Bacteriophage-modulated Production of Intestinal Immuno-modulatory Metabolites is Associated with Protection in Allogeneic Stem Cell Transplantation Patients
Creators
- Erik Thiele Orberg1
- Elisabeth Meedt1
- Andreas Hiergeist2
- Jinling Xue3
- Paul Heinrich4
- Sakhila Ghimire5
- Melanie Tiefgraber6
- Sophia Göldel6
- Tina Eismann6
- Alix Schwarz6
- Sascha Göttert4
- Sebastian Jarosch1
- Katja Steiger1
- Christian Schulz7
- Michael Gigl1
- Julius Fischer1
- Klaus-Peter Janssen1
- Michael Quante8
- Simon Heidegger1
- Peter Herhaus1
- Mareike Verbeek6
- Jürgen Ruland1
- Daniela Weber5
- Daniel Wolff9
- Matthias Edinger5
- Dirk Busch10
- Karin Kleigrewe1
- Wolfgang Herr9
- Florian Bassermann1
- André Gessner9
- Li Deng11
- Ernst Holler4
- Hendrik Poeck12
- 1. Technical University of Munich
- 2. Institute of Microbiology Regensburg,
- 3. nstitute of Virology, Helmholtz Zentrum Munich
- 4. University Medical Centre, Regensburg
- 5. University Medical Center Regensburg
- 6. University Hospital Rechts der Isar of the Technical University of Munich
- 7. Ludwig-Maximilians-Universität München
- 8. University Medical Center Freiburg
- 9. University Hospital Regensburg
- 10. Technichal University of Munich
- 11. Technical University of Munich,
- 12. Universitiy of Regensburg
Description
The human microbiome directly affects clinical outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungal and viral kingdoms as well as microbiota-derived metabolites play a role. Previous research has focused on their systemic effects, but increasingly their local, tissue-specific role e.g., in regulating intestinal homeostasis, is appreciated. Yet, it is still unclear how dynamic shifts in the three kingdoms contribute to the production of intestinal metabolites, how these metabolites are altered by microbiome modulation and whether they are associated with clinical outcome.
Here, 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 functional 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 consisting of five index immuno-modulatory metabolites (IMMs), which was associated with improved survival 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.
Via 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). By viral metagenomic sequencing from isolated viral particles, we detected BCoAT contained within two unique temperate bacteriophages, suggesting they may augment bacterial metabolite biosynthesis.
Our study demonstrates that bacteriophage-modulated bacterial consortia are 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
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