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

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.

The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression

“…Furthermore, the ability of bile acids to induce neoplasia has also been demonstrated; mice fed a diet with addition of deoxycholic acid developed more aberrant crypt foci, a precursor malignant lesion [40] as well as frank tumors [41]. Moreover, intestine-selective carcinogen treatment of mice with impaired bile acid transport and increased spillage of endogenous bile acids into the colon resulted in augmented colon neoplasia compared to wild-type mice with normal fecal bile acid levels [42,43].…”

Attenuated Accumulation of Novel Fluorine (19F)-Labeled Bile Acid Analogues in Gallbladders of Fibroblast Growth Factor-15 (FGF15)-Deficient Mice

“…We, and others, have shown that, like humans with FGF19 deficiency, FGF15-deficient mice have increased fecal bile acid excretion. 12–15 We detected low quantities of intact CA-lys-TFA and CA-sar-TFMA in the stool, with more in stool from FGF15-deficient mice than from wild-type mice (Supporting Information: Figure S9).…”

Intestinal Absorption of Bile Acids in Health and Disease

“…These methods are likely insufficient to study dynamic, posttranslational changes in ASBT activity, necessitating the development of real-time methods. Several recent approaches have been developed to quantify the aspects of bile acid physiology in -real time (76,115,263,311,389,392,(397)(398)(399). Additionally, a recent bioluminescence-based approach relying on a CA-luciferin-conjugated probe has shown promising results for measuring real-time ASBT activity in vitro and in isolated intestinal epithelial cells (377).…”