Microbiota-derived products function as immunoregulatory metabolites. In Nature Medicine, Quintana and colleagues show that dietary tryptophan is metabolized by the gut microbiota into agonists of the transcription factor AhR that act on astrocytes to limit inflammation of the central nervous system. Experimental autoimmune encephalomyelitis in mice induces a strong type I interferon response as well as upregulation of Ahr mediated by the transcription factors STAT1-STAT2 in astrocytes. Astrocyte-specific knockdown of the interferon receptor Ifnar1 or Ahr induces the expression of genes encoding pro-inflammatory products in astrocytes, microglia and Ly6Chi monocytes and increases the recruitment of inflammatory monocytes to the central nervous system. Dietary deficiency in tryptophan worsens experimental autoimmune encephalomyelitis in mice, a process linked to AhR expression in astrocytes. Patients with multiple sclerosis have lower expression of tryptophan-derived AhR ligands in the serum than that of healthy control subjects, which suggests that deficiency in AhR agonists linked to metabolism, diet or the microbiota can contribute to the pathogenesis of multiple sclerosis.

Nat. Med. (9 May 2016) doi:10.1038/nm.4106