Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice.

Kunrong Cheng,Grace L Guo,Aaron C Shang,Jean-Pierre Raufman,Justin Schumacher,Cinthia B Drachenberg,James E Polli,Su Xu,Min Zhan,Melissa Metry,Jessica Felton

doi:10.18632/oncotarget.25385

Abstract

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.

Highlights

Active uptake of bile acids from the distal small intestine and feedback inhibition of hepatic bile acid synthesis tightly regulate bile acid homeostasis; normally, each day only a small fraction of intestinal bile acids is excreted in the feces
Deficiency of either FGF19 or FGF15, intestinal hormones that serve as feedback brakes on hepatic bile acid production, results in increased bile acid synthesis www.oncotarget.com and enlargement of the bile acid pool
We used innovative in vivo and ex vivo imaging-based approaches to extend the previous observation that FGF15 regulates gallbladder function [14]

Summary

Introduction

Active uptake of bile acids from the distal small intestine and feedback inhibition of hepatic bile acid synthesis tightly regulate bile acid homeostasis; normally, each day only a small fraction of intestinal bile acids is excreted in the feces. The ileal apical sodium-dependent bile acid transporter (ASBT; encoded by SLC10A2) is a key regulator of bile acid absorption from the distal small intestine into the enterohepatic circulation; active uptake by ASBT and passive absorption throughout the gut results in the recovery of ~95% of intestinal bile acids. Deficiency or impaired function of ASBT increases bile acid spillage into the feces by 6- to 10-fold and strikingly reduces the size of the bile acid pool [1, 2]. In the absence of FGF19/15, hepatic bile acid overproduction may increase intestinal bile acids to a level exceeding ASBT transport (small intestinal uptake) capacity, thereby increasing bile acid spillage into the colon [4]

Methods

Results

Conclusion