title: Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous "black" pigment gallstone formation in germfree Swiss Webster mice.
abstract: "Black" pigment gallstones form in sterile gallbladder bile in the presence of excess bilirubin conjugates ("hyperbilirubinbilia") from ineffective erythropoiesis, hemolysis, or induced enterohepatic cycling (EHC) of unconjugated bilirubin. Impaired gallbladder motility is a less well-studied risk factor. We evaluated the spontaneous occurrence of gallstones in adult germfree (GF) and conventionally housed specific pathogen-free (SPF) Swiss Webster (SW) mice. GF SW mice were more likely to have gallstones than SPF SW mice, with 75% and 23% prevalence, respectively. In GF SW mice, gallstones were observed predominately in heavier, older females. Gallbladders of GF SW mice were markedly enlarged, contained sterile black gallstones composed of calcium bilirubinate and <1% cholesterol, and had low-grade inflammation, edema, and epithelial hyperplasia. Hemograms were normal, but serum cholesterol was elevated in GF compared with SPF SW mice, and serum glucose levels were positively related to increasing age. Aged GF and SPF SW mice had deficits in gallbladder smooth muscle activity. In response to cholecystokinin (CCK), gallbladders of fasted GF SW mice showed impaired emptying (females: 29%; males: 1% emptying), whereas SPF SW females and males emptied 89% and 53% of volume, respectively. Bilirubin secretion rates of GF SW mice were not greater than SPF SW mice, repudiating an induced EHC. Gallstones likely developed in GF SW mice because of gallbladder hypomotility, enabled by features of GF physiology, including decreased intestinal CCK concentration and delayed intestinal transit, as well as an apparent genetic predisposition of the SW stock. GF SW mice may provide a valuable model to study gallbladder stasis as a cause of black pigment gallstones.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts;
authors.forename: Stephanie E
authors.identifier: http://orcid.org/0000-0003-1891-8066
authors.initials: SE
authors.lastname: Woods
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Monika R
authors.initials: MR
authors.lastname: Leonard
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Hayden
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
authors.forename: Megan Brunjes
authors.initials: MB
authors.lastname: Brophy
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Kara R
authors.initials: KR
authors.lastname: Bernert
authors.affiliation: Department of Neurological Sciences, University of Vermont, Burlington, Vermont.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lavoie
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts;
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts; mwhary@mit.edu.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Whary
authors.affiliation: Department of Neurological Sciences, University of Vermont, Burlington, Vermont.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Mawe
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Nolan
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Martin C
authors.initials: MC
authors.lastname: Carey
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts;
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000367:Age Factors; D000818:Animals; D001654:Bile Pigments / Q000378:metabolism*; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism*; D005260:Female; D005704:Gallbladder / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D042882:Gallstones / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D005856:Germ-Free Life; D006863:Hydrogen-Ion Concentration; D016015:Logistic Models; D008297:Male; D051379:Mice; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012307:Risk Factors; D012737:Sex Factors; D013045:Species Specificity; D013997:Time Factors
chemical_list: D001654:Bile Pigments; D002766:Cholecystokinin; D002118:Calcium
keywords: black pigment gallstones; cholecystokinin; germfree mice; impaired gallbladder motility