Bacteroides dorei RX2020-derived bile acid alleviates influenza virus infection through TGR5 signaling.

Abstract

Background: The role of the gut microbiome in respiratory infections is increasingly recognized. We have found that a gut commensal strain, Bacteroides dorei RX2020 (B. dorei) previously isolated from healthy human fecal microbiota, alleviates influenza virus infection, but the underlying mechanisms remain elusive.

Methods: To explore the mechanism by which B. dorei alleviates influenza, we administered it via gavage to influenza virus-infected mice. Gene knockout mice were then used to verify the underlying signaling pathways involved in the antiviral action of B. dorei. Metabolomics analysis was conducted to identify effective metabolites of B. dorei against influenza, followed by complementary verification to confirm these metabolites.

Results: Metabolomics reveals that influenza virus infection significantly reduced the concentrations of secondary bile acid (BA) in feces at 7 post-infection (dpi). Oral administration of B. dorei increased bile salt hydrolase (BSH) activity and restored the BA metabolism, thereby protecting wild-type but not TGR5-deficient mice from influenza virus infection. B.dorei-mediated TGR5 activation inhibited influenza virus-induced lung inflammation via cAMP-PKA pathway. Supplementing exogenous Ursodeoxycholic acid (UDCA) and Hyodeoxycholic acid (HDCA), two metabolites changed dramatically after B. dorei treatment, reproduced the protective effect of B. dorei.

Conclusions: Overall, our work elucidates the protective efficacy of commensal microbes against influenza virus infection by modulating lung immunity and restoring BA metabolism, suggesting a potential strategy to intervene in distal infections by regulating gut microbial metabolism.