Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis

作者：Armin Rashidi, Maryam Ebadi, Tauseef Ur Rehman, Heba Elhusseini, David Kazadi, Hossam Halaweish, Mohammad H. Khan, Andrea Hoeschen, Qing Cao, Xianghua Luo, Amanda J. Kabage, Sharon Lopez, Sivapriya Ramamoorthy, Shernan G. Holtan, Daniel J. Weisdorf, Alexander Khoruts, Christopher Staley · 发表于：Cancer Research Communications · 年份：2024 · DOI：10.1158/2767-9764.crc-24-0138 · 被引用次数：14 · 研究领域：Gut microbiota and health、Clostridium difficile and Clostridium perfringens research、Neutropenia and Cancer Infections

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. ...