Research Group for Genomic Epidemiology, Technical University of Denmark, Kongens Lyngby, Denmark.
Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
Microbiome. 2019 Sep 13;7(1):131. doi: 10.1186/s40168-019-0745-z.
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.
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.
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.
越来越多的证据表明微生物组在健康和疾病中的重要性以及宿主与微生物之间不可分割的依存关系。宿主与微生物的相互作用在接受异基因造血干细胞移植（HSCT）的患者中非常重要，即患者免疫系统的细胞成分被外来供体替代。HSCT 被用作许多非恶性和恶性血液疾病的治愈性免疫疗法，包括急性淋巴细胞白血病等癌症。该过程可能伴有严重的副作用，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 的儿童的免疫标志物、免疫重建和肠道微生物组成进行了纵向分析，以了解与临床结果的关系。这种分析可以揭示生物标志物，例如在 HSCT 之前的时间点，可以在未来用于预测哪些患者存在与副作用和临床结果相关的高风险，并相应地指导治疗策略。
在两项多变量分析（稀疏偏最小二乘回归和典型对应分析）中，我们确定了三个一致的聚类：（1）移植前患者中抗菌肽人β防御素 2（hBD2）浓度高，乳杆菌科丰度高，随后发生中度或重度 aGvHD，死亡率高。（2）必需厌氧菌（如 Ruminococcaceae）丰度高的患者 NK 和 B 细胞快速重建，无或轻度 aGvHD，死亡率低。（3）兼性厌氧菌（如肠杆菌科）丰度高的患者炎症水平高，C 反应蛋白水平高。此外，我们观察到抗生素治疗会影响细菌群落状态。
我们确定了特定微生物类群、宿主免疫标志物、免疫细胞重建与 HSCT 相关的临床结果之间的多变量关联。我们的发现鼓励进一步研究建立 HSCT 患者肠道微生物组和相关免疫标志物（如 hBD2）的纵向监测。微生物组分析可能被证明是一种有用的预后工具，可以帮助识别免疫重建不良和不良结局（如 aGvHD 和死亡）风险较高的患者，为指导精准医学提供可操作的信息。
