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

• Final Report Year: 2021

Final Report Abstract

Multiple sclerosis (MS) is the most common neurological disorder among young adults which is mark ed by progressive demyelination and neuronal degradation. The disease is thought to be mainly driven by autoreactive T cells that accumulate within the central nervous system (CNS) and attack myelin prot eins and lipids but also neuronal and glial constituents. Recent preclinical data has suggested that th e gut microbiome is crucially involved in regulating autoreactive immune responses in a mouse model for MS, experimental autoimmune encephalomyelitis (EAE). Furthermore, it could be recently shown that the tryptophan (trp) metabolism is a key mechanism for restricting immune responses. We hypothesized that dietary tryptophan (trp) depletion regulates experimental autoimmune encephalomyelitis (EAE) via the gut microbiome, potentially via altering differentiation and/or trafficking of autoreactive cells as a result of an imbalanced gut microbiome and an altered phenotype and function of antigen-presenting cells. Verification of this hypothesis and identification of molecular key players involved in this process were the overall aim of this grant application. We could show that omission of a single essential amino acid - tryptophan – from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction res ult s in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiot a, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.

Publications

• "Dietary Tryptophan Links Encephalogenicity of Autoreactive T Cells with Gut Microbial Ecology." Nat Commun 10, no. 1 (Oct 25 2019): 4877
  Sonner, Jana K.; Keil, Melanie; Falk-Paulsen, Maren; Mishra, Neha; Rehman, Ateequr; Kramer, Magdalena; Deumelandt, Katrin; Röwe, Julian; Sanghvi, Khwab; Wolf, Lara; von Landenberg, Anna; Wolff, Hendrik; Bharti, Richa; Oezen, Iris; Lanz, Tobias V.; Wanke, Florian; Tang, Yilang; Brandao, Ines; Mohapatra, Soumya R.; ... & Platten, Michael
  
• "Tryptophan Metabolism as a Common Therapeutic Target in Cancer, Neurodegeneration and Beyond." Nat Rev Drug Discov 18, no. 5 (May 2019): 379-401
  Platten, Michael; Nollen, Ellen A. A.; Röhrig, Ute F.; Fallarino, Francesca & Opitz, Christiane A.
  
• "Constitutive Expression of the Immunosuppressive Tryptophan Dioxygenase Tdo2 in Glioblastoma Is Driven by the Transcription Factor C/Ebpβ." Front Immunol 11 (2020): 657
  Kudo, Takumi; Prentzell, Mirja T.; Mohapatra, Soumya R.; Sahm, Felix; Zhao, Zhongliang; Grummt, Ingrid; Wick, Wolfgang; Opitz, Christiane A.; Platten, Michael & Green, Edward W.