The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in patients receiving allo-HSCT. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DAT´s beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DAT's dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

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Publication Details

Journal
Nature Communications
Published
2025-10-20
DOI
https://doi.org/10.1038/s41467-025-65180-6
Citations
1
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.80

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article

The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Christian Schmidl, Markus Tschurtschenthaler, Marina Kreutz, Joachim Gläsner et al.
1 citations
Nature Communications
Immune Cell Function and Interaction
0.80
article

The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Christian Schmidl, Markus Tschurtschenthaler, Marina Kreutz, Joachim Gläsner, Kai Hildner, Daniela Weber, Lena Klostermeier, Maike Büttner‐Herold, Natalie Köhler, Sakhila Ghimire, Petra Hoffmann, Dirk Haller, Andreas Mamilos, Ernst Holler, Daniel Wolff, Klaus Neuhaus, Diana M. Matthe, Erik Thiele Orberg, Elisabeth Meedt, Hendrik Poeck, Daniela Hirsch, Michael Rehli, André Gessner, Matthias Edinger, Florian C. Bassermann, Sascha Göttert, Paul Heinrich, Jürgen Ruland, Nicholas Strieder, Klaus‐Peter Janssen, Simon Heidegger, Markus Perl, Eva Vonbrunn, Alix Schwarz, Andreas Hiergeist, Florian Voll, Karin Kleigrewe, Claudia Gebhard, Laura Joachim, Franziska Pielmeier, Kaiji Fan, Wolfgang Herr, Matthias Evert, Omer Khalid, Chiara Suriano
article en
1 citations

Abstract

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in patients receiving allo-HSCT. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DAT´s beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DAT's dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

Nature CommunicationsVol. 16(1)
University of Freiburg (DE), German Cancer Research Center (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Heidelberg University (DE), TUM Klinikum (DE), University Hospital Regensburg (DE), Leibniz Association (DE), Universitätsklinikum Erlangen (DE), Universitäres Kinderwunschzentrum Lübeck (DE), Limassol General Hospital (CY), Leibniz-Institute for Food Systems Biology at the Technical University of Munich (DE), Leibniz Institute for Immunotherapy, Deutsches Konsortium für Translationale Krebsforschung (DE), University of Regensburg (DE), Technical University of Munich (DE)
Wilhelm Sander-Stiftung, European Commission, Deutsche Forschungsgemeinschaft, Technische Universität München, Deutsche Krebshilfe
Openalex Percentile: Top 22%
Immune Cell Function and Interaction
0.80
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