2. Academic Validation
  3. Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD

Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD

  • J Exp Med. 2025 Sep 1;222(9):e20242180. doi: 10.1084/jem.20242180.
Sangya Chatterjee 1 2,  Tamina Rückert 1,  Ina Martin 1 2,  Elisa Michaeli 1 2,  Joerg Buescher 3,  Petya Apostolova 4 5,  Daniel Erny 6,  Maria-Eleni Lalioti 3 7,  Francesca Biavasco 1,  Alina Hartmann 1,  Solveig Runge 2 8 9 10,  Lukas M Braun 1 2,  Nana Talvard-Balland 1 11,  Rachael C Adams 12 13 14,  Annette Schmitt-Graeff 1,  James Cook 6,  Valentin Wenger 1,  Dimitrios Athanassopoulos 1,  Dilara Hasavci 2 6,  Alexander Paolo Vallejo-Janeta 6,  Thomas Blank 6,  Philipp Schaible 2 6,  Janaki Manoja Vinnakota 1,  Alexander Zähringer 1,  Stephanie C Ganal-Vonarburg 15 16,  Wolfgang Melchinger 1,  Dietmar Pfeifer 1 17,  Natalie Köhler 1 11,  Stephan P Rosshart 8 9 10,  David Michonneau 18 19,  Gérard Socié 18 19,  Geoffroy Andrieux 20,  Nina Cabezas-Wallscheid 3 7,  Melanie Boerries 20 21,  Marco Prinz 6 22 23,  Robert Zeiser 1 21 23
Affiliations

Affiliations

  • 1 Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • 2 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 3 Max Planck Institute of Immunobiology and Epigenetics , Freiburg, Germany.
  • 4 Division of Hematology, University Hospital Basel, Basel, Switzerland.
  • 5 Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
  • 6 Institute of Neuropathology, Medical Faculty, University of Freiburg , Freiburg, Germany.
  • 7 Laboratory of Stem Cell Biology and Ageing, Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland.
  • 8 Department of Medicine II, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • 9 Department of Microbiome Research, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 10 Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 11 CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg , Freiburg, Germany.
  • 12 Faculty of Medicine, The University of Queensland, Brisbane, Australia.
  • 13 QIMR Berghofer Medical Research Institute , Brisbane, Australia.
  • 14 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 15 Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 16 Department for Biomedical Research, University of Bern, Bern, Switzerland.
  • 17 Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 18 Hematology Transplantation, Saint Louis Hospital , Paris, France.
  • 19 INSERM U1342 Saint Louis Research Institute, IHU Leukemia Institute Paris Saint Louis, SIRIC InSitu, Université Paris Cité , Paris, France.
  • 20 Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg , Freiburg, Germany.
  • 21 German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg , Freiburg, Germany.
  • 22 Department of Neurology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • 23 Signaling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg , Freiburg, Germany.
PMID: 40627379 DOI: 10.1084/jem.20242180
Abstract

Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with Antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following Antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.

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