Butyrate Supplementation Restores Compensatory Plasticity Induced by Recurrent Reductions in Respiratory Neural Activity in Offspring Exposed to Gestational Intermittent Hypoxia

Abstract

Sleep disordered breathing (SDB) during pregnancy is increasing in parallel with the obesity epidemic, yet the long-term effect on the adult offspring are unknown. In our animal model of SDB during pregnancy, pregnant rats are exposed to chronic intermittent hypoxia (21/10.5% O2, 15 episodes/hr, 8 hrs/day) or intermittent normoxia from gestational days 10-21. Preliminary data show that adult male (but not female) offspring exposed to gestational intermittent hypoxia (GIH) show deficits in respiratory control that manifest as increased spontaneous central apneas during presumptive sleep and impaired compensatory responses to recurrent reductions in respiratory neural activity, a form of plasticity known as inactivity-induced inspiratory motor facilitation (iMF). Further, our data show that microglia isolated from male GIH offspring show primed inflammatory responses in respiratory control regions, and that microglial depletion or inhibition of inflammation in the region of the phrenic motor pool rescues deficits in respiratory control. Our preliminary data show that male GIH offspring suffer from gut dysbiosis. Most notably, they exhibit decreased levels of bacteria that produce butyrate, a short-chain fatty acid (SCFA) necessary for the proper development of microglia. Because butyrate supplementation reduces microglial inflammation, we tested the hypothesis that adult butyrate supplementation restores the capacity to elicit iMF in adult male GIH offspring. Vehicle or tributyrin was delivered by oral gavage in 8 doses over 22 days (2g/kg). Phrenic inspiratory output was measured in urethane-anesthetized, vagotomized, mechanically ventilated GIH offspring. As expected, recurrent neural apnea (5, ~1 min neural apnea episodes, separated by 5 minutes) elicited an increase in phrenic inspiratory output in GIH offspring treated with tributyrin compared to vehicle treated GIH offspring (78±30% and 15±2%, respectively, n = 3-4, p = 0.057), indicating that butyrate supplementation rescues the capacity to elicit iMF in GIH offspring. These data indicate that gut dysbiosis may contribute to impaired capacity for recurrent reductions in respiratory neural activity to trigger compensatory forms of neuroplasticity.