TY  - JOUR
AU  - Chatterjee, Sangya
AU  - Rückert, Tamina
AU  - Martin, Ina
AU  - Michaeli, Elisa
AU  - Buescher, Joerg
AU  - Apostolova, Petya
AU  - Erny, Daniel
AU  - Lalioti, Maria-Eleni
AU  - Biavasco, Francesca
AU  - Hartmann, Alina
AU  - Runge, Solveig
AU  - Braun, Lukas M
AU  - Talvard-Balland, Nana
AU  - Adams, Rachael C
AU  - Schmitt-Graeff, Annette
AU  - Cook, James
AU  - Wenger, Valentin
AU  - Athanassopoulos, Dimitrios
AU  - Hasavci, Dilara
AU  - Vallejo-Janeta, Alexander Paolo
AU  - Blank, Thomas
AU  - Schaible, Philipp
AU  - Vinnakota, Janaki Manoja
AU  - Zähringer, Alexander
AU  - Ganal-Vonarburg, Stephanie C
AU  - Melchinger, Wolfgang
AU  - Pfeifer, Dietmar
AU  - Köhler, Natalie
AU  - Rosshart, Stephan P
AU  - Michonneau, David
AU  - Socié, Gérard
AU  - Andrieux, Geoffroy
AU  - Cabezas-Wallscheid, Nina
AU  - Börries, Melanie
AU  - Prinz, Marco
AU  - Zeiser, Robert
TI  - Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.
JO  - Journal of experimental medicine
VL  - 222
IS  - 9
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DKFZ-2025-01359
SP  - e20242180
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Gastrointestinal Microbiome: drug effects
KW  - Microglia: metabolism
KW  - Microglia: drug effects
KW  - Graft vs Host Disease: microbiology
KW  - Graft vs Host Disease: metabolism
KW  - Graft vs Host Disease: pathology
KW  - Graft vs Host Disease: etiology
KW  - Mice
KW  - Toll-Like Receptor 4: metabolism
KW  - Mice, Inbred C57BL
KW  - Hematopoietic Stem Cell Transplantation: adverse effects
KW  - Humans
KW  - Anti-Bacterial Agents: pharmacology
KW  - Male
KW  - p38 Mitogen-Activated Protein Kinases: metabolism
KW  - Acute Disease
KW  - Central Nervous System: pathology
KW  - T-Lymphocytes: immunology
KW  - Female
KW  - Specific Pathogen-Free Organisms
KW  - Toll-Like Receptor 4 (NLM Chemicals)
KW  - Anti-Bacterial Agents (NLM Chemicals)
KW  - p38 Mitogen-Activated Protein Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40627379
DO  - DOI:10.1084/jem.20242180
UR  - https://inrepo02.dkfz.de/record/302819
ER  -