Early signature of aGvHD development in the gut microbiota composition of pediatric patients given allogeneic hematopoietic cell transplantation for hematological disorders. aGVHD in Italian Children

A correlation between acute Graft-versus-Host Disease (aGvHD) and gut microbiota (GM) composition has been hypothesized, but experimental observations are still few and involve only small cohorts of patients, particularly in children. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset. In the present work, thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and >30 days following HSCT. Changes in the GM phylogentetic structure were reconstructed by the16S rRNA gene sequencing.Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content, (iii) increase in Fusobacterium relative abundance. At time of engraftment, the GM resulted deeply affected in all patients, but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30. We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing to HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation.

急性移植物抗宿主病（acute Graft-versus-Host Disease, aGvHD）与肠道菌群（gut microbiota, GM）组成之间的相关性已被学界提出相关假说，但相关实验观测数据仍较为稀缺，且仅纳入小样本患者队列，针对儿童群体的研究尤为不足。当前，粪便菌群移植已作为治疗类固醇难治性aGvHD的开创性治疗手段得以应用，在此背景下，亟需扩大针对造血干细胞移植（hematopoietic stem cell transplantation, HSCT）患者肠道菌群动态变化的现有观察性研究规模。
本研究旨在探索36例儿童HSCT受者的肠道菌群变化轨迹及其与aGvHD发病的关联。本研究共纳入来自4家移植中心的36例接受HSCT的儿科患者，研究人员在三个时间点采集受试者粪便样本：HSCT术前、造血植活时，以及HSCT术后超过30天时。通过16S核糖体RNA基因测序技术，本研究重构了肠道菌群的系统发育结构变化。
研究发现，出现肠道aGvHD的患儿在HSCT术前即存在肠道菌群失调的结构特征。这种疑似可增加aGvHD发病风险的易感菌群生态状态，具有以下特征：（i）菌群多样性降低；（ii）布劳特氏菌属（Blautia）丰度下降；（iii）梭杆菌属（Fusobacterium）相对丰度升高。造血植活阶段，所有受试者的肠道菌群均受到显著扰动；但无论是否发生aGvHD、是否接受对应治疗，术后30天起肠道菌群均恢复至稳态构型。本研究明确了HSCT术前可预测后续肠道aGvHD发生的特异性肠道菌群特征谱。
本研究结果可为接受HSCT的儿童群体构建基于肠道菌群的aGvHD发病风险分层体系提供研究思路，同时或可用于筛选可从预防性粪便菌群移植中获益的患儿。