Safety and Feasibility of Selective Fecal Microbiota Transplantation (FMT) for Immune Reconstitution in Immunodeficient Patients After Hematopoietic Stem Cell Transplantation (HSCT)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 86
- 试验地点
- 1
- 主要终点
- Composite Endpoint of Safety and Feasibility of Selective FMT in Post-Allo-HSCT Patients
研究概览
简要总结
Patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) often experience slow and incomplete recovery of their immune system, particularly the part responsible for producing antibodies (humoral immunity). This can lead to increased risk of infections and other complications. Previous studies suggest that the gut microbiome and its metabolites, such as short-chain fatty acids (propionate and butyrate), play a critical role in immune recovery.
This study has two phases. In the first phase, we will observe changes in immune function, lymphocyte subsets, and gut metabolites (propionate and butyrate) before and at 1, 3, and 6 months after transplantation in 50-80 patients. We will compare patients with severe immune deficiency to those with normal recovery to identify differences in gut bacteria and metabolites.
In the second phase, we will perform selective fecal microbiota transplantation (FMT) in 6 patients who still have severe humoral immunodeficiency at 6 months post-transplant. The FMT capsules will be specially selected from donors whose gut bacteria are rich in both propionate-producing and butyrate-producing strains. Patients will receive 20 capsules daily for 3 consecutive days (60 capsules total). We will evaluate the safety and feasibility of this approach, and observe whether fecal secretory immunoglobulin A (sIgA) shows signs of recovery at 3 months after FMT.
The study is expected to take approximately 2 years to complete. Findings may provide a new precision microbiome-based strategy to promote immune recovery after transplantation.
详细描述
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for various hematological malignancies. However, B-cell-mediated humoral immune reconstitution after allo-HSCT is remarkably slow and often incomplete. Immunoglobulin M (IgM) typically recovers within 2-6 months, immunoglobulin G (IgG) within 3-18 months, while immunoglobulin A (IgA) recovery may be delayed up to 3 years or longer. Functional humoral immune recovery often requires more than 5 years. Previous studies have shown that acute and chronic graft-versus-host disease (GVHD) are significant contributors to persistent IgA deficiency.
The conditioning regimen prior to transplantation causes profound disruption of the gut microbiota, impairing the bidirectional regulatory network between the microbiome and host immunity. Microbial metabolites, particularly short-chain fatty acids (SCFAs) such as propionate and butyrate, play essential roles in B-cell differentiation and antibody production. Propionate is critical for inducing and maintaining intestinal regulatory T cells (Tregs), while butyrate provides energy for B-cell differentiation and immunoglobulin secretion.
Preliminary clinical data from the investigators' group show that 100% (5/5) of immunodeficient patients post-allo-HSCT exhibit specific propionate deficiency, whereas patients with general dysbiosis primarily show butyrate deficiency. This suggests that the propionate synthesis pathway, driven predominantly by Bacteroidetes, is more severely destroyed under the extreme post-transplant environment.
Based on ecological keystone species theory, propionate-producing bacteria (particularly Bacteroides species) are highly connected nodes in the gut microbial network. A cross-feeding relationship exists between propionate- and butyrate-producing bacteria, where the former degrade complex carbohydrates to provide growth substrates for the latter. The investigators propose the "propionate first, butyrate follows" two-stage synergistic reconstruction hypothesis:
Stage 1 (Microenvironment Preparation): Propionate-producing bacteria are preferentially restored, increasing intestinal propionate levels, inducing Treg cells, and creating an immune-permissive environment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Receiving first allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative or reduced-intensity conditioning
- •Able to complete scheduled follow-up visits and sample collections
- •Willing and able to provide written informed consent
- •For Phase 2 (FMT intervention): participants must additionally meet all of the following criteria at 6 months post-transplant:
- •Serum IgA < 0.07 g/L with IgG and IgM not yet recovered to normal range
- •No active grade III-IV acute graft-versus-host disease (GVHD)
- •Off systemic antibiotics for at least 2 weeks
- •Willing to receive fecal microbiota transplantation (FMT) and sign dedicated informed consent for the intervention
排除标准
- •Early post-transplant death or loss to follow-up
- •Active grade III-IV acute GVHD (at time of screening)
- •Continuous use of high-dose immunosuppressants (prednisone-equivalent dose > 1 mg/kg/day)
- •Refusal to participate or inability to comply with study procedures
- •For Phase 2 (FMT intervention): participants meeting any of the following criteria will be excluded from the FMT phase:
- •Gastrointestinal obstruction, perforation, or severe intestinal dysfunction
- •Severe cardiac, hepatic, or renal insufficiency that would preclude safe FMT administration
- •Known allergy or hypersensitivity to any component of the FMT preparation
研究组 & 干预措施
FMT Treatment Group
Oral administration of human-derived gut microbiota capsules, each containing no fewer than 2×10¹¹ organisms, given at a dose of 20 capsules per day for 3 consecutive days (total 60 capsules per course).
干预措施: Fecal microbiota transplantation (FMT) (Biological)
结局指标
主要结局
Composite Endpoint of Safety and Feasibility of Selective FMT in Post-Allo-HSCT Patients
时间窗: 3 months post-FMT
Safety is assessed by the incidence, severity (CTCAE v5.0), and attribution of treatment-emergent adverse events (TEAEs) within 3 months post-FMT, with particular monitoring for grade ≥3 AEs, serious adverse events (SAEs), and FMT-related exacerbation of GVHD or bacteremia. Feasibility is measured by the FMT completion rate, defined as the proportion of enrolled patients who successfully receive ≥90% of the planned total dose (≥54 of 60 oral capsules). The study will be considered to have demonstrated safety and feasibility if: (a) the completion rate is ≥80% (lower bound of 95% CI \>60%); (b) the incidence of FMT-related grade ≥3 AEs is ≤15% (upper bound of 95% CI \<30%); and (c) no FMT-related SAEs occur that are definitely or probably attributed to the intervention. Independent safety review will be performed after every 5 patients, with predefined stopping rules.
次要结局
- Change in Fecal Secretory Immunoglobulin A (sIgA) Concentration(Baseline to 3 months post-FMT)
- Change in Serum Immunoglobulin Levels(Baseline to 3 months post-FMT)
- Change in Fecal Short-Chain Fatty Acid Concentrations(Baseline to 2 weeks post-FMT)
- Change in Peripheral Blood B-Cell Subsets(Baseline to 3 months post-FMT)
- Donor Microbiota Engraftment Rate(3 months post-FMT)