The <i>Akkermansia muciniphila</i> Metabolite Harmaline Protects the Host From Systemic Viral Infection Through the Bile Acid-TGR5-NF-κB Axis

The microbiota-associated environmental factors that influence host susceptibility and disease outcome to systemic viral infection that could lead to high fatality remain largely unknown. By using severe fever with thrombocytopenia syndrome virus (SFTSV), infection with which can cause severe systemic inflammatory response syndrome, we identified that a metabolite, harmaline, from the commensal bacterium Akkermansia muciniphila protects germ-free or oral antibiotic-treated mice from SFTSV infection by suppressing NF-κBmediated systemic inflammation. Instead of modulating virus-induced inflammatory responses directly, harmaline upregulated the conjugated primary bile acids glycochenodeoxycholic acid (GCDCA) and taurochenodeoxycholic acid (TCDCA) to induce TGR5-dependent anti-inflammatory responses by specifically enhancing the expression of bile acid-CoA:amino acid N-acyltransferase (BAAT) in hepatic cells. Thus, we demonstrated that the specific metabolite harmaline secreted by the intestinal bacterium A. muciniphila possesses a probiotic effect that mitigates SFTSV infection through the bile acid-TGR5-NF-κB signaling axis.