title: 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.
  
  
  RESULTS
  Fasting gallbladder volumes were increased and the response of gallbladder emptying to the high-fat diet was impaired in CCK knockout (KO) 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 KO mice. In contrast, daily intraperitoneal administration of CCK-8 reduced gallstone formation in CCK KO mice even on the lithogenic diet.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA, USA.|Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Portincasa
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tso
authors.affiliation: Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA, USA.|Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: D Q-H
authors.initials: DQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002446:Celiac Disease / Q000150:complications; D002766:Cholecystokinin / Q000172:deficiency*; D016473:Gallbladder Emptying / Q000502:physiology*; D042882:Gallstones / Q000209:etiology* / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002766:Cholecystokinin
keywords: bile salt; celiac disease; cholesterol absorption; cholesterol crystallization; gallbladder motility; lithogenic bile