Prebiotics to Optimize the Microbiota and Improve Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

造血干细胞移植(HCT)具有治疗白血病等恶性和非恶性疾病的潜力。 恶性疾病。然而，这些过程与显著的发病率和治疗相关。 死亡率(TRM)为10%-30%。这在很大程度上是由于移植物抗宿主病(GVHD)，在这种疾病中，供者 免疫系统攻击宿主组织。移植物抗宿主病与肠道细菌的破坏有关( 微生物区系)，这又可能是由条件化疗、放射和抗生素等因素引起的 治疗。移植物抗宿主病和死亡率是由免疫系统调节的，免疫系统的活动又由肠道决定。 微生物区系。益生元是一种不可消化的纤维，可以安全地给HCT患者服用，并通过 肠道中现有的细菌对细菌群落和代谢产物(如丁酸盐)产生积极影响。 丁酸是一种短链脂肪酸，是结肠上皮细胞的重要能量来源，可以促进 调节T细胞发育，进而调节GVHD。我们的初步数据表明 将益生素半乳低聚糖(GOS)注射给接受HCT的小鼠，两者都可以增加 丁酸化和降低移植物抗宿主病。在这里，我们提出了以下目标：目标1.评估安全性、耐受性和 GOS在1期和2期随机试验中的疗效。目标1A：我们将确定最大耐受量 第1阶段剂量递增研究中的GOS剂量(MTD)(第1-2年)。我们假设GOS是可以容忍的 增加细菌多样性和丁酸水平的剂量。目标1B：我们将评估GOS对HCT的影响 2期随机安慰剂对照试验的结果。(二至五年级)。我们假设接受治疗的患者 GOS将有更好的结果，包括减少II-IV级GVHD。目标1C：我们将比较HCT前 GOS应答者的微生物群(在1期和2期试验中接受GOS并增加 细菌多样性)和无反应者(细菌多样性没有变化或减少的细菌)来确定 Hct前微生物群中可能与GOS反应相关的元素。目标2.评估影响 GOS在肠道和全身炎症生物标志物和移植物抗宿主病中的潜在作用 结果。再生的胰岛衍生蛋白3α(REG3A)尤其令人感兴趣。REG3A是一个 可能受微生物区系影响的抗菌肽，已被报道为移植物抗宿主病的生物标志物。 我们假设接受GOS治疗的患者在炎症和生物标志物方面会有积极的变化。 GVHD(增加的REG3A，主端点)。作为一个探索性目标，生物标志物将被研究 与益生菌干预相关的微生物群、细菌代谢物、免疫重建、 和HCT临床结局(GVHD、TRM、OS)。我们的长期目标是了解益生菌干预是如何 影响微生物区系和细菌代谢物，使用益生素减少炎症和改善红细胞压积 结果。我们预计，这项研究产生的数据将导致未来的临床试验，包括 多中心随机3期试验，或基于微生物区系的诊断分析，以实现个性化治疗。

Hematopoietic stem cell transplant (HCT) has the potential to cure leukemia and other malignant and non- malignant diseases. However, these processes are associated with significant morbidity, and treatment-related mortality (TRM) ranges from 10-30%. This is largely due to graft-versus-host disease (GVHD), in which the donor immune system attacks host tissues. GVHD has been linked to disruptions in the bacteria living in the gut (the microbiota), which in turn may be caused by factors such as conditioning chemotherapy, radiation and antibiotic treatment. GVHD and mortality are mediated by the immune system, whose activity in turn is shaped by gut microbiota. Prebiotics are nondigestible fibers that can be safely given to HCT patients and metabolized by existing bacteria in the gut to positively impact bacterial communities and metabolic products such as butyrate. Butyrate is a short chain fatty acid that is an important energy source for colonic epithelial cells and can promote regulatory T cell development, which in turn can modulate GVHD. Our preliminary data suggest that the administration of the prebiotic galacto-oligosaccharide (GOS) to mice undergoing HCT, can both increase butyrate and decrease GVHD. Here we propose the following aims: Aim 1. Evaluate the safety, tolerability, and efficacy of GOS in a phase 1 and randomized phase 2 trial. Aim 1A: We will determine the maximum tolerated dose (MTD) of GOS in a phase 1 dose escalation study (Years 1-2). We hypothesize that GOS is tolerable in doses that increase bacterial diversity and butyrate levels. Aim 1B: We will evaluate the impact of GOS on HCT outcomes in a randomized placebo-controlled phase 2 trial. (Years 2-5). We hypothesize that patients receiving GOS will have better outcomes including decreased grade II-IV GVHD. Aim 1C: We will compare the pre-HCT microbiome of GOS responders (those who received GOS in the phase 1 and phase 2 trials and had increased bacterial diversity) and non-responders (those with no change or decreased bacterial diversity) to determine elements of the pre-HCT microbiome that may be associated with GOS response. Aim 2. Evaluate the impact of GOS on biomarkers of intestinal and systemic inflammation and GVHD as potential mediators of HCT outcomes. The regenerating islet-derived protein 3 alpha (REG3A), is of particular interest. REG3A is an antimicrobial peptide that may be affected by the microbiota and has been reported as a biomarker of GVHD. We hypothesize that patients treated with GOS will have positive changes in biomarkers of inflammation and GVHD (increased REG3A, primary endpoint). As an exploratory aim, biomarkers will be studied for their associated with prebiotic interventions, changes in the microbiome, bacterial metabolites, immune reconstitution, and HCT clinical outcomes (GVHD, TRM, OS). Our long-term goal is to understand how prebiotic interventions impact the microbiota and bacterial metabolites and use prebiotics to decrease inflammation and improve HCT outcomes. We expect that the data generated from this study will lead to future clinical trials, including a multicenter randomized phase 3 trials, or to microbiota-based diagnostic assays to personalize therapies.