Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice
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Kunrong Cheng1,2,*, Melissa Metry3,*, Jessica Felton4,*, Aaron C. Shang2, Cinthia B. Drachenberg5, Su Xu6, Min Zhan7, Justin Schumacher8, Grace L. Guo8, James E. Polli3 and Jean-Pierre Raufman1,2,9,*
1VA Maryland Healthcare System, Baltimore, Maryland, 21201, USA
2Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
3Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, 21201, USA
4Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
5Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
6Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
7Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
8Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, 08854, USA
9Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
*These authors have contributed equally to this work
Jean-Pierre Raufman, email: [email protected]
Keywords: colon neoplasia; bile acids; cell proliferation; gallbladder; enterohepatic circulation
Received: January 19, 2018 Accepted: April 26, 2018 Published: May 22, 2018
Fibroblast growth factor-19 (human FGF19; murine FGF15) suppresses bile acid synthesis. In FGF19 deficiency, diarrhea resulting from bile acid spillage into the colon mimics irritable bowel syndrome. To seek other consequences of FGF19/15 deficiency, we used Fgf15-/- and wild-type (WT) mice to assess gallbladder filling, the bile acid pool, fecal bile acid levels, and colon neoplasia. We fasted mice for six hours before assessing gallbladder size by magnetic resonance imaging (MRI). We measured bile acid levels in different compartments by enzymatic assay, and induced colon neoplasia with azoxymethane (AOM)/dextran sodium sulfate (DSS) and quantified epithelial Ki67 immunostaining and colon tumors 20 weeks later. In vivo MRI confirmed the gross finding of tubular gallbladders in FGF15-deficient compared to WT mice, but fasting gallbladder volumes overlapped. After gavage with a bile acid analogue, ex vivo MRI revealed diminished gallbladder filling in FGF15-deficient mice (P = 0.0399). In FGF15-deficient mice, the total bile acid pool was expanded 45% (P <0.05) and fecal bile acid levels were increased 2.26-fold (P <0.001). After AOM/DSS treatment, colons from FGF15-deficient mice had more epithelial cell Ki67 staining and tumors (7.33 ± 1.32 vs. 4.57 ± 0.72 tumors/mouse; P = 0.003 compared to WT mice); carcinomas were more common in FGF15-deficient mice (P = 0.01). These findings confirm FGF15, the murine homolog of FGF19, plays a key role in modulating gallbladder filling and bile acid homeostasis. In a well-characterized animal model of colon cancer, increased fecal bile acid levels in FGF15-deficient mice promoted epithelial proliferation and advanced neoplasia.
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