Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria.
Hepatol Commun. 2023 May 15;7(6). doi: 10.1097/HC9.0000000000000151. eCollection 2023 Jun 1.
Biliary atresia (BA) causes neonatal cholestasis and rapidly progresses into cirrhosis if left untreated. Kasai portoenterostomy may delay cirrhosis. BA remains among the most common indications for liver transplantation (LT) during childhood. Liver function and gut microbiome are interconnected. Disturbed liver function and enterohepatic signaling influence microbial diversity. We, herein, investigate the impact of LT and reestablishment of bile flow on gut microbiome-bile acid homeostasis in children with BA before (pre, n = 10), 3 months (post3m, n = 12), 12 months (post12m, n = 9), and more than 24 months (post24 + m, n = 12) after LT.
We analyzed the intestinal microbiome of BA patients before and after LT by 16S-rRNA-sequencing and bioinformatics analyses, and serum primary and secondary bile acid levels.
The gut microbiome in BA patients exhibits a markedly reduced alpha diversity in pre (p = 0.015) and post3m group (p = 0.044), and approximated healthy control groups at later timepoints post12m (p = 1.0) and post24 + m (p = 0.74). Beta diversity analysis showed overall community structure similarities of pre and post3m (p = 0.675), but both differed from the post24 + m (p < 0.001). Longitudinal analysis of the composition of the gut microbiome revealed the Klebsiella genus to show increased abundance in the post24 + m group compared with an age-matched control (p = 0.029). Secondary bile acid production increased 2+ years after LT (p = 0.03). Multivariable associations of microbial communities and clinical metadata reveal several significant associations of microbial genera with tacrolimus and mycophenolate mofetil-based immunosuppressive regimens.
In children with BA, the gut microbiome shows strongly reduced diversity before and shortly after LT, and approximates healthy controls at later timepoints. Changes in diversity correlate with altered secondary bile acid synthesis at 2+ years and with the selection of different immunosuppressants.
先天性胆道闭锁（BA）导致新生儿胆汁淤积，如果不治疗，会迅速发展为肝硬化。葛西肝门空肠吻合术可能会延迟肝硬化的发生。BA 仍然是儿童时期肝移植（LT）最常见的适应证之一。肝功能和肠道微生物群是相互关联的。肝功能障碍和肠肝信号转导会影响微生物多样性。在此，我们研究了 LT 后胆汁再通对 BA 患儿的肠道微生物群-胆汁酸稳态的影响，分析了 LT 前（pre，n=10）、LT 后 3 个月（post3m，n=12）、LT 后 12 个月（post12m，n=9）和 LT 后超过 24 个月（post24+m，n=12）患儿的肠道微生物组，并通过 16S-rRNA 测序和生物信息学分析以及血清初级和次级胆汁酸水平进行分析。
我们通过 16S-rRNA 测序和生物信息学分析以及血清初级和次级胆汁酸水平分析 BA 患者 LT 前后的肠道微生物组。
BA 患者的肠道微生物组在 pre 组（p=0.015）和 post3m 组（p=0.044）中具有明显降低的 alpha 多样性，在 post12m 时接近健康对照组（p=1.0），在 post24+m 时接近健康对照组（p=0.74）。beta 多样性分析显示，pre 和 post3m 的整体群落结构相似（p=0.675），但均与 post24+m 不同（p<0.001）。肠道微生物群组成的纵向分析显示，与年龄匹配的对照组相比，post24+m 组的克雷伯氏菌属丰度增加（p=0.029）。LT 后 2 年次级胆汁酸生成增加（p=0.03）。微生物群落与临床元数据的多变量关联揭示了几个与他克莫司和吗替麦考酚酯免疫抑制方案相关的微生物属的显著关联。
在 BA 患儿中，LT 前和 LT 后不久，肠道微生物组的多样性明显降低，在后期接近健康对照组。多样性的变化与 2 年后次级胆汁酸合成的改变以及不同免疫抑制剂的选择有关。
