Gut microbiota-derived cholic acid mediates neonatal brain immaturity and white matter injury under chronic hypoxia

Chronic hypoxia, common in neonates, disrupts gut microbiota balance, which is crucial for brain development. This study utilized cyanotic congenital heart disease (CCHD) patients and a neonatal hypoxic rat model to explore the association. Both hypoxic rats and CCHD infants exhibited brain immaturity, white matter injury (WMI), brain inflammation, and motor/learning deficits. Through 16s rRNA sequencing and metabolomic analysis, a reduction in B. thetaiotaomicron and P. distasonis was identified, leading to cholic acid accumulation. This accumulation triggered M1 microglial activation and inflammation-induced WMI. Administration of these bacteria rescued cholic acid-induced WMI in hypoxic rats. These findings suggest that gut microbiota-derived cholic acid mediates neonatal WMI and brain inflammation, contributing to brain immaturity under chronic hypoxia. Therapeutic targeting of these bacteria provides a non-invasive intervention for chronic hypoxia patients. [Display omitted] •Neonatal brain immaturity and WMI were seen in CCHD patients and chronic hypoxic rats•B. theta and P. dis were reduced under chronic hypoxia•Microbiota-derived cholic acid led to brain immaturity, WMI, and inflammation•Administration of B. theta and P. dis rescued WMI and inflammation in chronic hypoxia Microbiome; Molecular biology; Neuroscience; Physiology