EBMT 2023 | Impact of microbiome signatures & production of intestinal metabolites on alloSCT outcomes

Well first of all, on behalf of my coauthors, I was honored to accept the Basic Science Award and present our abstract. The rationale for our study was that previous research had established that the human microbiome is a predictor of outcomes in allogeneic stem cell transplantation. However, it has been unclear why higher diversity of intestinal microbiota is associated with improved outcomes and therefore, we hypothesize that microbiota derived metabolites might constitute the missing link. Therefore, our goals were to integrate the bacterium, fungome and virome with intestinal metabolites to identify a functional microbiome signature associated with the production of metabolites that contribute to clinical outcomes. Therefore, at EBMT we reported a two-year follow-up of a two centric prospective longitudinal cohort of patients undergoing allogeneic stem cell transplantation both in Munich and in Regensburg in Germany. Patient samples were screened by 16S amplicon sequencing, 18S sequencing, viral metagenomic sequencing as well as targeted mass spectrometry. These four omic-modalities were then integrated via a tool known as Multi-Omics Factor Analysis, which enables us to identify a functional microbiome signature associated with metabolite production. Via MOFA, we identified metabolite producing taxa within the families of Lachnospiraceae and Oscillospiraceae which co-vary with their bacteriophages and were associated with the production of intestinal immunomodulatory metabolites. We compounded five of these metabolites most strongly associated with clinical outcomes to establish the immunomodulatory metabolite risk index and this predicted overall survival as well as relapse after adjusting for transplant related mortality as a competing risk. By metagenomic sequencing, we learned that microbial pathways related to the microbial metabolism were differentially abundant in patients with a low versus high-risk immunomodulatory metabolite risk index and indeed, patients with a low-risk IMM risk index were able to sustain metabolite production via increased abundance of these pathways. One of the most differentially abundant pathways involves the biosynthesis of butyric acid via the enzyme Butyryl-CoA: acetate CoA-transferase, BCoAT in short. We then mined our viral metagenomic sequencing dataset and identified BCoAT to be encoded in bacteriophages as novel auxiliary metabolic genes in humans. Finally, we proposed to translate these findings into clinical practice via a multicentric validation of the IMN risk index within an international consortium such as the MaGIC consortium. In the future, we envision metabolites to be applied in future trials of microbiome-based therapies where they can be synthesized locally via defined bacterial bacteriophage consortia or applied directly via metabolite combination drugs.