturation index and the fraction of deoxy-hypothesis. In each condition, either prolonged wholecholic acid in the pool doubled, whereas the total bile gut transit or lengthened small intestinal transit has salt pool size remained unchanged in cholesterol-fed an-been linked to an increased production of deoxycholate, imals. In this model, a high-cholesterol diet is associated saturated gallbladder bile, and the subsequent formawith altered small intestinal smooth muscle contractility tion of cholesterol gallstones. [16][17][18] The importance of the

Effect of the prokinetic agent, erythromycin, in the richardson ground squirrel model of cholesterol gallstone disease

“…Serum cholesterol levels were also determined by the Ames cholesterol kit. 17,24 Gallbladder Contractility In Vitro. The gallbladder preparation and organ bath system for the in vitro contractile studies followed that published previously.…”

“…After 3 weeks on their respective diets, 10 erythromycin-and 10 placebo-treated animals in each diet group (40 animals in total) were anesthetized with halothane (Ayerst Laboratories) and surgically prepared with a jejunal cannula placed just distal to the ligament of Treitz. 17 Animals were allowed 6 days to recover, fed ad libitum on their respective diets, and received assigned treatment with erythromycin or placebo until the terminal experiment. The intestinal transit study was performed at the beginning of the fifth week.…”

“…As soon as the abdomen was opened, the gut was removed and divided into the cecum, the remaining colon, and eight equal segments of small intestine. 17,25 Each segment of the intestine as well as the cecum and colon and a 1-mL sample of blood were placed in separate vials. The distribution of 51 Cr throughout the small intestine, cecum, colon, and blood was determined by a gamma-counter (LKB-Wallac, 1282 CompuGamma, Stockholm, Sweden).…”

“…3,4,[8][9][10][11][12] Among the growing list of pathogenic events implicated in cholesterol gallstone formation, prolonged intestinal transit and gallbladder stasis both impede enterohepatic cycling and are thus able to lower the bile salt secretion, predisposing to the formation of bile with an increased cholesterol saturation. 10,[13][14][15][16][17] Ground squirrels fed a 1% high-cholesterol diet exhibit abnormal biliary lipid secretion, increased mucin accumulation on the epithelial surface of the gallbladder, defective gallbladder motility, and delayed intestinal transit as the cholesterol saturation in bile increases. [17][18][19] These unique features characterize this well-established animal model and mimic the proposed sequential events in cholesterol gallstone formation in humans.…”

“…10,[13][14][15][16][17] Ground squirrels fed a 1% high-cholesterol diet exhibit abnormal biliary lipid secretion, increased mucin accumulation on the epithelial surface of the gallbladder, defective gallbladder motility, and delayed intestinal transit as the cholesterol saturation in bile increases. [17][18][19] These unique features characterize this well-established animal model and mimic the proposed sequential events in cholesterol gallstone formation in humans. 19 Using this model, we sought to determine if erythromycin, a motilin agonist with known prokinetic properties, [20][21][22][23] could simultaneously stimulate gallbladder and intestinal motor function with a resultant increase in the enterohepatic cycling of bile salts.…”