MultiOmics_aSCT

The human microbiome has a direct effect on clinical outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungi, viruses and microbiota-derived metabolites are involved but not as well studied. Previous research has focused on their systemic effects, but increasingly their local, tissue-specific role e.g., in regulating intestinal homeostasis, is increasingly appreciated. However, it is still unclear how dynamic shifts in these three kingdoms contribute to the production of intestinal metabolites, how metabolites are altered by microbiome modulation and whether they are associated with clinical outcome. To address this, we performed a prospective, longitudinal study that combined three-kingdom (bacteria, fungi, viruses) analysis of intestinal microbial communities with targeted metabolomics in allo-SCT patients (n=78) at two different transplantation centers. We uncovered a microbiome signature of bacteria from the Lachnospiraceae and Oscillospiraceae families and their associated bacteriophages, which correlated with the production of immuno-modulatory metabolites including short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFA), metabolites associated with induction of type-I IFN signaling (IIMs) and immuno-modulatory secondary bile acids. We established an Immuno-modulatory Metabolite Risk Index (IMM-RI) consisting of five index immuno-modulatory metabolites (IMMs), which was associated with improved survival, less mortality and reduced relapse rate. Microbiome modulation, either inadvertently by onset of GI-GvHD or exposure to antibiotics, or as proof-of-concept via fecal microbiome transplantation (FMT) significantly impacted intestinal levels of protective IMMs. Using metagenomic sequencing, we observed that in IMM-RI low-risk patients, sustained production of protective IMMs was associated with a high abundance of SCFA biosynthesis pathways, specifically butyric acid via butyryl-CoA:acetate CoA-transferase (BCoAT). We detected two BCoAT-coding bacteriophage contigs through viral metagenomic assembled genome, which were positively correlated with butyric acid concentration, suggesting that bacteriophages may modulate bacterial metabolite biosynthesis. Our study identifies a specific microbiome signature associated with protective IMMs and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies.