严重高胆红素血症新生儿肠道菌群构成情况及对胆红素脑损伤的影响

Composition of gut microbiome in neonates with severe hyperbilirubinemia and its effect on bilirubin brain injury

目的探讨严重高胆红素血症（血清总胆红素水平〉342 μmol/L）新生儿肠道菌群的构成情况及其与胆红素脑损伤之间的关系。方法采取前瞻性研究，选择2016年9月至2017年3月广州医科大学附属广州市妇女儿童医疗中心入院时血清总胆红素值〉342 μmol/L的新生儿54例作为研究对象，采用16S rDNA序列分析技术检测所有研究对象入院时肠道菌群构成，根据头颅磁共振成像（MRI）、脑干听觉诱发电位（BAEP）及临床表现，将研究对象分为脑损伤组（26例）和无脑损伤组（28例），比较2组新生儿肠道菌群构成的差异，同时比较2组血清和脑脊液中未结合胆红素水平。结果脑损伤组血清未结合胆红素水平为（463.51±110.62） μmol/L，无脑损伤组血清未结合胆红素水平为（364.18±63.13） μmol/L，2组血清未结合胆红素水平比较差异有统计学意义（t＝4.090，P＝0.000 1）。脑损伤组脑脊液未结合胆红素水平为（9.53±2.68） μmol/L，无脑损伤组脑脊液未结合胆红素水平为（6.94±2.31） μmol/L，2组脑脊液未结合胆红素比较差异有统计学意义（t＝3.812，P＝0.000 3）。2组新生儿脑脊液中未结合胆红素水平与血清中未结合胆红素水平无相关性（r＝0.137、0.081，均P〉0.05）。脑损伤组肠道菌群在属水平上丰度低于无脑损伤组，其中以Fusobacterium、Catabacter、Succinivibrio、Clostridium、Bacteroides这5类菌属差异有统计学意义（均P〈0.05）。结论胆红素脑损伤的发生与血清胆红素水平相关，但可能更直接取决于新生儿脑脊液中胆红素的水平。胆红素脑损伤新生儿肠道菌群多样性明显低于无脑损伤新生儿。高胆红素血症新生儿脑脊液胆红素水平的高低可能与肠道菌群构成不同引起的胆红素血脑脊液屏障通透性差异有关。

ObjectiveTo study the composition of gut microbiome in neonates with severe bilirubinemia （serum total bilirubin〉 342 μmol/L）, and to explore the relationship between gut microbiome and bilirubin brain injury.MethodsA prospective study was conducted.The neonates with serum total bilirubin〉 342 μmol/L from September 2016 to March 2017 in Guangzhou Women and Children′s Medical Center, Guangzhou Medical University, were enrolled in the study and 16S rDNA sequence analysis technology was used to detect the composition of gut microbiome in all subjects.According to the results of brain magnetic resonance imaging（MRI）, brain stem auditory evoked potential（BAEP） and clinical manifestations, the subjects were divided into the brain injury group （26 cases） and no brain injury group （28 cases）. The differences of the composition of gut microbiome between the 2 groups were compared, and the levels of unconjugated bilirubin in serum and cerebrospinal fluid were also compared.ResultsThe level of unconjugated bilirubin in serum of the brain injury group was （463.51±110.62） μmol/L, but in no brain injury group was （364.18±63.13） μmol/L, and there was significant difference between the 2 groups（t=4.090, P=0.000 1）. The level of unconjugated bilirubin in the cerebrospinal fluid of the brain injury group was （9.53±2.68） μmol/L, but in no brain injury group was （6.94±2.31） μmol/L, and there was significant difference between the 2 groups （t=3.812, P=0.000 3）. There was no correlation between the level of unconjugated bilirubin in the cerebrospinal fluid and serum between the 2 groups（r=0.137, 0.081, all P〉0.05）. The abundance of gut microbiome in the brain injury group was lower than that in no brain injury group in genus level, among which Fusobacterium, Catabacter, Succinivibrio, Clostridium and Bacteroides were significantly different （all P〈0.05）.ConclusionsThe occurrence of bilirubin brain injury depends on the level of unconjugated bilirubin in serum cerebrospinal fluid, but it may be more directly dependent on the level of bilirubin in the cerebrospinal fluid.The diversity of gut microbiome in neonates with bilirubin brain injury was significantly lower than that in no brain injury group.The level of unconjugated bilirubin in cerebrospinal fluid may be related to the different blood-brain barrier permeability caused by different composition of gut microbiome.