Tryptophan Metabolism (Part A) - Why it matters #2
SUMMARY
1. Introduction
2. The 3 catabolic pathways of Tryptophan
2.1. The serotonergic axis
2.2. The kynurenic axis
2.3. The indolic axis
3. Conclusion
4. Scientific references
1. INTRODUCTION
Tryptophan is an essential amino acid derived from food sources such as animal proteins, bananas, oats, dried fruits or chocolate. It is the lowest concentration amino acid in the body, but fulfills a great number of functions in the body. These include protein biosynthesis, which alone consumes 95% of the absorbed tryptophan [1], but also the production of key regulatory molecules in the body.
Popularized by nutraceutical formulas addressing mood and sleep stability, tryptophan is best known for its key role in the neuroendocrine metabolism. It is the precursor for serotonin synthesis (also known as 5-HT) and melatonin (whose synthesis intermediate is serotonin), two neuroactive molecules that are essential for emotional regulation and the circadian cycle [2].
And while the serotonergic metabolism is crucial for physiological balance, it is far from being the only metabolic pathwath to carry potent health implications. In fact, serotonin synthesis is only a minor function of tryptophan catabolism: it is an essential component of mammalian physiology that is also involved in the function of many mechanisms related to the nervous system, immunity, gastrointestinal tract and metabolism [3].
In this first part of the article, we lay the foundations of the 3 main metabolic pathways in which tryptophan is involved, before addressing their implications and applicative potential for gut-brain axis nutraceutical developments in a second part.
2. THE 3 CATABOLIC PATHWAYS OF TRYPTOPHAN
While protein biosynthesis alone consumes about 95% of the available substrate (anabolism), the remaining intestinal tryptophan is involved in 3 important catabolic axes [3-5]:
2.1. The serotonergic axis
Serotonin plays a critical role in the interactions between the gastrointestinal tract and the central nervous system; its site-specific synthesis in two different parts of the body – namely the intestine and the brain - is a determinant of its function.
It is estimated that 95% of body serotonin (5-HT) is synthesized in enterochromaffin cells (ECCs) in the intestinal epithelium by the action of tryptophan hydroxylase (TpH1). TpH1 enzymes metabolize tryptophan to the intermediate 5-hydroxytryptophan (5-HTP) and then to serotonin [3-4, 6-7].
Peripheral serotonin synthesized in the gut is involved in many functions of the gastrointestinal tract, including motility and peristalsis (transit), secretion and vasodilation, and nutrient absorption [1, 3-5, 7]. The inability of intestinal serotonin to cross the blood-brain barrier is what distinguishes it from brain serotonin. However, it should also be noted that the pineal gland is not protected by this barrier; peripheral serotonin can therefore contribute to the synthesis of melatonin by this gland. As a reminder, Melatonin - also knows as the sleep hormone - is responsible for the regulation of the circadian cycle [3-4].
As previously mentioned, intestinal serotonin does not cross the blood-brain barrier under physiological conditions; it is its precursor 5-HTP that is transported to the brain for in-situ conversion to brain serotonin, crucial for neurological function.
In the brain, serotonin acts as a neurotransmitter and neuromodulator in the regulation of emotional state (anxiety, energy, well-being).
2.2. The kynurenic axis
The kynurenic axis is the catabolic pathway that consumes the most tryptophan: it is estimated that it metabolizes about 90% of the available substrate on its own [1]. Active in many cell types throughout the body, in particular immune cells, this metabolic pathway is crucial for:
Although its main role is to promote immune homeostasis, the kynurenine pathway is paradoxically more solicited in cases of chronic inflammation. In the context of inflammation, the expression of TDO enzymes in the liver and IDO1 in tissues (both limiting enzymes of the kynurenic pathway) is activated by increased levels of inflammatory cytokines and corticosteroids, including interleukins such as IL-1 and IL-6 [4]. TDO and IDO1 activate/catabolize the conversion of tryptophan to kynurenic acid derivatives, which in turn trigger an anti-inflammatory and immunosuppressive response to promote immunotolerance – therefore promoting a return to homeostasis [5].
It is also worth mentioning that several studies have demonstrated the direct interaction between the microbiota and the expression of the limiting enzyme of the kynurenic pathway, IDO1. Indeed, while some pathogens in the microbiota stimulate IDO1, other microorganisms are able to suppress its expression [1]. IDO1 therefore modulates the availability of tryptophan to the gut microbiota, converting it into antimicrobial intermediates such as kynurenine.
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IDO1 itself may also exert a regulatory effect on the inflammatory status (pro- and anti-inflammatory balance), as well as influence host-microbiota interactions through the production of kynurenic derivatives with antimicrobial activity [1].
This tolerogenic activity is due to the fact that several metabolites of the kynurenic pathway are aryl-hydrocarbon receptors (AhR) antagonists. AhR pathway activation promotes the production of immune cells, particularly those related to immunotolerance, and supports the Treg/Th17 ratio, among other things. It is also involved in the production of interleukins such as IL-22 that promote intestinal barrier (IB) integrity [1, 3-5].
However, stimulation of this pathway can also lead to the production and accumulation of neurotoxic or pro-inflammatory intermediates, such as quinolinic acid, that can sustain the inflammation phenomenon. Prolonged chronic inflammation, aggravated by the overexpression of kynurenic pathway activating enzymes and reflected in an increased kynurenine/tryptophan ratio, has ideed been correlated with various (auto)inflammatory diseases, including IBS/IBD, cancer and also neurodegenerative disorders [1].
2.3. The indolic axis
Finally, the indole pathway involves the catalysis of tryptophan conversion into indole and indole derivatives (IAld, IAA, IPA, IAAId, ILA...) by the intestinal microbiota [3-4, 9]. It is carried out by 85 species of indole-producing bacteria [9].
Indole metabolism produces a variety of local and systemic pleiotropic effects, mainly at the intestinal level but also throughout the body by circulation of the derivatives, in the liver in particular. On the one hand, several indolic derivatives can regulate the maintenance of intestinal homeostasis (intestinal barrier function and immunity) and on the other hand modulate hepatic metabolism [9] and the synthesis pathways of various neurotransmitters, neurotoxic factors and antimicrobial metabolites [1].
Like some kynurenic derivatives, some of these indole derivatives are AhR agonists [4] and therefore promote immunotolerance and the integrity of the intestinal barrier through the same mechanism [9].
In contrast, significant indole synthesis (and not of the previously mentioned metabolites) can turn out to be problematic: it can serve as a substrate for the metabolization of indoxyl sulfate (also called indican). This molecule may not only trigger pro-inflammatory and pro-oxidative mechanisms [10], but also lead to the development of liver and cardiovascular pathologies, among which metabolic syndrome [4]. High levels of indoxyl sulfate in the brain have also been correlated with psychiatric symptoms (anxiety, depression) and neurodevelopmental (autism spectrum) and neurodegenerative disorders (Parkinson's) [10].
Moreover, in a context of chronic intestinal inflammation, local accumulation of Indole-3-lactic acid (ILA) has been shown to be detrimental to epithelial autophagy and susceptibility to colonic injury. ILA could even promote the progression of colitis symptoms in mice [9].
3. CONCLUSION
Tryptophan metabolism goes far beyond the synthesis of neuroactive substances: its microbiotic and endogenous pathways produce a multitude of derivatives with both local (gut) and systemic action. Some of these derivates are involved in the crucial mechanisms of immune/inflammatory response, metabolic regulation and even cellular energy production.
Tryptophan is thus a versatile and essential substrate for many aspects of human physiology: preserving the function of its metabolic pathways is a key factor in maintaining a healthy inflammatory and neurological status, and even longevity (by combating the age-related decline of NAD+) [8].
Indeed, tryptophan deficiency is correlated with various mood disorders and depression as well as inflammatory diseases such as IBD [5]. Although the link remains to be demonstrated, the involvement of the gut microbiota in tryptophan metabolism could also partly explain the recurrent link between digestive disorders and neurological symptoms.
While it is now commonly accepted that the relationship between the microbiota and its host significantly affects the neurological, immune and even hepatic spheres [9-10], there are still many mechanisms that need to be elucidated to understand them. Dysbiosis as well as intestinal permeability are indeed proven risk factors for immune hyperreactivity and chronic inflammation and can lead to significant neurobehavioral and metabolic disorders [9].
These observations thus seem to corroborate the involvement of tryptophan in the bidirectional communication between the gut and the brain and the central role of the microbiota in this mediation.
In-depth investigation of the interactions between the microbiota and tryptophan availability could reveal new preventive leads or therapeutic strategies in the field of inflammatory/autoimmune and neurodegenerative diseases as well as in mitochondrial function and aging.
Stay tuned for the second part of this article on Tryptophan, in which we will discuss the implications of this metabolic versatility on human health and the interest of phytonutrients in the regulation of these mechanisms. Something to inspire nutraceutical formulas that capitalize on this gut-brain axis.
4. SCIENTIFIC REFERENCES
[1] Dehhaghi M, Kazemi Shariat Panahi H, Guillemin GJ (2019) - “Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status”. Int J Tryptophan Res. 2019 Jun 19;12:1178646919852996.
[2] Martin CR, Osadchiy V, Kalani A, Mayer EA (2018) – “The Brain-Gut-Microbiome Axis”. Cell Mol Gastroenterol Hepatol. 2018 Apr 12;6(2):133-148.
[3] Modoux M, Rolhion N, Mani S, Sokol H (2021) – “Tryptophan Metabolism as a Pharmacological Target”. Trends Pharmacol Sci. 2021 Jan;42(1):60-73.
[4] Agus A, Planchais J, Sokol H (2018) – “Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease”. Cell Host Microbe. 2018 Jun 13;23(6):716-724.
[5] Grifka-Walk HM, Jenkins BR, Kominsky DJ (2021) - “Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism”. Front Immunol. 2021 Jun 4;12:653208.
[6] El-Merahbi, R., Löffler, M., Mayer, A., & Sumara, G. (2015) – “The roles of peripheral serotonin in metabolic homeostasis”. FEBS letters, 589(15), 1728-1734.
[7] Kennedy PJ, Cryan JF, Dinan TG, Clarke G (2017) – “Kynurenine pathway metabolism and the microbiota-gut-brain axis”. Neuropharmacology. 2017 Jan;112(Pt B):399-412.
[8] Castro-Portuguez R, Sutphin GL (2020) – “Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan”. Exp Gerontol. 2020 Apr;132:110841.
[9] Li X, Zhang B, Hu Y, Zhao Y (2021) – “New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases”. Front Pharmacol. 2021 Dec 13;12:769501.
[10] Brydges CR, Fiehn O, Mayberg HS, Schreiber H, Dehkordi SM, Bhattacharyya S, Cha J, Choi KS, Craighead WE, Krishnan RR, Rush AJ, Dunlop BW, Kaddurah-Daouk R (2021) – “Mood Disorders Precision Medicine Consortium. Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature”. Sci Rep. 2021 Oct 25;11(1):21011.