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FIGURE 4 from Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis

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posted on 2024-06-10, 14:20 authored by Armin Rashidi, Maryam Ebadi, Tauseef U. 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

Serum metabolomics before and after FMT versus placebo. A, Distribution of serum metabolites across different pathways. B, PCA using logarithmically transformed metabolite levels, centered and scaled. 50% ellipses are shown. C, sPLS-DA loading plot for significant contributors to the first latent component in treatment arm-based classification. Each variable's contribution is shown by a vector. Vectors pointing to the right versus left represent differentially abundant metabolites in baseline versus pre-FMT/placebo samples, respectively. Longer vectors correspond to metabolites with more importance in group classification. D, Serum metabolomic heatmap among baseline and pre-FMT/placebo samples using the best classifying metabolites from sPLS-DA. Each row is a sample, and each column is a metabolite. The blue-red gradient shows metabolite levels scaled column-wise. E, Same analysis as in D, but for early post-FMT and early post-placebo samples. Logarithmically transformed metabolite values, Euclidean distance, and the complete method for hierarchical clustering were used to generate the heat maps in D and E. FMT: fecal microbiota transplantation, PC: principal component.

Funding

Foundation for the National Institutes of Health (FNIH)

HHS | NIH | National Cancer Institute (NCI)

UMN | Clinical and Translational Science Institute, University of Minnesota (CTSI)

Achieving Cures Together

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ARTICLE 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. 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.