Lack of endogenous cholecystokinin promotes cholelithogenesis in mice

Abstract

Background Celiac disease is an autoimmune enteropathy caused by a permanent intolerance to dietary gluten in genetically predisposed individuals. Cholecystokinin (CCK) release from the proximal small intestine and gallbladder emptying in response to a fatty meal are greatly reduced in celiac patients before they start the gluten-free diet, showing a genetic predisposition to gallstones. Methods To elucidate the complex pathophysiological mechanisms determining the biliary characteristic of celiac disease, we investigated the effect of the absence of endogenous CCK on cholesterol crystallization and gallstone formation in mice fed a lithogenic diet for 28 days. Key Results Fasting gallbladder volumes were increased and the response of gallbladder emptying to the high-fat diet was impaired in CCK knockout mice compared to wild-type mice. Because of the absence of CCK, small intestinal transit time was prolonged and intestinal cholesterol absorption was increased. During 28 days of feeding, elevated biliary cholesterol concentrations and gallbladder stasis promoted the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. Thus, cholesterol crystallization and gallstone formation were accelerated in CCK knockout mice. In contrast, daily intraperitoneal administration of CCK-8 reduced gallstone formation in CCK knockout mice even on the lithogenic diet. Conclusion & Inferences The lack of endogenous CCK enhances susceptibility to gallstones by impairing gallbladder contractile function and small intestinal motility function. These findings show that celiac disease is an important risk factor for gallstone formation and the gallbladder motility function should be routinely examined by ultrasonography and gallbladder stasis should be prevented in celiac patients.

Impaired intestinal cholecystokinin secretion, a fascinating but overlooked link between coeliac disease and cholesterol gallstone disease

“…More importantly, biliary cholesterol secretion is almost doubled in coeliac patients, indicating that hepatic hypersecretion of biliary cholesterol is a primary factor for the formation of supersaturated bile . By studying CCK knockout (KO) mice, an excellent animal model relevant to the biliary characteristic of coeliac disease, it is observed that hepatic secretion of biliary cholesterol and phospholipids, but not bile salts, is significantly increased after 56 days of lithogenic diet feeding . These abnormalities enhance biliary lithogenicity, thereby leading to rapid cholesterol crystallization and gallstone formation in CCK KO mice compared to wild‐type (WT) mice.…”

“…It has been found that CCK plays a role in the regulation of small intestinal motility because Cck‐1r is expressed in the smooth muscle of small intestine, which is a variable known to influence intestinal cholesterol absorption in humans . Indeed, small intestinal transit time is significantly retarded not only in CCK KO mice , but also in CCK‐1R KO mice . As a result, intestinal cholesterol absorption efficiency is significantly increased in these knockout mice.…”

“…This, in turn, amplifies cholesterol's incorporation into mixed micelles and also enhances partitioning of cholesterol monomers out of micelles, rendering them available for intestinal uptake by cholesterol influx sterol transporter, Niemann‐Pick C1‐like protein 1 (NPC1L1), on the apical membrane of enterocytes. Accumulated evidence has shown that sluggish small intestinal transit rate augments intestinal cholesterol absorption efficiency not only in CCK and CCK‐1R KO mice , but also in humans with pharmacological intervention . Increased intestinal cholesterol absorption is also a risk factor for the formation of lithogenic bile and gallstones .…”

“…The lack of endogenous CCK in mice with disruption of the Cck gene markedly increases fasting and postprandial gallbladder volumes by impairing gallbladder emptying function, leading to gallbladder stasis . This greatly facilitates the crystallization of cholesterol monohydrate crystals and their growth and agglomeration to gallstones .…”

Cd36 knockout mice are protected against lithogenic diet-induced gallstones

“…Beyond the metabolic alterations alluded to above, there is a role for altered gallbladder motility in promoting gallstone susceptibility, evidenced by findings in both Cck KO mice and in Cckr1 KO mice (18,19). These findings, coupled with findings that CD36-dependent signaling promotes secretin and cholecystokinin (CCK) release from enteroendocrine cells (20), raised the question of whether CD36 might function more broadly in modifying gallstone susceptibility, specifically via alterations in gallbladder contractility.…”