Farnesoid X Receptor Agonist Tropifexor Improves Intestinal Defense Response and Epithelial Barrier Function in Neonatal Piglets Receiving Parenteral Nutrition

Long-term parenteral nutrition (PN) can lead to liver and intestinal injury in neonates, but effective prevention strategies are limited. Our previous research demonstrated that activation of farnesoid X receptor (FXR) signaling with tropifexor (TXR) could mitigate PN-induced liver damage in neonatal piglets, but its effect on intestinal injury remains to be addressed. In this study, two-day-old Bama minipigs were randomly allocated into three groups (n = 6/group): EN (receiving enteral nutrition, serving as a control), PN, and PT (PN + TXR treatment). Consequently, TXR treatment significantly mitigated PN-induced intestinal injury, including villus atrophy, hyper-permeability, and impaired defense responses. Transcriptomic profiling identified 1188 differentially expressed genes (DEGs) in the PN group compared to EN, among which 108 genes could be substantially attenuated by TXR. Notably, bioinformatics analysis suggested that these DEGs could be classified into "positive regulation of defense response" and "cell-cell adhesion". Moreover, the top 25 hub genes were identified, including EPCAM, CD28, and IFNG. Furthermore, we demonstrated that EPCAM decreased significantly upon PN administration, which could be substantially attenuated by TXR. Finally, in order to further validate the role of TXR in modulating intestinal barrier function, patient-derived organoids (PDOs) were used as a mini-gut model in vitro. Consequently, pharmacological activation of FXR by TXR substantially induced EPCAM expression and enhanced epithelial barrier integrity, particularly in the PDOs derived from pediatric patients receiving PN, while no significant changes were found in those derived from patients receiving oral feeding. In conclusion, this study suggested that TXR treatment could alleviate PN-induced impairment of defense responses and epithelial barrier dysfunction, potentially offering a preventive strategy for neonates receiving long-term PN therapy.