Tryptophan Metabolism as a Pharmacological Target

Abstract

L-Tryptophan is an essential amino acid required for protein synthesis. It undergoes an extensive and complex metabolism along several pathways, resulting in many bioactive molecules acting in various organs through different action mechanisms. Enzymes involved in its metabolism, metabolites themselves, or their receptors, represent potential therapeutic targets, which are the subject of dynamic research. Disruptions in L-tryptophan metabolism are reported in several neurological, metabolic, psychiatric, and intestinal disorders, paving the way to develop drugs to target it. This review will briefly describe L-tryptophan metabolism and present and discuss the most recent pharmacological developments targeting it. Highlights L-Tryptophan (L-Trp) is metabolized via three pathways: the indole pathway in bacteria and the kynurenine and serotonin pathways in mammalian cells. Disruptions in L-Trp metabolism are reported in several diseases making L-Trp metabolism a promising therapeutic target. Manipulating L-Trp metabolism is an attractive therapeutic strategy. Key enzymes of L-Trp metabolism are targets of inhibitors currently undergoing clinical trials in cancerology, dermatology, and gastroenterology. Serotonin and aryl hydrocarbon receptor (AhR) receptors are targeted in the treatment of gastrointestinal diseases, inflammation, and many cancers. Next-generation probiotics producing indoles are being developed for their ability to activate AhR in the gut.

Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor

“…Impaired production of AhR ligands has been observed in the intestinal microbiota of patients suffering from inflammatory bowel disease ( 45 ) and celiac disease ( 22 ). Given the critical impact of dietary AhR ligands on ILC3 numbers and the maintenance of barrier integrity, diet supplementation with AhR ligands, or AhR ligand-producing bacteria, is an attractive strategy to improve the treatment of inflammatory gastrointestinal diseases ( 24 ). However, a better understanding of the role of nutritional AhR ligands on the immune homeostasis of distant tissues and on myeloid cells will be essential to optimize these therapeutic approaches.…”

“…In addition, after 4 weeks of tryptophan-low diet, the abundance of Lactobacillus reuteri is also decreased in the stomach ( 15 ). Of note, tryptophan is metabolized in the gut not only into AhR ligands by microbiota, but also through the serotonin and kynurenine pathways by host cells ( 5 , 24 ). Whether the observed alterations in microbiota composition are entirely dependent on changes in AhR ligands availability remains to be confirmed.…”

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

“…In contrast, Cheng and colleagues recently set out to evaluate the existence of a causal relationship between metabolites of the tryptophan pathway and kidney function using a bidirectional Mendelian randomization analysis, and they revealed that the increased blood levels of tryptophan metabolites were a consequence rather than a cause of a reduced eGFR [ 24 ]. However, it is becoming clear that IDO has a complex role in chronic inflammatory and metabolic diseases and remains an interesting therapeutic target [ 25 ], however, in-depth knowledge about its regulation and interconnection to other enzyme systems is essential in the development of effective therapies [ 26 ].…”

Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism

“…It is especially difficult to establish candidate probiotic strains as thriving members of complex the gut microbiome ecosystem, so the current paradigm of probiotic therapy could be transient at best. Currently, promising studies are exploring small molecules that act directly on host proteins such as IDO and AHR (69). A key hallmark of IBD is dysbiosis of the gut microbiome, or alteration of the abundance and distribution of gut bacteria (70,71).…”