Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis

Abstract

Key points• Peristaltic function of the small intestine is compromised in cholelithogenic humans and in animal models of cholesterol gallstones.• In a mouse gallstone model fed a cholesterol-and cholic acid-enriched diet, we show that slowing of small intestinal transit is due to absorption of excess cholesterol molecules from the upper small intestine followed by their incorporation into sarcolemmal membranes of smooth muscle cells.• Blocking cholesterol absorption with ezetimibe (Zetia), an inhibitor of intestinal sterol transport, prevents cholesterol enrichment of sarcolemmal membranes and normalizes the motility disorder.• Although the primary source of intestinal cholesterol in mice is the lithogenic diet, in most cholesterol gallstone-prone humans, the small intestine is flooded continuously with an abundance of liver-secreted cholesterol molecules via bile.• Our findings imply that small intestinal hypomotility will amplify the cholelithogenic state because of hyperabsorption of cholesterol and 'secondary' bile salt synthesis by the gut's anaerobic microbiota.Abstract Cholesterol gallstones are associated with slow intestinal transit in humans as well as in animal models, but the molecular mechanism is unknown. We investigated in C57L/J mice whether the components of a lithogenic diet (LD; 1.0% cholesterol, 0.5% cholic acid and 17% triglycerides), as well as distal intestinal infection with Helicobacter hepaticus, influence small intestinal transit time. By quantifying the distribution of 3 H-sitostanol along the length of the small intestine following intraduodenal instillation, we observed that, in both sexes, the geometric centre (dimensionless) was retarded significantly (P < 0.05) by LD but not slowed further by helicobacter infection (males, 9.4 ± 0.5 (uninfected), 9.6 ± 0.5 (infected) on LD compared with 12.5 ± 0.4 and 11.4 ± 0.5 on chow). The effect of the LD was reproduced only by the binary combination of cholesterol and cholic acid. We inferred that the LD-induced cholesterol enrichment of the sarcolemmae of intestinal smooth muscle cells produced hypomotility from signal-transduction decoupling of cholecystokinin (CCK), a physiological agonist for small intestinal propulsion in mice. Treatment with ezetimibe in an amount sufficient to block intestinal cholesterol absorption caused small intestinal transit time to return to normal. In most cholesterol gallstone-prone humans, lithogenic bile carries large quantities of hepatic cholesterol into the upper small intestine continuously, thereby reproducing this dietary effect in mice.

Endogenous elevation of plasma cholecystokinin does not prevent gallstones

“…We show here that feeding the lithogenic diet has the same effect due to impairment of CCK secretion. Our findings are also consistent with the previous demonstration that feeding mice a lithogenic diet slows small intestinal motility due to excessive incorporation of absorbed cholesterol into intestinal smooth muscle sarcolemmal membranes [34]. The authors inferred that this excessive cholesterol enrichment of intestinal smooth muscle cells produced hypomotility by uncoupling CCK signal transduction, a physiological mechanism of stimulated small intestinal propulsion.…”

Roles of cholesterol and bile salts in the pathogenesis of gallbladder hypomotility and inflammation: cholecystitis is not caused by cystic duct obstruction

“…This engenders hyperabsorption of Ch from the upper small intestine generation of a secondary bile acid deoxycholic acid in the distal small intestine. 29 Inflammatory changes in the lamina propria and muscle hypertrophy occur in these mice 4 weeks after they are fed lithogenic diets but before gallstones are formed. 30 These changes do not occur when mice are pretreated with maximum doses of ezetimibe that blocks completely the intestinal absorption of Ch.…”

“…Lithogenic diets fed to C57L mice impair the contractility of muscle cell layers of the small bowel resulting in slower intestinal transit. This engenders hyperabsorption of Ch from the upper small intestine generation of a secondary bile acid deoxycholic acid in the distal small intestine . Inflammatory changes in the lamina propria and muscle hypertrophy occur in these mice 4 weeks after they are fed lithogenic diets but before gallstones are formed .…”

Helicobacter spp. Other than H. pylori

“…The authors observed a chemoprotective action of FA supplementation in this gastric cancer model because of the ability of FA to prevent global loss of methylation and suppress inflammation. In addition, Xie et al [40] demonstrated that the lithogenic diet, but not H. hepaticus infection, significantly contributes to slowing of small intestinal transit in C57L/J mice.…”