Gut Microbiota-bile acid-progesterone Axis Mediates White Matter Injury in Infant Chronic Hypoxia

Adverse child development has been implicated to the systemic chronic hypoxia since infant stage. Lately research suggested chronic hypoxia could disturb gut microbial balance which is essential to the brain development. However, mechanisms underlying such association remain largely unknown. Here, we found a strong correlation between severe brain immature and white matter injury (WMI) in infants underwent chronic hypoxia. Mechanistically, in a neonatal rat model of chronic hypoxia, we characterized severe brain immature and WMI with the deficits of motor coordination and learning. By combining 16S rRNA gene sequencing with untargeted metabolic profiling, we identified a reduction of intestinal Bacteroides and Parabacteroides under chronic hypoxia which causes the low production of progesterone, which is mainly due to the impair of the synthesis of progesterone by the accumulation of cholic acid. Administration of either Bacteroides, Parabacteroides or progesterone rescues the brain immature and WMI in the chronic hypoxia neonatal rats. Notably, the decreased levels of Bacteroides, Parabacteroides and progesterone were also discovered in infant patients with chronic hypoxia, implicating a universal crosstalk between the gut and brain across human and rat species under chronic hypoxia and shedding lights on the clinical therapeutics targeting the Bacteroides, Parabacteroides and their microbial metabolic product of progesterone for patients with systemic chronic hypoxia. In this dataset, you could find all my original data of all figures. It is named by the number of the figure order.