Deciphering the role of intestinal microbiome-derived metabolites on microglial activation during GVHD and ICANS

Prof. Dr. Robert Zeiser

• B06

Jun.-Prof. Dr. Natalie Köhler

• B06

Project Summary

During the previous funding periods, we showed that microglia activation plays a central role during inflammation in the central nervous system (CNS) in mice that experienced graft-versus-host disease (GVHD) and CAR T cell-induced Immune effector cell-associated neurotoxicity syndrome (ICANS) induced neuroinflammation. Host microbiota play an important role in regulating microglial homeostasis and function and our preliminary data indicate that manipulation of the microbiome by antibiotics in mice increases T cell infiltration in the CNS as well as microglial activation and metabolite levels after allogeneic hematopoietic cell transplantation (allo-HCT). The role of the intestinal microbiome and the derived metabolites for microglia activation during GVHD and ICANS is unclear. We will therefore use our well established GVHD and ICANS mouse models to study the effects of microbiome modulation on the transcriptional profile and phenotype of microglia (Aim 1). We are going to characterize microglia activation using high resolution microscopy and 3D reconstruction, single-cell analyses, computational modelling and cell-specific knock out lines. Metabolomics and kinome profiling will be used to decipher the impact of the microbiome on the metabolome and signaling in microglia in during GVHD and ICANS development (Aim 2). Using functional studies we will inhibit the identified kinases or substitute the identified metabolites and test if the neurocognitive deficits and microglia activation following microbiome depletion can be antagonized (Aim 3). We will use genetic mouse models to specifically target the identified molecules in microglia, to functionally validate their importance for the observed effects (Aim 3). Lastly, we will use samples from patients undergoing allo-HCT to study the effects of anti biotics on microglial activati on and levels of the metabolite trimethyl 5-aminovalerate in the serum (Aim 4). The planned studies will help to better understand how microbiome modifications, which are frequently induced by antibiotics used in patients with GVHD or ICANS, will impact microglia activation and if certain metabolites can help to reverse the phenotype.