Microbiome-emitted scents activate olfactory neuron-independent airway-gut-brain axis to promote host growth in Drosophila.

While it is now accepted that the microbiome has strong impacts on animal growth promotion, the exact mechanism has remained elusive. Here we show that microbiome-emitted scents contain volatile somatotrophic factors (VSFs), which promote host growth in an olfaction-independent manner in Drosophila. We found that inhaled VSFs are readily sensed by olfactory receptor 42b non-neuronally expressed in subsets of tracheal airway cells, enteroendocrine cells, and enterocytes. Olfaction-independent sensing of VSFs activates the airway-gut-brain axis by regulating Hippo, FGF and insulin-like growth factor signaling pathways, which are required for airway branching, organ oxygenation and body growth. We found that a mutant microbiome that did not produce (2R,3R)-2,3-butanediol failed to activate the airway-gut-brain axis for host growth. Importantly, forced inhalation of (2R,3R)-2,3-butanediol completely reversed these defects. Our discovery of contact-independent and olfaction-independent airborne interactions between host and microbiome provides a novel perspective on the role of the airway-gut-brain axis in microbiome-controlled host development.