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@ARTICLE{Chatterjee:302819,
author = {S. Chatterjee and T. Rückert and I. Martin and E. Michaeli
and J. Buescher and P. Apostolova and D. Erny and M.-E.
Lalioti and F. Biavasco and A. Hartmann and S. Runge and L.
M. Braun and N. Talvard-Balland and R. C. Adams and A.
Schmitt-Graeff and J. Cook and V. Wenger and D.
Athanassopoulos and D. Hasavci and A. P. Vallejo-Janeta and
T. Blank and P. Schaible and J. M. Vinnakota and A.
Zähringer and S. C. Ganal-Vonarburg and W. Melchinger and
D. Pfeifer and N. Köhler and S. P. Rosshart and D.
Michonneau and G. Socié and G. Andrieux and N.
Cabezas-Wallscheid and M. Börries$^*$ and M. Prinz and R.
Zeiser$^*$},
title = {{G}ut microbiota-derived {TMAVA} is a modulator of acute
{CNS}-{GVHD}.},
journal = {Journal of experimental medicine},
volume = {222},
number = {9},
issn = {0022-1007},
address = {New York, NY},
publisher = {Rockefeller Univ. Press},
reportid = {DKFZ-2025-01359},
pages = {e20242180},
year = {2025},
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.},
keywords = {Animals / Gastrointestinal Microbiome: drug effects /
Microglia: metabolism / Microglia: drug effects / Graft vs
Host Disease: microbiology / Graft vs Host Disease:
metabolism / Graft vs Host Disease: pathology / Graft vs
Host Disease: etiology / Mice / Toll-Like Receptor 4:
metabolism / Mice, Inbred C57BL / Hematopoietic Stem Cell
Transplantation: adverse effects / Humans / Anti-Bacterial
Agents: pharmacology / Male / p38 Mitogen-Activated Protein
Kinases: metabolism / Acute Disease / Central Nervous
System: pathology / T-Lymphocytes: immunology / Female /
Specific Pathogen-Free Organisms / Toll-Like Receptor 4 (NLM
Chemicals) / Anti-Bacterial Agents (NLM Chemicals) / p38
Mitogen-Activated Protein Kinases (NLM Chemicals)},
cin = {FR01},
ddc = {610},
cid = {I:(DE-He78)FR01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40627379},
doi = {10.1084/jem.20242180},
url = {https://inrepo02.dkfz.de/record/302819},
}