Impact of dietary tryptophan on the gut microbiome and autoimmune neuroinflammation

• Applicant: Professor Dr. Michael Platten
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406052676

Multiple sclerosis (MS), the most common neurological disorder among young adults, is thought to be mainly driven by autoreactive T cells that accumulate within the central nervous system (CNS) and attack myelin proteins. Recent preclinical data suggest that both dietary constituents and the gut microbiome composition, potentially via a tightly regulated interplay between the two components, shape autoreactive T cell responses. The essential amino acid tryptophan (trp) and its metabolites have been identified as important immune modulators.Previous studies performed in our lab demonstrated that dietary trp depletion results in complete abrogation of experimental autoimmune encephalomyelitis (EAE), a murine model for MS. The absence of clinical signs was accompanied by a lack of T cell infiltration into the CNS, however, trp-depleted mice were still able to mount an antigen-specific T cell response. When EAE was induced in germ-free mice, clinical signs of autoimmune neuroinflammation were also detected in trp-depleted mice. Analysis of the gut microbiome composition by 16S rDNA sequencing revealed that omission of trp from the diet induces expansion of pro-inflammatory taxa. In line with this, we found mild, but evident gut inflammation in trp-depleted mice. However, intestinal inflammation was not sufficient to prevent CNS autoimmunity, as mice treated with low-dose dextran sulfate sodium (DSS) to induce a mild gut inflammation were still susceptible to EAE induction. Based on these data we hypothesize that dietary trp depletion limits autoimmune neuroinflammation via the gut microbiome. Alterations in the gut microbiome composition may affect T cell differentiation and trafficking either by direct effects or via antigen-presenting cells. We aim to verify this hypothesis and identify molecular key players that mediate resistance to EAE induction upon trp deprivation. To this end we will analyse the effects of defined species on the regulation of CNS autoimmunity by faecel transplantation. In a second work package we would like to examine the impact of dietary trp depletion on the gut metabolome and to discover metabolites that either augment or limit accumulation of antigen-specific T cells within the CNS. To obtain a better understanding of the cellular components that are involved in key processes of EAE induction, we will track spatial and temporal distribution of autoreactive T cells in vivo and analyse gene expression profiles to identify relevant signaling pathways. Additionally we would like to characterize the phenotype of antigen-presenting cells that may induce a reversible "re-differentiation" of autoreactive T cells. Identification of molecular targets within the local gut microenvironment will add to the picture. Verification of the effects of dietary trp depletion in the clinically more relevant relapsing-remitting MS model will help us to translate findings into therapeutic approaches.

• DFG Programme: Research Grants