The extent to which microbiota alterations define or influence the outcome of metabolic diseases is still unclear, but the byproducts of microbiota metabolism are known to have an important role in mediating the host-microbiota interaction. Here, we identify that in both pre-clinical and clinical settings, metabolic syndrome is associated with the reduced capacity of the microbiota to metabolize tryptophan into derivatives that are able to activate the aryl hydrocarbon receptor. This alteration is not merely an effect of the disease as supplementation with AhR agonist or a Lactobacillus strain, with a high AhR ligand-production capacity, leads to improvement of both dietary- and genetic-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis, through improvement of intestinal barrier function and secretion of the incretin hormone GLP-1. These results highlight the role of gut microbiota-derived metabolites as a biomarker and as a basis for novel preventative or therapeutic interventions for metabolic disorders.

Reactive oxygen species (ROS) are generated by virally-infected cells however the physiological significance of ROS generated under these conditions is unclear. Here we show that inflammation and cell death induced by exposure of mice or cells to sources of ROS is not altered in the absence of canonical ROS-sensing pathways or known cell death pathways. ROS-induced cell death signaling involves interaction between the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5−/− mice show exacerbated lung inflammation and proinflammatory cytokines in an ozone exposure model. Similarly, challenge with influenza A virus leads to increased virus infiltration, lymphocytic bronchiolitis and reduced survival of Pgam5−/− mice. This pathway, which we term ‘oxeiptosis’, is a ROS-sensitive, caspase independent, non-inflammatory cell death pathway and is important to protect against inflammation induced by ROS or ROS-generating agents such as viral pathogens.