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

Göttert S, Thiele Orberg E, Fan K, Heinrich P, Matthe D, Khalid O, Klostermeier L, Suriano C, Strieder N, Gebhard C, Vonbrunn E, Mamilos A, Hirsch D, Meedt E, Kleigrewe K, Hiergeist A, Schwarz A, Gläsner J, Ghimire S, Joachim L, Voll F, Neuhaus K, Janssen KP, Perl M, Pielmeier F, Ruland J, Kreutz M, Weber D, Schmidl C, Köhler N, Tschurtschenthaler M, Hoffmann P, Edinger M, Wolff D, Bassermann F, Rehli M, Haller D, Evert M, Hildner K, Büttner-Herold M, Herr W, Gessner A, Heidegger S, Holler E, Poeck H (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 16

Article Number: 9282

Journal Issue: 1

DOI: 10.1038/s41467-025-65180-6

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.

Authors with CRIS profile

Involved external institutions

Universität Regensburg Germany (DE) Universitätsklinikum Regensburg Germany (DE) Technische Universität München (TUM) Germany (DE) Klinikum rechts der Isar Germany (DE) Leibniz-Institut für Immuntherapie (LIT) / Leibniz Institute for Immunotherapy Germany (DE) Universitätsklinikum Freiburg Germany (DE)

How to cite

APA:

Göttert, S., Thiele Orberg, E., Fan, K., Heinrich, P., Matthe, D., Khalid, O.,... Poeck, H. (2025). The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-65180-6

MLA:

Göttert, Sascha, et al. "The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration." Nature Communications 16.1 (2025).

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