Journal Article

DKFZ-2025-01359

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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, M.-E. ; Biavasco, F. ; Hartmann, A. ; Runge, S. ; Braun, L. M. ; Talvard-Balland, N. ; Adams, R. C. ; Schmitt-Graeff, A. ; Cook, J. ; Wenger, V. ; Athanassopoulos, D. ; Hasavci, D. ; Vallejo-Janeta, A. P. ; Blank, T. ; Schaible, P. ; Vinnakota, J. M. ; Zähringer, A. ; Ganal-Vonarburg, S. C. ; Melchinger, W. ; Pfeifer, D. ; Köhler, N. ; Rosshart, S. P. ; Michonneau, D. ; Socié, G. ; Andrieux, G. ; Cabezas-Wallscheid, N. ; Börries, M.DKFZ* ; Prinz, M. ; Zeiser, R.DKFZ*

2025
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Gastrointestinal Microbiome: drug effects (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: drug effects (MeSH) ; Graft vs Host Disease: microbiology (MeSH) ; Graft vs Host Disease: metabolism (MeSH) ; Graft vs Host Disease: pathology (MeSH) ; Graft vs Host Disease: etiology (MeSH) ; Mice (MeSH) ; Toll-Like Receptor 4: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Hematopoietic Stem Cell Transplantation: adverse effects (MeSH) ; Humans (MeSH) ; Anti-Bacterial Agents: pharmacology (MeSH) ; Male (MeSH) ; p38 Mitogen-Activated Protein Kinases: metabolism (MeSH) ; Acute Disease (MeSH) ; Central Nervous System: pathology (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Female (MeSH) ; Specific Pathogen-Free Organisms (MeSH) ; Toll-Like Receptor 4 ; Anti-Bacterial Agents ; p38 Mitogen-Activated Protein Kinases

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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