Tryptophan metabolism in health and disease- implications for non-communicable diseases

Tryptophan, an essential amino acid, is primarily metabolized through four key pathways: the kynurenine pathway, serotonin pathways, indole pathways and interleukin 4-induced gene 1 (IL-4I1) pathways. Dysregulation of tryptophan metabolism is implicated in various non-communicable diseases including psychiatric disorders, inflammatory and autoimmune diseases, as well as metabolic diseases. The dogma in the field is that tryptophan is metabolized via the kynurenine pathway in the liver mainly by indoleamine 2,3-dioxygenase 1/2 (IDO 1/2) and Tryptophan dioxygenase 2 (TDO2) enzymes. However, there is growing evidence demonstrating that IL-4I1 and tryptophanase are also crucial tryptophan catabolizing enzymes resulting in metabolites that activate aryl hydrocarbon receptor (AhR) and modulate immune responses. Tryptophan metabolism is crucial in cellular, tissue and organismal function and its disruption is linked to conditions such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and psychiatric disorders like depression, anxiety and metabolic diseases such as obesity and Type 2 diabetes. It is unclear though whether only specific tryptophan pathways are associated with disease or there is a level of redundancy. Some key metabolites from tryptophan catabolism can come from multiple pathways, with opposing or converging effects on cellular functions. This review will explore the critical role of tryptophan metabolism in health and diseases, focusing on its implications in non-communicable diseases. Importantly, this review will focus on recent developments in tryptophan metabolism and strengthen the argument for a revised schematic tryptophan catabolic pathway.