Enteral agonism of farnesoid X receptor-fibroblast growth factor 19 prevents cholestasis in TPN-fed neonatal pigs

Administration of total parenteral nutrition (TPN) ensures the delivery of necessary nutrients to infants who cannot tolerate enteral feeding. However, long-term use of TPN can result in cholestasis. Currently, the enteral administration of the bile acid, ursodeoxycholic acid (UDCA), is used clinically to treat cholestasis by promoting enterohepatic bile flow but has mixed results. We hypothesize that modulation of the nuclear receptor farnesoid X receptor (FXR) signaling is important to restore normal bile flow. FXR is part of a negative feedback loop through the production of the gut hormone fibroblast growth factor 19 (FGF19) to regulate bile acid synthesis. Tropifexor (TPX) is a new, non-bile acid therapeutic agent with potent FXR agonist activity that we hypothesize can be used to mitigate cholestasis. Additionally, as TPX is a non-bile acid it does not have side effects, like pruritis, that other bile acid FXR agonists cause. The study objective was to determine if UDCA, TPX, or FGF19 administration will activate the FXR-FGF19 axis and prevent or mitigate cholestasis. TPN was administered to piglets for three weeks. During this time, piglets were treated enterally with either UDCA (25 mg/kg*day) or TPX (7.5 µg/kg*day) in minimal milk-based formula (12 mL/kg*day), or with daily intravenous FGF19 (0.25 mg/d) injection. Control and FGF19 pigs also received minimal milk-based formula (12 mL/kg*day). After three weeks, serum markers for cholestasis direct bilirubin, gamma glutamyl transferase, and plasma bile acids were lower for TPX pigs compared to the control. Quantitation of colonic bile acids demonstrated TPX promoted increased bile flow into the intestines. This increased bile flow was facilitated by bile acid transport expression in both the liver and intestine. TPX significantly elevated the liver bile acid efflux transporters organic solute transporter alpha (OSTα) and bile salt export pump (BSEP), compared to the control. Furthermore, while control and FGF19 treated pigs had a large increase in hyocholic acid, pigs that received TPX tended to have an increased relative concentration of chenodeoxycholic acid, making the profile more FXR agonistic compared to other treatments. To delve further into tissue-specific responses, we first tested ileal explants from newborn pigs and three-week-old pigs were treated with UDCA, TPX, and obeticholic acid. There was an increased amount of FGF19 released into media from explants treated with TPX for 6 hr. We also tested liver-specific responses using hepatocyte spheroids and showed that TPX treatment decreased cholesterol 7α-hydroxylase, but induced a robust increase in OSTα expression. Overall, FGF19 and UDCA treatments had minimal effects, while TPX activated the FXR-FGF19 axis and prevented cholestasis in TPN-fed piglets via increased hepatobiliary transport of bile acids. NIDDK R01-DK094616 T32 NIH grant DK07664 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.