Evaluating Effects of Age-related Microbiota Modulations in Hematopoietic Stem Cell Transplant Patients

异基因造血干细胞移植（HCT）有可能治愈血液病患者， 恶性肿瘤。然而，HCT与显著的治疗相关死亡率（TRM）相关，范围为20- 30%。 百分之三十（一）. TRM在高龄患者中尤其高（风险比1.84，年龄>60岁vs.<20岁）， 身体功能下降（风险比2.94，下四分位数与上四分位数）。TRM的一个主要原因是移植- 抗宿主病（GVHD），影响40-60%的患者。我们假设与年龄相关的微生物组 变化将影响HCT临床结局，除年龄外，其他因素如饮食、体力活动 护理环境也会影响微生物组的分布。 GVHD和肠道微生物群破坏之间的相关性已经在几项研究中报道， 尽管目前还不清楚微生物群是如何引起或预防GVHD的。虽然长期住院治疗是 对于HCT患者的标准，在更正常的护理环境中护理患者可能会保留自然 微生物群我们假设将护理环境从医院转移到一个更正常的环境 像家里一样，可以保护肠道微生物群，从而减少肠道炎症和GVHD。我们有 在1期试验中成功地试点了家庭HCT（co-PI Chao，Sung，clinicaltrials.gov NCT 01725022），并且已经 将我们的试验扩展到家庭与标准护理的随机2期研究（clinicaltrials.govNCT02218151， co-PI Chao，Sung），由NCI 1 R 01 CA 203950（PI Chao，co-I Sung）资助。 虽然年龄不能改变，但克服与年龄有关的负面影响的其他策略 微生物组的变化可以通过饮食和身体活动干预来实现。我们已经开始了第一/第二阶段， 前和围HCT优化程序（PPOP）。PPOP有两部分：临床部分（C-PPOP）， 为所有杜克HCT患者的HCT前评估建立了新的护理标准， 组成部分（R-PPOP），其中包括额外的评估和干预措施，以优化健康和功能 包括饮食和身体活动。在这个项目中，我们的目标是：1）评估与年龄相关的微生物组 变化及其对HCT结局的影响，包括TRM（主要终点）、感染、GVHD和 免疫功能; 2）评估饮食和身体活动干预对老年人微生物组的影响 以及对HCT结果的影响。 对于本研究，将能够使用来自杜克血液肿瘤的现有样本 生物储藏库。本研究为白血病GVHD的发生机制提供了新的认识， 其他恶性疾病。如果成功，这项研究将确定年龄相关的微生物组变化对 HCT结果和免疫系统，以及针对老年微生物组的策略，以更好地促进 HCT患者的结局。

Allogeneic hematopoietic stem cell transplant (HCT) has the potential to cure patients with hematologic malignancies. However, HCT is associated with significant treatment related mortality (TRM) ranging from 20- 30%. (1). TRM is particularly high in patients with advanced age (hazard ratio 1.84, age >60 years vs. <20) and decreased physical function (hazard ratio 2.94, bottom quartile vs. top quartile). A major cause of TRM is graft- versus-host disease (GVHD), which affects 40-60% of patients. We hypothesis that age related microbiome changes will affect the HCT clinical outcomes, and in addition to age other factors such as diet, physical activity and the care environment can influence the microbiome profiles as well. Correlations between GVHD and disruptions in the gut microbiota have been reported in several studies, though it remains unclear how the microbiota causes or prevents GVHD. While lengthy hospitalizations are standard for HCT patients, caring for patients in a more normal care environment may preserve the natural microbiota. We hypothesized that shifting the care environment from the hospital to a more normal environment like the home can preserve the gut microbiota, thereby decreasing intestinal inflammation and GVHD. We have successfully piloted home HCT in a phase 1 trial (co-PIs Chao, Sung, clinicaltrials.gov NCT01725022) and have expanded our pilot into a randomized phase 2 study of home vs. standard care (clinicaltrials.gov NCT02218151, co-PIs Chao, Sung) funded by NCI 1R01CA203950 (PI Chao, co-I Sung). While age cannot be changed, other strategies to overcome the negative effects of aging-related microbiome changes can be the use of dietary and physical activity interventions. We have started a Phase I/II, pre- and peri-HCT optimization program (PPOP). PPOP has two pieces: a clinical component (C-PPOP), which establishes a new standard of care for the pre-HCT evaluation of all Duke HCT patients, and a research component (R-PPOP), which includes additional assessments and interventions to optimize health and function including diet and physical activity. In this proposed project we aim to: 1) evaluate the age related microbiome changes and their implications on HCT outcomes including TRM (primary endpoint), infections, GVHD, and immune function; 2) evaluate the effects of a dietary and physical activity intervention on the aged microbiome and implications on HCT outcomes. For this study will be able to utilize existing samples from the Duke Hematologic Malignancies Biorepository. This study can provide new insights into the underlying mechanisms of GVHD in Leukemia and other malignant diseases. If successful, this study will identify the impact of age related microbiome changes on HCT outcomes and the immune system, as well as strategies to target the aged microbiome to promote better outcomes for HCT patients.