Butyrate supplementation rescues sex-specific deficits in respiratory plasticity and mean arterial pressure in adult offspring exposed to gestational intermittent hypoxia.

Sleep disordered breathing (SDB) in pregnancy is increasing in parallel with the obesity epidemic, and is linked to adverse perinatal outcomes in the offspring. Consequences of maternal SDB during pregnancy on the adult offspring are not well-understood. Preliminary data indicate that adult male, but not female, offspring of dams exposed to intermittent hypoxia during gestation (GIH - gestational intermittent hypoxia), a rat model of SDB during pregnancy, have elevated mean arterial pressure (MAP), increased neuroinflammation, inflammation-induced impairment of homeostatic plasticity in the respiratory control system, and gut dysbiosis. Specifically, adult male GIH offspring have decreased relative abundance of gut bacteria that produce butyrate, a short-chain fatty acid that has potent anti-inflammatory properties and regulates immune function in the central nervous system. Since literature suggests that gut dysbiosis, neuroinflammation, and hypertension exist in a complicated vicious cycle, we treated male GIH offspring with tributyrin, a butyrate prodrug. Prior to tributyrin treatment, MAP in male GIH offspring was 96±3 mmHg, versus 76±1 mmHg in control rats receiving gestational intermittent normoxia (GNX). Similarly, male GIH offspring exhibited deficits in respiratory plasticity in response to recurrent central apneas (3.6±6.8% plasticity), when compared to GNX offspring (59.3±4.8% plasticity). GIH offspring exhibited evidence of elevated neuroinflammation in brain regions underlying cardiorespiratory control (e.g., IL-1β expression 1.6±0.2-fold higher than GNX controls (1.0±0.2)). Following three weeks of tributyrin treatment, MAP had normalized (80±2 mmHg), neuroinflammation was reduced to control levels, and the ability to express respiratory neuroplasticity was rescued (78±30%). These data indicate that gut dysbiosis may contribute to sex-specific impairments induced by maternal exposure to intermittent hypoxia during gestation that can be rescued in adulthood by supplementing with butyrate.