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denotes that this is a ticketed session.Type: Oral
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Emerging Insights in GVHD Immunobiology
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Translational Research, Clinical Research, Therapies, metabolism, Biological Processes, microbiome, Transplantation
We report the two-year follow-up of a prospective, observational, longitudinal cohort of allo-SCT patients (n=78) at two German transplantation centers that combined three-kingdom (bacteria, fungi, viruses) analysis of intestinal microbial communities with targeted metabolomics (Figure 1). Using Multi-omics factor analysis (MOFA), we uncovered a functional microbiome signature of bacteria from the Lachnospiraceae and Oscillospiraceae families and their associated bacteriophages, which correlated with the production of immuno-modulatory metabolites (IMMs) 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 (Figure 2). We established an Immuno-modulatory Metabolite Risk Index (IMM-RI) consisting of five index IMMs, which was associated with improved survival, less transplant-related mortality and reduced relapse rate. Onset of gastrointestinal GvHD and exposure to antibiotics significantly impacted intestinal levels of protective IMMs.
Using whole shotgun metagenomic sequencing, we observed that in IMM-RI low-risk patients, sustained production of protective IMMs was associated with a high abundance of microbial SCFA biosynthesis pathways, specifically butyric acid via butyryl-CoA:acetate CoA-transferase (BCoAT). Through genome assembly from viral metagenomic sequencing data, we detected two distinct bacteriophages which encoded BCoAT as an auxiliary metabolic gene. They were more abundant in IMM-RI low-risk patients and positively correlated with intestinal butyric acid levels, suggesting that these bacteriophages may modulate bacterial metabolite biosynthesis.
Our study identifies a specific microbiome signature associated with protective IMMs that could improve fecal microbiota transplantation (FMT) donor selection and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies for cancer patients.
Disclosures: Verbeek: Novartis: Honoraria; Jazz: Honoraria, Other: travel support, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Abbvie: Honoraria, Other: travel support, Speakers Bureau; medac: Other: travel support; Pfizer: Honoraria. van den Brink: Nektar Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pluto Immunotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Frazier Healthcare Partners: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rheos Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: IP licensing , Research Funding; Thymofox: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; DKMS (a non-profit organization): Membership on an entity's Board of Directors or advisory committees; Notch Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ceramedix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lygenesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vor Biopharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Da Volterra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Other: IP licensing; Wolters Kluwer: Patents & Royalties. Wolff: Gilead: Honoraria; Takeda: Honoraria; Behring: Honoraria; Incyte: Honoraria; Mallickrodt: Honoraria; Sanofi: Honoraria; Novartis: Honoraria, Research Funding. Herr: Amgen: Honoraria, Other: Travel expenses; Janssen-Cilag: Honoraria, Other: Travel expenses. Holler: MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Poeck: Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria.