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Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation.
Microbiome ( IF 15.5 ) Pub Date : 2019-09-13 , DOI: 10.1186/s40168-019-0745-z
Anna Cäcilia Ingham 1, 2 , Katrine Kielsen 3, 4 , Malene Skovsted Cilieborg 5 , Ole Lund 6 , Susan Holmes 7 , Frank M Aarestrup 1 , Klaus Gottlob Müller 3, 4 , Sünje Johanna Pamp 1
Affiliation  

BACKGROUND Increasing evidence reveals the importance of the microbiome in health and disease and inseparable host-microbial dependencies. Host-microbe interactions are highly relevant in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), i.e., a replacement of the cellular components of the patients' immune system with that of a foreign donor. HSCT is employed as curative immunotherapy for a number of non-malignant and malignant hematologic conditions, including cancers such as acute lymphoblastic leukemia. The procedure can be accompanied by severe side effects such as infections, acute graft-versus-host disease (aGvHD), and death. Here, we performed a longitudinal analysis of immunological markers, immune reconstitution and gut microbiota composition in relation to clinical outcomes in children undergoing HSCT. Such an analysis could reveal biomarkers, e.g., at the time point prior to HSCT, that in the future could be used to predict which patients are of high risk in relation to side effects and clinical outcomes and guide treatment strategies accordingly. RESULTS In two multivariate analyses (sparse partial least squares regression and canonical correspondence analysis), we identified three consistent clusters: (1) high concentrations of the antimicrobial peptide human beta-defensin 2 (hBD2) prior to the transplantation in patients with high abundances of Lactobacillaceae, who later developed moderate or severe aGvHD and exhibited high mortality. (2) Rapid reconstitution of NK and B cells in patients with high abundances of obligate anaerobes such as Ruminococcaceae, who developed no or mild aGvHD and exhibited low mortality. (3) High inflammation, indicated by high levels of C-reactive protein, in patients with high abundances of facultative anaerobic bacteria such as Enterobacteriaceae. Furthermore, we observed that antibiotic treatment influenced the bacterial community state. CONCLUSIONS We identify multivariate associations between specific microbial taxa, host immune markers, immune cell reconstitution, and clinical outcomes in relation to HSCT. Our findings encourage further investigations into establishing longitudinal surveillance of the intestinal microbiome and relevant immune markers, such as hBD2, in HSCT patients. Profiling of the microbiome may prove useful as a prognostic tool that could help identify patients at risk of poor immune reconstitution and adverse outcomes, such as aGvHD and death, upon HSCT, providing actionable information in guiding precision medicine.

中文翻译:

在小儿同种异体造血干细胞移植中,特定的肠道微生物组成员与独特的免疫标记有关。

背景技术越来越多的证据揭示了微生物组在健康和疾病以及不可分离的宿主-微生物依赖性中的重要性。在接受同种异体造血干细胞移植(HSCT)的患者中,宿主与微生物的相互作用高度相关,即用外源供体替代患者免疫系统的细胞成分。HSCT被用作许多非恶性和恶性血液病的治愈性免疫疗法,包括癌症,例如急性淋巴细胞白血病。该过程可能伴有严重的副作用,例如感染,急性移植物抗宿主病(aGvHD)和死亡。在这里,我们对接受HSCT的儿童的临床结局进行了免疫学标记,免疫重建和肠道菌群组成的纵向分析。这样的分析可以揭示生物标志物,例如在HSCT之前的时间点,将来可以用来预测哪些患者的副作用和临床结局具有高风险并相应地指导治疗策略。结果在两个多变量分析(稀疏偏最小二乘回归和典范对应分析)中,我们确定了三个一致的簇:(1)高丰度患者的移植前高浓度的抗菌肽人β-防御素2(hBD2)。乳杆菌科,后来发展为中度或重度aGvHD,并表现出高死亡率。(2)大量的专性厌氧菌,如Ruminococcaceae,未发育或出现轻度的aGvHD,并且死亡率低,可快速重建NK和B细胞。(3)高发炎,高水平的兼性厌氧细菌(如肠杆菌科)患者中C反应蛋白水平高表明。此外,我们观察到抗生素治疗会影响细菌群落状态。结论我们确定了特定的微生物分类群,宿主免疫标记,免疫细胞重构以及与HSCT相关的临床结局之间的多变量关联。我们的发现鼓励对在HSCT患者中建立肠道微生物组和相关免疫标记(例如hBD2)的纵向监测进行进一步的研究。进行微生物组分析可能是一种有用的预后工具,可帮助鉴定HSCT时存在免疫重建不良和aGvHD和死亡等不良后果的风险的患者,为指导精确医学提供可行的信息。
更新日期:2019-09-13
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