Divisions of Gastroenterology, Hepatology and Nutrition and The Liver Care Center at Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
Nat Commun. 2022 Jan 10;13(1):18. doi: 10.1038/s41467-021-27689-4.
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.
母体微生物组在新生儿中的定植促进了持久的生物学印记，但它如何影响生命早期的疾病易感性尚不清楚。我们假设给怀孕的老鼠喂食丁酸盐会影响新生儿对先天性胆道闭锁（一种严重的新生儿胆管病）的易感性。在这里，我们表明，给母亲喂食丁酸盐可使新生小鼠对胆管炎症和损伤具有抗性，并提高其存活率。肝免疫细胞激活和存活特征的预防与拟杆菌门和梭菌门的粪便特征有关，并增加了新生小鼠粪便代谢物中的谷氨酸/谷氨酰胺和次黄嘌呤。在患有先天性胆道闭锁的人类新生儿中，这些细菌的粪便微生物组特征不足，谷氨酸/谷氨酰胺受到抑制，次黄嘌呤途径增加。丁酸盐或谷氨酰胺的直接给予可减轻疾病表型，但只有谷氨酰胺可使胆管上皮细胞对自然杀伤细胞的细胞毒性具有抗性。因此，母体丁酸盐的摄入会影响新生小鼠的粪便微生物群和代谢物，以及实验性先天性胆道闭锁的表型表达，而谷氨酰胺可促进胆管上皮细胞的存活。
