PDF(Pubmed)
Abstract：
Acute GVHD (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) associated with gut microbiota disruptions. However, whether therapeutic microbiota modulation prevents aGVHD is unknown. We conducted a randomized, placebo-controlled trial of third-party fecal microbiota transplantation (FMT) administered at the peak of microbiota injury in 100 patients with acute myeloid leukemia receiving induction chemotherapy and alloHCT recipients. Despite improvements in microbiome diversity, expansion of commensals, and shrinkage of potential pathogens, aGVHD occurred more frequently after FMT than placebo. Although this unexpected finding could be explained by clinical differences between the two arms, we asked whether a microbiota explanation might be also present. To this end, we performed multi-omics analysis of preintervention and postintervention gut microbiome and serum metabolome. We found that postintervention expansion of Faecalibacterium, a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, predicted a higher risk for aGVHD. Faecalibacterium expansion occurred predominantly after FMT and was due to engraftment of unique donor taxa, suggesting that donor Faecalibacterium-derived antigens might have stimulated allogeneic immune cells. Faecalibacterium and ursodeoxycholic acid (an anti-inflammatory secondary bile acid) were negatively correlated, offering an alternative mechanistic explanation. In conclusion, we demonstrate context dependence of microbiota effects where a normally beneficial bacteria may become detrimental in disease. While FMT is a broad, community-level intervention, it may need precision engineering in ecologically complex settings where multiple perturbations (e.g., antibiotics, intestinal damage, alloimmunity) are concurrently in effect.
UNASSIGNED: Post-FMT expansion of Faecalibacterium, associated with donor microbiota engraftment, predicted a higher risk for aGVHD in alloHCT recipients. Although Faecalibacterium is a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, our findings suggest that it may become pathogenic in the setting of FMT after alloHCT. Our results support a future trial with precision engineering of the FMT product used as GVHD prophylaxis after alloHCT.
UNASSIGNED: Post-FMT expansion of Faecalibacterium, associated with donor microbiota engraftment, predicted a higher risk for aGVHD in alloHCT recipients. Although Faecalibacterium is a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, our findings suggest that it may become pathogenic in the setting of FMT after alloHCT. Our results support a future trial with precision engineering of the FMT product used as GVHD prophylaxis after alloHCT.
摘要：
急性移植物抗宿主病（aGVHD）是与肠道微生物群破坏相关的异基因造血细胞移植（alloHCT）的主要并发症。然而,治疗性微生物群调节是否能预防aGVHD尚不清楚.我们做了一个随机的,在100例接受诱导化疗的急性髓性白血病患者和alloHCT受者中，在微生物群损伤高峰时进行第三方粪便微生物群移植（FMT）的安慰剂对照试验。尽管微生物多样性有所改善，共生节的扩张，和潜在病原体的减少，aGVHD发生在FMT后比安慰剂更频繁。尽管这一意外发现可以通过两臂之间的临床差异来解释，我们询问是否也可能存在微生物群解释。为此,我们对干预前后的肠道微生物组和血清代谢组进行了多组学分析.我们发现，在干预后扩大了Faecalibacterium，在稳态条件下具有肠道保护和抗炎特性的共生属，预测aGVHD的风险更高。Faecalibacterium扩增主要发生在FMT之后，这是由于独特的供体分类群的植入，表明供体粪杆菌来源的抗原可能刺激了同种异体免疫细胞。粪杆菌和熊去氧胆酸（一种抗炎次级胆汁酸）呈负相关，提供另一种机械解释。总之,我们证明了微生物群效应的背景依赖性，其中正常有益的细菌可能对疾病有害。虽然FMT是一个广泛的，社区层面的干预，在生态复杂的环境中，它可能需要精确的工程，在这些环境中，多重扰动(例如抗生素，肠道损伤,同种免疫)同时有效。
