Dietary Tryptophan Augments Cancer-Associated Venous Thrombosis Mitigated by Indoleamine 2,3-Dioxygenase 1 Inhibition.

Abstract

Studies related to cardio-oncology remain of high priority, considering that venous thromboembolism (VTE) in cancer survivors is the second most common cause of death. While diet-derived metabolites are emerging contributors to VTE, the influence of specific dietary components, their underlying mechanisms, and means to mitigate cancer-associated VTE remain poorly investigated. This point is important as population studies point to a protein-rich diet associated with VTE. Leveraging a new colon cancer-VTE mouse model, we show that an imbalanced protein-rich diet augments venous thrombogenicity in tumor-bearing mice. Further probing showed that tryptophan in the diet induces a procoagulant venous wall characterized by the upregulation of tissue factor, plasminogen activator inhibitor-1 and von Willebrand Factor, and downregulation of thrombomodulin. Targeted metabolomics of sera from tumor-bearing mice revealed a pattern consistent with increased biogenesis of kynurenine (Kyn) and its suppressed catabolism, despite equal diet consumption in all groups. Kyn levels positively correlated with venous clots. Indolamine-2,3-dioxygenase (IDO1) is a key rate-limiting enzyme converting tryptophan to Kyn. Sera and the inferior vena cava of tumor-bearing mice showed greater IDO1 activity and protein level, respectively. A specific IDO1 inhibitor reduced serum levels of Kyn, restored the balance of pro- and anti-coagulant factors in the venous endothelium, and significantly suppressed venous thrombogenicity in tumor-bearing mice. Taken together, our results uncovered a prothrombotic effect of a protein or tryptophan-rich diet in a syngeneic colon cancer model, which is significantly attenuated by an IDO1 inhibitor.