Maternal regulation of biliary disease in neonates via gut microbial metabolites

Jai Junbae Jee, Li Yang, Pranavkumar Shivakumar, Pei-pei Xu, Reena Mourya, Unmesha Thanekar, Pu Yu, Yu Zhu, Yongkang Pan, Haibin Wang, Xufei Duan, Yongqin Ye, Bin Wang, Zhu Jin, Yuanmei Liu, Zhiqing Cao, Miki Watanabe-Chailland, Lindsey E. Romick-Rosendale, Michael Wagner, Lin Fei, Zhenhua Luo, Nicholas J. Ollberding, Shao-tao Tang () and Jorge A. Bezerra ()
Additional contact information
Jai Junbae Jee: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center
Li Yang: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center
Pranavkumar Shivakumar: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center
Pei-pei Xu: Huazhong University of Science and Technology
Reena Mourya: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center
Unmesha Thanekar: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center
Pu Yu: Xi’an Children’s Hospital
Yu Zhu: Sichuan University
Yongkang Pan: Xi’an Children’s Hospital
Haibin Wang: Huazhong University of Science and Technology
Xufei Duan: Huazhong University of Science and Technology
Yongqin Ye: Shenzhen Children’s Hospital
Bin Wang: Shenzhen Children’s Hospital
Zhu Jin: The Affiliated Hospital of Zunyi Medical University
Yuanmei Liu: The Affiliated Hospital of Zunyi Medical University
Zhiqing Cao: Jiangmen Maternity and Child Health Care Hospital
Miki Watanabe-Chailland: Cincinnati Children’s Hospital Medical Center
Lindsey E. Romick-Rosendale: Cincinnati Children’s Hospital Medical Center
Michael Wagner: Huazhong University of Science and Technology
Lin Fei: Huazhong University of Science and Technology
Zhenhua Luo: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center
Nicholas J. Ollberding: Cincinnati Children’s Hospital Medical Center
Shao-tao Tang: University of Cincinnati, College of Medicine
Jorge A. Bezerra: Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children’s Hospital Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.

Date: 2022
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DOI: 10.1038/s41467-021-27689-4

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