儿童克罗恩病粪便微生物群特征及其在英夫利昔单抗治疗中的动态变化

Characteristics of Faecal Microbiota in Paediatric Crohn’s Disease and Their Dynamic Changes During Infliximab Therapy

Wang et al. Journal of Crohn's and Colitis (2017)

DOI 10.1093/ecco-jcc/jjx153

Journal of Crohn's and Colitis

Abstract

BACKGROUND: Crohn’s disease [CD] is known to be associated with gut microbial dysbiosis.

Infliximab [IFX] is increasingly used to treat paediatric CD; however, it is not clear how the gut microbiota is modified during IFX treatment. The aim of this study was to characterise the faecal microbiota community composition in paediatric CD patients and to assess its dynamic changes during IFX therapy.

Methods: A 16S rRNA sequencing approach was applied to determine the compositions of microbial communities in faecal samples. The composition and function of the faecal microbiota were compared between CD patients and healthy controls.

Results: Characteristics of faecal microbiome composition in paediatric CD patients before IFX treatment were represented by a lower biodiversity, a gain in Enterococcus, and a significant loss in multiple short-chain fatty acid [SCFA]-producing bacteria, including Anaerostipes, Blautia, Coprococcus, Faecalibacterium, Lachnospira, Odoribacter, Roseburia, Ruminococcus,and Sutterella. Additionally, alterations were observed in metabolic functions of the gut microbial community in CD. IFX treatment increased the biodiversity of gut microbiota and shifted its composition as well as its functional capabilities in the paediatric CD patients toward a healthy status. However, multiple SCFA-producing taxa were not significantly expanded. The sustained response of paediatric CD patients to IFX was associated with abundance of SCFA-producing bacteria.

Conclusions: A lower biodiversity with alterations in the composition and function of faecal microbial community, characterising gut microbial dysbiosis, was observed in Chinese paediatric CD patients. IFX diminished the CD-associated gut microbial dysbiosis but was deficient in increasing certain SCFA-producing taxa.

关键词：克罗恩病；肠道微生物群；英夫利昔单抗

炎症性肠病（IBD）是指一组慢性、复发性胃肠道炎症性疾病，主要包括克罗恩病（CD）和溃疡性结肠炎（UC）。IBD发生在成人和儿童中，但较多发于儿童。北美、北欧/西欧和澳大利亚的IBD发病率和流行率较高；但是，新的流行病学数据显示东欧和亚洲地区的发病率呈上升趋势。

炎症性肠病（IBD）患者中微生物组成发生改变，发生菌群失调。与健康对照组相比，IBD患者特别是CD患者的微生物多样性降低，肠道微生物群组成失衡。IBD与多种放线菌（Actinobacteria）和变形杆菌（Proteobacteria）丰度增加有关，与厚壁菌和类杆菌丰度减少有关。儿科IBD患者中的Coriobacteria科和毛螺菌科（Lachnospirace）细菌数量减少，瘤胃球菌科（Ruminococcaceae）和双歧杆菌种群（Bifidobacterial populations）的多样性降低。研究显示，新发病的儿科CD患者中的肠杆菌科（Enterobacteriaceae）、梭杆菌科（Fusobacteriaceae）、巴氏杆菌科（Pasteurellacaea）和维氏杆菌科（Veillonellaceae）丰度增加，拟杆菌目（Bacteroidales）、梭菌目（Clostridiales）和丹毒丝菌目（Erysipelotrichales）丰度减少。

目前对IBD的治疗方式包括抗炎和免疫调节治疗，包括5-氨基水杨酸盐、皮质类固醇、硫嘌呤、甲氨蝶呤和抗肿瘤坏死因子[TNF]α等，以期达到临床缓解和粘膜愈合。本研究旨在研究CD患儿肠道菌群的组成和功能特征，并评估其在IFX治疗中的变化。

研究对象：11例CD患儿，来自于上海儿童医院。

入组标准：诊断为CD的患儿。

实验方法： 

1. 11例CD患儿作为试验组，16例正常儿童作为健康对照；

2. IFX治疗按目前临床实践进行，在治疗前和治疗期间收集粪便样本。

检测方法：16S rRNA 基因测序及功能预测

研究结果：

1. IFX治疗前CD患儿粪便菌群组成的多样性降低，肠球菌属（Enterococcus）富集，多种产生短链脂肪酸（SCFA）的菌属显著缺乏，包括厌氧棒状菌属（Anaerostipes）、劳特式菌属（Blautia）、粪球菌属（Coprococcus）、粪杆菌属（Faecalibacterium）、毛螺菌属（Lachnospira）、异味杆菌属（Odoribacter）、罗斯式菌属（Roseburia）、瘤胃球菌属（Ruminococcus）和萨特式菌属（Sutterella）；

2. IFX治疗前CD患儿肠道菌群代谢功能的发生改变；

3. IFX治疗使菌群多样性上升，使菌群组成和功能都变得更为健康，但多种SCFA产生菌未显著增多；

4. IFX的持久疗效与SCFA产生菌丰度相关。

结论：中国CD患儿的肠道菌群失衡，表现在多样性较低，以及粪便菌群的组成和功能发生了变化。IFX治疗可以缓解CD相关的肠道菌群失调，但不能是特定SCFA产生菌增加。

Figure 1. Richness and diversity in the faecal microbiota of the healthy control subjects and paediatric Crohn’s disease [CD] patients before and during infliximab [IFX] therapy. [A] Alpha diversity was calculated using observed number of operational taxonomic units [OTUs], Shannon index, Simpson index, and inverse Simpson index: *p < 0.05; **p < 0.01; ***p < 0.001. [B] Principal coordinate analysis [PCoA] profile of microbial diversity across all samples using Bray-Curtis distance, unweighted and weighted UniFrac metric. Each dot stands for one sample, and the ellipses group stands for the three different clinical groups. The clustering based on microbial distribution is significant [analysis of variance using PERMANOVA test, p-value: 0.001].

图 1. 健康受试者和英夫利昔单抗（IFX）治疗前后儿童克罗恩病（CD）患者粪便微生物群的丰富性和多样性。[A] α多样性 *p<0.05；**p<0.01；**p<0.001。[B]主坐标分析（PCOA）。每个点代表一个样本，椭圆组代表三个不同的临床组。

知几未来研究院正在搭建一个“疾病-肠道菌群”知识库。

你可以在公众号菜单栏“学术工具“版块直接查阅疾病和肠道菌群的相关信息；

也可以在公众号对话框回复疾病名称，如“IBD”或“肠易激综合征”，查看与疾病相关的菌群；

或回复菌种名称，如“双歧杆菌”或“Hp”，查看与细菌相关的疾病。

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