Gut Commensals Regulate the Intestinal Kynurenine Pathway

The kynurenine pathway (KP) of tryptophan metabolism shapes host immunity and is implicated in inflammatory, malignant, and neurodegenerative diseases. Although it is well known that inflammation influences KP activity, whether and how gut microbiota regulates KP in the intestine remains unclear. Here, we find that in allogeneic hematopoietic cell transplant patients, the kynurenine-to-tryptophan ratio tracks plasma neopterin, whereas intestinal levels do not, suggesting that local KP regulation is not explained by inflammation alone. In mice, targeted microbiota perturbation downregulates intestinal expression of indoleamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme of the KP, while microbiota restoration reversed this effect. Computational analyses associate Lachnospiraceae and Oscillospiraceae with colonic IDO1 in mice and inflammatory bowel disease cohorts. In vitro experiments support a mechanism whereby microbiota perturbation alters host absorption of the vitamin E isoform, γ-tocotrienol, which impacts IDO1 expression. Our findings support that the gut microbiota controls colonic KP through micronutrient absorption.