Role of intestinal tryptophan metabolism in atherosclerosis

Abstract

The obesogenic diet (HFD) is responsible for intestinal dysbiosis observed especially in obesity. Indoleamine 2,3-dioxygenase 1 (IDO) is the main enzyme responsible for the degradation of Tryptophan (Trp), an essential amino acid, in extra-hepatic organs. Our team has shown that the total invalidation of IDO in the presence of HFD contributes to the reduction of metabolic complications. However, the specific role of intestinal IDO locally in the gut as well as its systemic effects on the development of atherosclerosis are unknown. Study of the impact of HFD (High Fat Diet) and HC (High Cholesterol), in the context of a specific invalidation of IDO in intestinal epithelial cells (IEC) on intestinal homeostasis and atherosclerosis. Mice genetically deficient for IDO in IEC and for LDLr (low density lipoprotein receptor) were created. They were subjected to HFD + HC or HC diet for 8 or 13 weeks, to develop atherosclerosis. Feces were collected to characterize microbiota. The heart and the aorta were harvested to analyze the development of atheromatous plaques as well as the inflammatory infiltrate. The invalidation of IDO in IEC contributes to a significant decrease in its expression in the intestine, indicating the importance of IEC in the intestinal expression of IDO. This invalidation in HFD + HC condition but not HC condition contributes to a significant increase in the size of atherosclerotic plaques in the aortic sinus as well as lymphocyte accumulation within the plaques, without any significant changes in plasma cholesterol. It also contributes to dysbiosis as well as intestinal inflammation. The expression of IDO in IEC has a local protective role at the intestine and on the systemic development of atherosclerosis, in the HFD condition. We will continue this project by determining the impact of other pathways of intestinal tryptophan catabolism on atherosclerosis.