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