Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD
Chatterjee S, Rückert T, Martin I, Michaeli E, Buescher J, Apostolova P, Erny D, Lalioti ME, Biavasco F, Hartmann A, Runge S, Braun LM, Talvard-Balland N, Adams RC, Schmitt-Graeff A, Cook J, Wenger V, Athanassopoulos D, Hasavci D, Vallejo-Janeta AP, Blank T, Schaible P, Vinnakota JM, Zähringer A, Ganal-Vonarburg SC, Melchinger W, Pfeifer D, Köhler N, Rosshart SP, Michonneau D, Socié G, Andrieux G, Cabezas-Wallscheid N, Boerries M, Prinz M, Zeiser R (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Book Volume: 222
Journal Issue: 9
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.
Involved external institutions
Universitätsklinikum Freiburg
Germany (DE)
Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics
Germany (DE)
Universitätsspital Basel
Switzerland (CH)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
University of Queensland
Australia (AU)
Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal
France (FR)
Inselspital, Universitätsspital Bern
Switzerland (CH)
Germany (DE)
Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics
Germany (DE)
Universitätsspital Basel
Switzerland (CH)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
University of Queensland
Australia (AU)
Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal
France (FR)
Inselspital, Universitätsspital Bern
Switzerland (CH)
How to cite
APA:
Chatterjee, S., Rückert, T., Martin, I., Michaeli, E., Buescher, J., Apostolova, P.,... Zeiser, R. (2025). Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD. Journal of Experimental Medicine, 222(9). https://doi.org/10.1084/jem.20242180
MLA:
Chatterjee, Sangya, et al. "Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD." Journal of Experimental Medicine 222.9 (2025).
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