Tryptophan: From Diet to Cardiovascular Diseases

Abstract

Cardiovascular disease (CVD) is one of the major causes of mortality worldwide. Inflammation is the underlying common mechanism involved in CVD. It has been recently related to amino acid metabolism, which acts as a critical regulator of innate and adaptive immune responses. Among different metabolites that have emerged as important regulators of immune and inflammatory responses, tryptophan (Trp) metabolites have been shown to play a pivotal role in CVD. Here, we provide an overview of the fundamental aspects of Trp metabolism and the interplay between the dysregulation of the main actors involved in Trp metabolism such as indoleamine 2, 3-dioxygenase 1 (IDO) and CVD, including atherosclerosis and myocardial infarction. IDO has a prominent and complex role. Its activity, impacting on several biological pathways, complicates our understanding of its function, particularly in CVD, where it is still under debate. The discrepancy of the observed IDO effects could be potentially explained by its specific cell and tissue contribution, encouraging further investigations regarding the role of this enzyme. Thus, improving our understanding of the function of Trp as well as its derived metabolites will help to move one step closer towards tailored therapies aiming to treat CVD.

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

“…In the kynurenine pathway (KP), which accounts for around 95% of tryptophan catabolism, tryptophan is oxidized to N-formylkynurenine (NFK) mainly by tryptophan 2,3-dioxygenase (TDO) located in the liver [18,74]. It is the first and rate-limiting step in this pathway and its activity is regulated by steroids, including cortisol, and systemic levels of tryptophan [75].…”

“…It is further metabolized by numerous enzymes into its derivatives such as anthranilic acid, kynurenic acid and quinolinic acid. The latter is converted into nicotinamide adenine dinucleotide (NAD) in a final step of KP [18,74].…”

“…Gut bacteria use this amino acid for their own needs, simultaneously producing biologically active metabolites that can influence the host's homeostasis. Symbiotic microorganisms directly convert tryptophan to indole, skatole, indole-3-acetic acid (IAA), IPA, and indole-3-aldehyde (IAld) [9,18,73].…”

“…Microbial pathway of IPA production is primarily controlled by tryptophan aminotransferase (TAA, aromatic amino acid aminotransferase, ArAT) [73,89]. Additionally, it has been also established that bacterial tryptophanase enables synthesis of IPA in the gut [18].…”

“…Until now, the biological actions of indole-3-propionic acid (IPA), another microbiota derived metabolite of tryptophan, have not been properly reviewed in the scientific literature. A review of articles summarizing the impact of tryptophan metabolism on cardiovascular system homeostasis has recently been published, however; the main focus of that paper was kynurenine-and the serotonin pathway [18]. The aim of our study is to provide a comprehensive review of the physiological roles of IPA, and changes in its synthesis in neurological, gastrointestinal and cardiovascular diseases.…”