Identification of Protective, Metabolite-producing Bacterial and Viral Consortia in Allogeneic Stem Cell Transplantation Patients

Abstract: The intestinal bacteriome directly affects outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungal and viral communities as well as microbiota-derived metabolites play a role. Yet, it is still unclear how dynamic shifts in these three communities contribute to (1) clinical outcome of allo-SCT patients, (2) production of metabolites and (3) how they are affected by microbiome modulation via antibiotics or fecal microbiota transplantation (FMT). Here, we performed a prospective, longitudinal study that combined transkingdom (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 metabolite-producing bacteria from the Lachnospiraceae and Oscillospiraceae families and their corresponding bacteriophages, which correlated with the production of immunomodulatory metabolites including short-chain fatty acids (SCFAs), metabolites associated with induction of type-I IFN signaling (IIMs) and bile acids. Sustained production of these “protective” metabolites after allo-SCT was associated with improved survival and reduced transplantation-related mortality, whereas antibiotic exposure significantly impaired metabolite expression. We demonstrate that single taxa domination and metabolite depletion in a patient suffering from graft versus host disease (GvHD) could be rescued by transfer of metabolite-producing bacterial consortia via fecal microbiota transplantation (FMT). FMT led to resolution of steroid refractory GvHD and was accompanied by an increase of bacterial and viral alpha diversity, restoration of SCFAs and IIMs and accumulation of regulatory T cells to the intestine. Our study demonstrates that microbiome modulation (via antibiotics or FMT) can affect the identified bacterial/bacteriophage network and their associated protective metabolites thereby determining clinical outcomes and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies.