Fig. 8: Model for the olfactory neuron-independent sensing of the microbiome-emitted (2R,3 R)-2,3-butanediol for the activation of somatotrophic airway-gut-brain axis.

Traditional mechanism (i.e., olfactory neuron-dependent) of OR42b-mediated scent sensing (shown in the left panel) is based on the previous studies^{18,31,32,33,34}. In this case, OR42b (shown in blue) expressed in olfactory neurons may form a heterotetramer (possibly two OR42b and two ORCO molecules) with co-receptor ORCO (shown in yellow). An olfactory neuron-independent mechanism of OR42b-mediated scent sensing discovered in the present study is shown in the right panel. In this case, OR42b (non-neuronally expressed in subsets of tracheal airway cells, EECs, and enterocytes) likely forms a homotetramer without the assistance of ORCO. In the absence of microbiome-emitted (2R,3R)-2,3-butanediol, Merlin (Mer) complex composed of Mer-kibra-Expanded (Ex) is tethered to the membrane-localized OR42b to sequentially activate Hippo (Hpo) kinase and Warts (Wts) kinase. Activated-Wts kinase phosphorylates Yorkie (Yki) for its cytoplasmic retention. Binding of (2R,3R)−2,3-butanediol to the OR42b initiates the dispersal of membrane-localized OR42b and Mer complex. Dispersed Mer complex inactivates Hpo-Wts kinases, resulting in Yki dephosphorylation for nuclear localization and target gene activation; Branchless (Bnl, a homolog of mammalian FGF) in the enterocytes, Breathless (Btl, a homolog of the mammalian FGF receptor) in the tracheal airway cells, and Allatostatin A (AstA) in the EECs. Bnl in enterocytes guides the migration of Btl⁺ tracheal airway cells during tracheal branching formation to deliver oxygen to the target organs for organ growth. Yki-dependent AstA expression in EECs induces CCHA2 peptide expression in AstA receptor-2 (AstAR2)-expressing EECs. CCHA2 peptide hormones in turn act on their receptors for DILP2 secretion from brain insulin-producing cells, thereby forming the somatotrophic gut-brain axis for systemic growth. CCHA2 peptide hormones in turn act on their receptors for DILP2 secretion from brain IPCs, thereby forming the somatotrophic gut-brain axis for systemic growth. Although the CCHA2 receptor (CCHA2R) has been shown to be expressed in larval IPCs⁵¹, it remains to be elucidated whether gut-derived CCHA2 directly activates CCHA2R-expressing IPCs or indirectly activates IPCs (e.g., via CCHA2R-expressing enteric neurons).