Gut microbiome derived N,N,N-trimethyl-5-aminovaleric acid (TMAVA) is a modulator of CNS-aGVHD

Acute graft-vs-host disease (aGVHD) can affect the central nervous system (CNS) through activation of microglia and infiltration of T cells. However, it is unclear how microbiome modifications impact CNS-aGVHD. Here, we analyzed the role of the microbiome in facilitating microglia activation during aGVHD using antibiotics-treated, germ-free (GF) and wildling mice. Antibiotics-mediated microbiome depletion caused infiltration of IFN-γ producing T cells in the brain, activation of microglia via the TLR4/p38MAPK pathway and deficits in neurocognitive functions in aGVHD mice. We observed similar microbiome-dependent microglia activation after allo-HCT in microbiome-disrupted wildling mice, and in GF mice compared to Oligo-Mouse-Microbiota (OMM12) mice. The bacteria-derived metabolite N,N,N-trimethyl-5-aminovalerate (TMAVA) was decreased in microglia of antibiotics-treated mice. TMAVA administration diminished the activity of TLR4/p38MAPK pathway in microglia, and reversed T cell infiltration in the brain. We also found reduced TMAVA abundance in the blood of patients after GVHD onset compared to before onset. In summary, we identified the loss of bacteria-derived TMAVA upon antibiotics treatment as a central causative factor for CNS-aGVHD. 2 biological replicates each of ABX-treated allo-HCT mice and vehicle-treated allo-HCT mice are analysed.