Ursodeoxycholic acid shows unexpected gut FXR agonism in liver FXR-deficient mice

Associated with dysregulation of bile acid (BA) homeostasis, MASH continues to impose a major global disease burden, with limited pharmacologic options and no FDA approved FXR modulators owing to safety concerns. FXR plays an essential role in maintaining BA homeostasis and lipid metabolism and inhibiting inflammatory signaling, making it one of the most intensively studied targets in MASH therapeutics. Against this backdrop, UDCA - a widely used hydrophilic BA approved for primary biliary cholangitis-has drawn growing attention for its potential therapeutic role in metabolic liver diseases. Although traditionally regarded as a gut FXR antagonist, its true molecular action has remained controversial.

A new mechanistic investigation published in eGastroenterology challenges this long-held assumption. In an extensive mouse study employing hepatic FXR-deficient (FXR^hep-/-) and littermate control mice. Professor Grace Guo and colleagues reveal that UDCA behaves as an ileal FXR agonist, not an antagonist, and that its metabolic impact differs profoundly between male and female mice. These findings reshape current understanding of UDCA-FXR interactions and inform the design of organ-specific strategies targeting FXR for MASH therapy.

1. UDCA Preferentially Protects Male Mice from Steatosis and Injury

1.1 Liver lipid reduction and histology

UDCA modestly reduced liver triglycerides and cholesterol in male mice across diets. Histological assessment confirmed decreased steatosis, particularly in UDCA-treated males on the control diet, where fewer lipid droplets were observed. These beneficial changes were not mirrored in female mice, who maintained higher baseline liver lipid levels and did not exhibit comparable improvements.

1.2 Serum liver injury markers

In males, alanine aminotransferase (ALT) activities trended downward with UDCA supplementation, especially in the FXR^hep+/+ mice on the control diet. In contrast, female cohorts exhibited minimal changes across biochemical parameters.

1.3 Fibrosis and inflammatory signaling

UDCA reduced expression of fibrosis-related genes (Colla 1, Timp 1) in males more consistently than females. Although histological fibrosis did not significantly change, likely due to the limited duration of MASH diet feeding-lower gene expression suggests early antifibrotic effects. UDCA also suppressed hepatic Lcn2 expression specifically in FXR^hep-/- males on the control diet, pointing to reduced inflammatory stress under FXR-deficient conditions.

2. Ileal FXR Activation-Not Antagonism-Is the Dominant Effect of UDCA

One of the most striking results was the discovery that UDCA activates ileal FXR signaling, contradicting previous models suggesting UDCA inhibits gut FXR.

2.1 Upregulation of gut FXR-FGF15 pathway (male mice)

In the ileum of male mice, UDCA supplementation significantly increased the mRNA levels of: (1) Fxr; (2) Fgf15, the canonical FXR downstream hormone; and (3) Ibabp, a FXR target gene involved in intracellular BA binding. This pattern is indicative of a robust ileal FXR activation.

2.2 Female mice show blunted FXR activation

Female mice did not demonstrate equivalent induction of ileal FXR targets. The authors propose that higher intestinal tauro-muricholic acids (T-MCAs), potent endogenous FXR antagonists, may compete with UDCA in females, limiting receptor activation. This notion was supported by bile acid profiling: UDCA feeding markedly reduced T-MCAs only in males, providing a biochemical basis for sex-specific FXR responsiveness.

3. UDCA Profoundly Reshapes the BA Pool in a Sex-Dependent Manner

Comprehensive BA profiling in liver, serum, and intestine yielded multiple insights:

3.1 Higher UDCA and TUDCA accumulation in males

Across tissues, male mice displayed more than twice the levels of UDCA and its conjugate TUDCA compared with females. These hydrophilic BAs are known to reduce ER stress and hepatocellular injury, likely contributing to the stronger protective phenotype in males.

3.2 Altered classical BA synthesis

UDCA reduced the mRNA expression of Cyp7a1, which encodes a key enzyme in classical synthesis pathway of cholic acid, in both genotypes, consistent with enhanced FGFl5 feedback signaling. In males, Cyp8b1 expression increased with UDCA supplementation on the MASH diet, possibly reflecting compensatory BA synthesis shifts.

3.3 Sex differences in primary/secondary BA ratios

Male UDCA-fed mice showed a notable shift toward lower 12a-OH BA ratios and decreased T-MCAs, changes consistent with enhanced ileal FXR activity. Female mice, in contrast, retained higher levels of T-MCAs and tri-hydroxylated BAs, which may dampen FXR activation.

4. UDCA Provides Limited Benefit in MASH Reduction

While UDCA had measurable protective effects under control diet conditions, its benefits in diet-induced MASH were less evident: (l) Inflammatory markers (F4/80, Tnfα, Il-6) did not decrease consistently in MASH males; (2) Lcn2 increased in MASH+UDCA groups, suggesting that UDCA's anti-inflammatory effect was overwhelmed by ongoing liver injury; (3) Fibrosis markers trended down but without histologic confirmation.

These results underscore the complexity of using UDCA as a monotherapy for diet-driven MASH progression.

5. Implications for Research and Clinical Translation

5.1 UDCA is not a simple FXR antagonist

The demonstration of ileal FXR agonism contradicts earlier assumptions and clarifies UDCA's mechanistic profile, with direct implications for therapeutic design aimed at FXR modulation.

5.2 Sex differences must guide dose and therapeutic expectation

Male mice exhibited stronger UDCA uptake, more pronounced FXR activation, and greater improvement in injury markers. The muted response in females highlights the need for female-specific dose-response studies in BA-based therapies.

5.3 Caution when extrapolating to human MASH therapy

Although UDCA is safe and clinically available, its modest benefits in this model-especially under MASH-inducing conditions-suggest limited efficacy as a standalone therapy.

Conclusion

This comprehensive mouse study reshapes the understanding of how UDCA interacts with the FXR signaling network. Rather than acting as a gut FXR antagonist, UDCA serves as an ileal FXR agonist in male mice and modulates BA composition in a distinctly sex-dependent manner. While it provides mild hepatoprotection, most evident in male cohorts on control diets, its impact under strong MASH-driving conditions is limited. These findings provide a refined mechanistic framework to guide future development of targeted FXR-modulating therapies for MASH.

 

See the article:

Henry ZR, Maliha S, Basaly V, Yang Z, Taylor RE, Otersen K, et al. Ursodeoxycholic acid acts as an ileal FXR agonist in male mice with hepatic deficiency of FXR. eGastroenterology. 2025;3:e100227.  https://doi.org/10.1136/egastro-2025-100227

 

About eGastroenterology

eGastroenterology, a BMJ journal partnered with Gut and launched by leading scientists in gastroenterology and hepatology, has been indexed in the Web of Science Core Collection (ESCI), PubMed, DOAJ, Scopus, CAS, ROAD, and many other major international databases within just two years of its launch. The journal is expecting to receive its first Impact Factor in June 2026.

For more information, please visit: egastroenterology.bmj.com and follow us on Twitter (@eGastro_BMJ).

Sign-up to Email Alerts for eGastroenterology: 

https://emails.bmj.com/k/Bmj/jausu/egastroenterology

---

---