Indoleamine 2-3 dioxygenase shapes microbiota to reduce IL-22 and promote metabolic disease

The association between an altered gut microbiota, intestinal permeability and metabolic disorders, including obesity, diabetes, and cardiovascular disease (CAD), is becoming increasingly clear but remains poorly understood. Indoleamine 2-3 dioxygenase (IDO) is a rate-limiting enzyme induced during inflammation, and catalyses the degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway. Here we show that obesity is associated with an increase of intestinal IDO activity, which shifts Trp metabolism from indole derivative and IL-22 production towards Kyn production. IDO deletion or inhibition improves insulin sensitivity, preserves gut mucosal barrier, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of Trp metabolism towards a microbiota-dependent production of IL-22, and are abrogated after treatment with a neutralizing anti-IL22 antibody. In summary, we identify a novel function of IDO in the fine tuning of intestinal Trp metabolism with major consequences on microbiota-dependent control of metabolic disease, making IDO an attractive novel therapeutic target.