Homeostasis between gut-associated microorganisms and the immune system in Drosophila

• Uracil is a metabolic signature of noncommensal bacteria in Drosophila gut epithelia.
• The Drosophila gut mounts innate immune response by sensing bacterial uracil.
• Uracil release is absent or reduced in major commensal bacteria.
• Bacterial-derived uracil acts as a pro-oxidant in gut epithelia.

The metabolic activities of a given gut bacterium or gut commensal community fluctuate in a manner largely depending on the physicochemical parameters within the gut niche. Recognition of the bacterial metabolic status in situ, by a sensing of the gut metabolites as a signature of a specific bacterial metabolic activity, has been suggested to be a highly beneficial means for the host to maintain gut–microbe homeostasis. Recently, analysis of Drosophila gut immunity revealed that bacterial-derived uracil and uracil-modulated intestinal reactive oxygen species (ROS) generation play a pivotal role in diverse aspects of host–microbe interactions, such as pathogen clearance, commensal protection, intestinal cell regeneration, colitogenesis, and possibly also interorgan immunological communication. A deeper understanding of the role of uracil in Drosophila immunity will provide additional insight into the molecular mechanisms underlying host–microbe symbiosis and dysbiosis.