Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system

Abstract

Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.