A microbiota-bile acid-immune axis orchestrates intestinal antiviral defense: CDCA-to-UDCA biotransformation by Limosilactobacillus reuteri LRM2293 is associated with PEDV resistance

Abstract Porcine epidemic diarrhea virus (PEDV) causes severe intestinal injury and high mortality in neonatal piglets, and effective immunomodulatory strategies remain limited. Here, we investigate a probiotic-derived metabolic axis associated with resistance to PEDV infection through bile acid–immune crosstalk. A Limosilactobacillus reuteri strain (LRM2293), isolated from disease-resistant Min pigs, efficiently converted CDCA into ursodeoxycholic acid (UDCA). Both LRM2293 and UDCA significantly reduced PEDV replication in intestinal epithelial cells and ameliorated clinical symptoms in neonatal piglets. UDCA treatment increased type III interferon (IFN-λ3) expression, while pharmacological inhibition of TGR5 partially reversed both the antiviral effects of UDCA and IFN-λ3 induction. These findings support the potential involvement of TGR5-associated IFN-λ3 signaling in UDCA-mediated antiviral activity. In addition, UDCA preserved epithelial barrier integrity and attenuated oxidative stress, inflammatory responses, and endoplasmic reticulum stress in infected intestines. Collectively, our findings suggest that LRM2293-mediated bile acid remodeling is associated with enhanced resistance to PEDV infection. TGR5-associated IFN-λ3 signaling may represent one mechanism contributing to the antiviral effects of UDCA.