β3-Adrenergic Signaling Preserves Postnatal Maturation of the Enteric Nervous System and Gut Microbiome During Neonatal Hyperoxia

Oxygen availability is a key regulator of organ maturation during the perinatal period. Disruption of physiological oxygen homeostasis contributes to prematurity-associated disorders, yet its effects on the coordinated maturation of the enteric nervous system (ENS) and gut microbiome remain poorly understood. Because β3-adrenergic receptor (β3-AR) signaling has emerged as a mediator of tissue adaptation to oxygen, we investigated whether activation of this pathway modulates hyperoxia-induced alterations in the developing colon. Newborn rats were exposed to normoxia or hyperoxia (85% O2) from birth to postnatal day 14 and treated with the β3-AR agonist BRL37344 (1 or 3 mg/kg). Enteric neuronal and glial populations were evaluated by quantitative immunofluorescence, whereas the colonic microbiome (CM) was characterized by 16S rRNA gene sequencing. Hyperoxia reduced neuronal density and altered neurochemical coding within the submucosal plexus, disrupted enteric glial organization in both the colonic submucosal plexus and mucosa, and remodeled the intestinal microbiome without affecting overall community diversity. BRL37344 treatment partially preserved submucosal neurochemical coding, modulated neuron–glia organization within the submucosal plexus, prevented the loss of mucosal enteric glial cells, and reshaped microbial composition. Collectively, these findings demonstrate that neonatal hyperoxia disrupts coordinated postnatal maturation of the ENS and CM and indicate that β3-AR signaling may contribute to postnatal intestinal adaptation to neonatal oxygen imbalance.