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

Yichen Yan; Xiaoli Zheng; Gang Liu; Guocheng Shi; Cong Li; Hongtong Chen; Xiaomin He; Kana Lin; Zhaohui Deng; Hao Zhang; Wei-Guang Li; Huiwen Chen; Xiaoping Tong; Zhongqun Zhu

doi:10.1016/j.isci.2024.109633

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

iScience. 2024 Mar 29;27(5):109633. doi: 10.1016/j.isci.2024.109633. eCollection 2024 May 17.

Authors

Yichen Yan^{1

2}, Xiaoli Zheng^{3

4}, Gang Liu^{1

5}, Guocheng Shi¹, Cong Li¹, Hongtong Chen¹, Xiaomin He¹, Kana Lin^{2

6}, Zhaohui Deng⁷, Hao Zhang¹, Wei-Guang Li², Huiwen Chen¹, Xiaoping Tong^{3

4}, Zhongqun Zhu^{1

2}

Affiliations

¹ Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Center for Brain Science, Shanghai Children's Medical Center, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁶ Department of Pharmacy, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Gastroenterology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

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.

Keywords: Microbiome; Molecular biology; Neuroscience; Physiology.