OC-079FGF19 expression is highly responsive to bile acids compared to other bile acid regulatory genes within the human ileum

IntroductionThe expression of the enteric hormone FGF15 is largely restricted to the ileum in the mouse. FGF15 has also been shown to be the most BA responsive gene in mouse ileum. FGF19 is the human orthologue of FGF15 and is thought to have roles in the regulation of bile acid pool sizes and BA homeostasis. We set out to investigate the distribution of FGF19 expression in the human GI tract and FGF19 gene responses to BA in human ileum.MethodsBiopsies of normal ileal mucosa were obtained from 29 patients undergoing colonoscopy. Basal ileal FGF19 expression was compared to colonic (n=9) and duodenal FGF19 expression (n=3). Ileal biopsies (explants) from 20 patients were incubated for 6h in short term tissue culture in parallel with BA (chenodeoxycholic acid [CDCA] or glyco-chenodeoxycholic acid [GCDCA]) or without (control explants). 3 Duodenal and colonic explants from were also studied. Real-time qRT-PCR was used to measure expression of transcripts for FGF19, and several other ileal BA regulatory genes (ASBT, IBABP, SHP, FXR, OST alpha and OST beta ). FGF19 protein levels in culture fluid were also measured by specific ELISA.ResultsTranscripts for FGF19 were detected in human ileum, but not colon or duodenum. FGF19 expression was greatly induced in all ileal explants incubated with BA: geometric mean induction of 316-fold by 50 mu M CDCA (n=17, p=0.0003), and 231-fold by 50 mu M GCDCA (n=11, p=0.001). Measured by ELISA, the amount of FGF19 protein released into the culture media was significantly higher from the explants incubated with 50 mu M of BA (CDCA 51pg/explant, range 8-169, n=11 and GCDCA 38pg/explant, range 3-113, n=10) compared to the matched control explants (8pg/explant, range 0-46 [p=0.0008] and 6pg/explant, range 0-13 [p=0.0022] respectively). The EC50 for CDCA was 20 mu M and 24 mu M for GCDCA. Responses to both BA were similar at 50 mu M and 100 mu M. 6h incubation of duodenal and colonic explants with 100 mu M CDCA or GCDCA showed that FGF19 expression levels were