Aging-associated dysbiosis increases susceptibility to enteric viral infection in Drosophila

Age is associated with increased susceptibility to enteric infections, but the molecular mechanisms are unclear. We find that aged Drosophila are more susceptible to enteric viral infections and that this increase in susceptibility is due to the aged microbiota, since depletion of the microbiota or reconstitution with a young microbiome suppressed infection. Metagenomic analysis of the aged microbiome revealed dysbiosis with an increased abundance in reactive oxygen species (ROS) producing pathways. This aged microbiota drives intestinal ROS production and we could restore immune function in old flies by reducing ROS genetically or pharmacologically. Moreover, we found that reconstitution of old flies with a cocktail of commensals, including L. fructivorans and heat-killed A. pomorum, could fully restore immunity. Altogether, these findings provide a mechanistic link between age-dependent dysbiosis and antiviral immunity and show that we can restore innate protection in aged animals, suggesting that this is a treatable and reversible state.