Commensal bacteria inhibit viral infections via a tryptophan metabolite

Clinical outcomes following viral exposures exhibit substantial interindividual variability. Although developing evidence suggests commensal bacteria modulate viral infections, the specific bacteria and mechanisms remain underexplored. Here, we define a pathway by which viral infections are inhibited by specific tryptophan-catabolizing bacteria. Using HIV as a model, we bioinformatically associated and experimentally validated several bacterial species that inhibited viral replication. This activity required the aromatic amino acid aminotransferase (ArAT) to metabolize tryptophan into 3-indolelactic acid, which agonizes the aryl hydrocarbon receptor (AhR). Given that AhR regulates multiple viral infections, we found that commensal bacteria also inhibit cytomegalovirus (CMV) in an ArAT-dependent manner. Finally, we used fecal shotgun metagenomic data to confirm that ArAT is associated with improved disease outcomes in three distinct human cohorts at-risk for HIV, CMV, or symptomatic COVID-19. Taken together, our results provide mechanistic insight into how commensal bacteria impact viral infections, thereby adding to an emerging field focused on host–commensal–virus interactions. Previous studies suggest that commensal bacteria modulate viral infections. Here, the authors use HIV as a model to show that commensal bacteria impact viral infections, pinpointing a specific tryptophan metabolite as a key player.