Tryptophan Metabolic Pathways and Brain Serotonergic Activity: A Comparative Review

Abstract

The essential amino acid L-tryptophan (Trp) is the precursor of the monoaminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Numerous studies have shown that elevated dietary Trp has a suppressive effect on aggressive behavior and post-stress plasma cortisol concentrations in vertebrates, including teleosts. These effects are believed to be mediated by the brain serotonergic system, even though all mechanisms involved are not well understood. The rate of 5-HT biosynthesis is limited by Trp availability, but only in neurons of the hindbrain raphe area predominantly expressing the isoform TPH2 of the enzyme tryptophan hydroxylase (TPH). In the periphery as well as in brain areas expressing TPH1, 5-HT synthesis is probably not restricted by Trp availability. Moreover, there are factors affecting Trp influx to the brain. Among those are acute stress, which, in contrast to long-term stress, may result in an increase in brain Trp availability. The mechanisms behind this stress induced increase in brain Trp concentration are not fully understood but sympathetic activation is likely to play an important role. Studies in mammals show that only a minor fraction of Trp is utilized for 5-HT synthesis whereas a larger fraction of the Trp pool enters the kynurenic pathway. The first stage of this pathway is catalyzed by the hepatic enzyme tryptophan 2,3-dioxygenase (TDO) and the extrahepatic enzyme indoleamine 2,3-dioxygenase (IDO), enzymes that are induced by glucocorticoids and pro-inflammatory cytokines, respectively. Thus, chronic stress and infections can shunt available Trp toward the kynurenic pathway and thereby lower 5-HT synthesis. In accordance with this, dietary fatty acids affecting the pro-inflammatory cytokines has been suggested to affect metabolic fate of Trp. While TDO seems to be conserved by evolution in the vertebrate linage, earlier studies suggested that IDO was only present mammals. However, recent phylogenic studies show that IDO paralogues are present within the whole vertebrate linage, however, their involvement in the immune and stress reaction in teleost fishes remains to be investigated. In this review we summarize the results from previous studies on the effects of dietary Trp supplementation on behavior and neuroendocrinology, focusing on possible mechanisms involved in mediating these effects.

Composition of Gut Microbiota in Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

“…Returning to the microbiota, animal studies have reported that the serotonergic systems in the brain are influenced by gut bacterial composition, which in turn leads to GI problems and emotional disorders [60,63]. It is therefore expected that when the abundance of Trp-metabolizing bacteria such as Bacteroides and Clostridium increases, serotonin concentrations also increase as a result of their metabolic activity [64,65]. Meanwhile, lower levels of glutathione, homocysteine, methionine, and S-adenosylmethionine have been observed more in ASD children than in neurotypical children [66,67].…”

Antidepressant-like effects of kynurenic acid in a modified forced swim test

“…It may also be assumed that the icv KYNA injection alters the KYN pathway balance, resulting in increased nicotinamide adenine dinucleotide (NAD + ), which is responsible for the feedback inhibition of TDO. Thus it facilitates the shunt of TRP metabolism from the KYN pathways toward the SER pathways to increase SER production [10].…”

Rickettsial pathogen uses arthropod tryptophan pathway metabolites to evade reactive oxygen species in tick cells

“…Initial studies were focused on the characterisation of kynurenine pathway in the biogenesis of nicotinamide adenine dinucleotide (NAD) (Badawy, 2017). However, recent studies link kynurenine pathway with neurodegenerative diseases, tumour proliferation, inflammation, immunity and depression (Badawy, 2017;Davis & Liu, 2017;Höglund, Øverli, & Winberg, 2019;Zhuravlev et al, 2016). Furthermore, L-tryptophan pathway was also reported to have a role during infections caused by virus like HIV (Lyons, Tovar-y-Romo, Thakur, McArthur, & Haughey, 2014) and bacteria like Rickettsia conorii (Feng & Walker, 2000) and A. phagocytophilum (Taank et al, 2017).…”