Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD

Area of Science:

• Neuroimmunology
• Microbiology
• Hematology

Background:

• Acute graft-versus-host disease (aGVHD) can impact the central nervous system (CNS).
• The specific role of gut microbiota in CNS aGVHD pathogenesis is not well understood.
• Microglial activation and T cell infiltration are implicated in CNS complications of aGVHD.

Purpose of the Study:

• To investigate the influence of gut microbiota on microglial activation during aGVHD.
• To elucidate the mechanisms by which microbiota affect CNS aGVHD.
• To identify potential therapeutic targets for CNS aGVHD.

Main Methods:

• Utilized antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice models.
• Administered allogeneic hematopoietic cell transplantation (allo-HCT) to induce aGVHD.
• Analyzed microglial activation via the TLR4/p38 MAPK pathway and assessed neurocognitive deficits.
• Measured levels of the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA).

Main Results:

• Antibiotic-mediated microbiota depletion in SPF mice led to T cell infiltration, microglial activation, and neurocognitive deficits.
• Depletion of microglia reversed the observed neurocognitive deficits.
• GF and wildling mice treated with antibiotics showed similar microglial activation post-allo-HCT.
• Reduced TMAVA levels were observed in microglia after antibiotic treatment, and TMAVA administration ameliorated deficits.
• TMAVA abundance decreased in patients after allo-HCT and GVHD onset.

Conclusions:

• Loss of gut microbiota and subsequent decrease in TMAVA is a key driver of CNS aGVHD.
• TMAVA suppresses microglial activation through the TLR4/p38 MAPK pathway.
• TMAVA represents a potential therapeutic target for managing CNS aGVHD.