Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice
“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 f...
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| Format: | Article |
| Language: | en_US |
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American Physiological Society
2015
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| Online Access: | http://hdl.handle.net/1721.1/96251 https://orcid.org/0000-0002-6153-8803 https://orcid.org/0000-0001-9307-6116 |
| _version_ | 1826195218932695040 |
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| author | Woods, Stephanie E. Leonard, Monika R. Hayden, Joshua A. Brophy, Megan Brunjes Bernert, Kara R. Lavoie, Brigitte Muthupalani, Sureshkumar Whary, Mark T. Mawe, Gary M. Nolan, Elizabeth M. Carey, Martin C. Fox, James G. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Woods, Stephanie E. Leonard, Monika R. Hayden, Joshua A. Brophy, Megan Brunjes Bernert, Kara R. Lavoie, Brigitte Muthupalani, Sureshkumar Whary, Mark T. Mawe, Gary M. Nolan, Elizabeth M. Carey, Martin C. Fox, James G. |
| author_sort | Woods, Stephanie E. |
| collection | MIT |
| description | “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. |
| first_indexed | 2024-09-23T10:09:16Z |
| format | Article |
| id | mit-1721.1/96251 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:09:16Z |
| publishDate | 2015 |
| publisher | American Physiological Society |
| record_format | dspace |
| spelling | mit-1721.1/962512022-09-26T16:02:28Z Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice Woods, Stephanie E. Leonard, Monika R. Hayden, Joshua A. Brophy, Megan Brunjes Bernert, Kara R. Lavoie, Brigitte Muthupalani, Sureshkumar Whary, Mark T. Mawe, Gary M. Nolan, Elizabeth M. Carey, Martin C. Fox, James G. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Division of Comparative Medicine Nolan, Elizabeth M. Nolan, Elizabeth M. Woods, Stephanie E. Hayden, Joshua A. Brophy, Megan Brunjes Muthupalani, Sureshkumar Whary, Mark T. Fox, James G. “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. National Institutes of Health (U.S.) (Training Grant T32-OD10978-26) National Institutes of Health (U.S.) (Training Grant P30-ES002109) Kinship Foundation. Searle Scholars Program 2015-03-30T17:24:01Z 2015-03-30T17:24:01Z 2014-12 2014-12 Article http://purl.org/eprint/type/JournalArticle 0193-1857 1522-1547 http://hdl.handle.net/1721.1/96251 Woods, Stephanie E., Monika R. Leonard, Joshua A. Hayden, Megan Brunjes Brophy, Kara R. Bernert, Brigitte Lavoie, Sureshkumar Muthupalani, et al. “Impaired Cholecystokinin-Induced Gallbladder Emptying Incriminated in Spontaneous ‘black’ Pigment Gallstone Formation in Germfree Swiss Webster Mice.” Am J Physiol Gastrointest Liver Physiol 308, no. 4 (December 4, 2014): G335–G349. https://orcid.org/0000-0002-6153-8803 https://orcid.org/0000-0001-9307-6116 en_US http://dx.doi.org/10.1152/ajpgi.00314.2014 American Journal of Physiology - Gastrointestinal and Liver Physiology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Physiological Society Prof. Nolan via Erja Kajosalo |
| spellingShingle | Woods, Stephanie E. Leonard, Monika R. Hayden, Joshua A. Brophy, Megan Brunjes Bernert, Kara R. Lavoie, Brigitte Muthupalani, Sureshkumar Whary, Mark T. Mawe, Gary M. Nolan, Elizabeth M. Carey, Martin C. Fox, James G. Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice |
| title | Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice |
| title_full | Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice |
| title_fullStr | Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice |
| title_full_unstemmed | Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice |
| title_short | Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice |
| title_sort | impaired cholecystokinin induced gallbladder emptying incriminated in spontaneous black pigment gallstone formation in germfree swiss webster mice |
| url | http://hdl.handle.net/1721.1/96251 https://orcid.org/0000-0002-6153-8803 https://orcid.org/0000-0001-9307-6116 |
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