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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},
}