Tryptophan Metabolism (Part B) - Why it matters #4

SUMMARY

1.??????Introduction

2. ?????Nutraceutical means of action

3.??????Most relevant use cases

4.??????Conclusion

5.??????Scientific references

1. INTRODUCTION

Tryptophan metabolism is involved in many physiological phenomena. It is essentially composed of 3 catabolic axes: the kynurenic, indolic and serotoninergic axis. This network of enzymatic reactions is a key element of our health: it participates in immune homeostasis, digestion and mood stability.

Moreover, research shows that diet and phytonutrients can influence tryptophan metabolism. This correlation with nutrition could therefore provide innovation opportunities for nutraceutical brands in search of cutting-edge formulas with long-lasting effectiveness.

In this second part of the article about Tryptophan metabolism (Part A available HERE), we examine various intervention possibilities by identifying the active ingredients that could positively influence said metabolism, while giving specific examples of applications where this influence could be particularly relevant.

2. NUTRACEUTICAL MEANS OF ACTION

2.1. ... on the kynurenic axis

As previously mentionned in the first part of the article, the kynurenine pathway can be a double-edged sword. It is able, on the one hand, to promote immune homeostasis (via AhR pathway activation by some of its metabolites), while generating a supply of NAD precursors. On the other hand, the kynurenine axis consumes a significant portion of the available tryptophan and generates quinolinic acid, a metabolite whose excessive accumulation can promote neuroinflammation.

While the occasional stimulation of this pathway can activate the negative feedback loop that helps restoring immune homeostasis, its continuous and excessive stimulation (notably in cases of chronic inflammation) can increase the risk of serotonergic deficit and neuroinflammation.

Conversely, complete inhibition of the kynurenine pathway can cause a decrease in AhR-activating metabolites, thus leading to an alteration of immune homeostasis, while depriving the organism of a source of NAD (although most of it is produced through other metabolic pathways) in the process.

Luckily, diet, microbiota and phytonutrients allow a fine modulation of this phenomenon. Some phytonutrients are even able to partially inhibit IDO (the limiting enzyme of the kynurenic pathway) and stimulate the AhR pathway at the same time. This is especially true in the case of Korean ginseng (Panax ginseng) whose specific phytonutrients both show inhibitory properties against IDO [1-3] and AhR activating potential [4-7]. The same can be said about Baikal Lake Skullcap (Scutellaria baicalensis): its specific flavonoids have been demonstrated to inhibit IDO [8] and Baicalein has been shown to activate the AhR pathway [9, 10]. For more information on baicalein, read our dedicated article HERE.

Some probiotics have also shown potential to limit IDO [11], in particular through the production of Butyrate, which is a known IDO inhibitor [12, 13]. The use of postbiotics such as Sodium Butyrate or prebiotics with demonstrated potential to promote the proliferation of butyrate-producing bacteria (e.g. Faecalibacterium prausnitzii), such as Anagenix Ltd 's gold kiwifruit ingredient Livaux, could therefore be contemplated in this area.

When selecting a probiotic strain, however, one should be aware that some strains appear to stimulate the kynurenic pathway rather than to inhibit it [14].

2.2. ... on the indolic axis

The indolic pathway is essentially dependent on microbiotic balance. Its primary interest is its contribution to the production of indole derivatives that promote immune homeostasis through AhR stimulation. In cases of indolic imbalance (through dysbiosis), a decreased activation of the AhR pathway is observed, and in some cases, even an increased production of potentially problematic metabolites such as indoxyl sulfate (also called indican).

The first way to act on this axis is to modulate microbiotic balance. To do this, prebiotics, probiotics and postbiotics can be of interest. In addition, numerous phytonutrients also show potential to promote microbiotic balance, something we will cover in detail in a future article. Among these, Korean ginseng (Panax ginseng) phytonutrients are once again of particular interest [15]. Another good example of this is pomegranate (Punica granatum), especially extracts rich in ellagic acid. This particular compound has indeed been identified as a strong stimulator of indole-3-pyruvate (IPA) production, a beneficial indole derivative [16]. Given the microbiotic benefits of punicalagins (a type of ellagitannins and precursors of ellagic acid), extracts concentrated in these precursors could also be a good option.

At first glance, direct supplementation of indole derivatives such as indole-3-carbinol from cruciferous vegetables (from broccoli for instance), may appear as a simple and viable solution to regulate of the indole axis [17]. However, it should be noted that this approach leads to a specific activation of the AhR pathway specifically in the small intestine (and not at a systemic level), which leads to a completely different physiological impact [18]. This approach should therefore be reserved for very specific cases.

2.3. ...on the serotoninergic axis

Serotonin metabolism ensures a sufficient supply of peripheral and central serotonin. It also ensures the production of melatonin through the pineal gland. It is therefore not surprising that numerous mood and sleep disorders are associated an imbalance of this axis. A healthy serotoninergic balance depends both on precursor availability (tryptophan in particular) and on the activity of enzymes involved in the synthesis and degradation of serotonin.

With regard to precursor availability, tryptophan supplementation can be considered a viable solution; however, this strategy could prove problematic for people whose kynurenic pathway is excessively activated. In order to ensure a sufficient and safe supply of precursors, supplementation with 5-hydroxytryptophan (5-HTP) is usually preferred. Like tryptophan, 5-hydroxytryptophan is a precursor of serotonin, with the difference that it cannot be used by the kynurenic pathway. This way can 5-HTP be used for the serotonergic pathway preferentially. It should also be noted that 5-HTP supplementation appears to have a beneficial impact on microbiotic balance (and therefore a potential indirect effect on the indole axis) [19].

The enzymatic activity of the serotoninergic axis can also be modulated. Several phytonutrients have indeed been shown to partially inhibit monoamine oxidase (essentially the MOA-A for serotonin), the enzyme responsible for the degradation of several neurotransmitters, among which serotonin. Many phytonutrients have been identified as partial inhibitors of this enzyme [20].

3. MOST RELEVANT USE CASES

As previously mentioned, tryptophan catabolism is linked to both neurological and inflammatory processes. In general, an imbalance in this metabolism can lead to two main consequences:

• A serotonergic deficit: the kynurenic axis "monopolizes" the absorbed tryptophan and limits its availability to the serotonergic axis. This deficit can lead to various health issues, ranging from mood to digestive disorders and altered sleep quality.
• A chronic inflammatory state: caused by either excessive production of quinolinic acid (neuroinflammation) through the kynurenic axis or by insufficient production of tolerogenic indole derivatives (or in some cases excessive production of toxic indoxyl sulfate), an imbalance in tryptophan catabolism can lead to chronic low-grade inflammation, with all the health issues that this implies.

In the context of Nutraceuticals, addressing the balance of these 3 metabolic pathways can therefore prove relevant for a diversity of product categories and offer numerous opportunities for innovation. Among these, here are two examples of innovative concepts with great potential for application :

3.1. The concept of "Mental Load"

All too often, the nutraceutical industry addresses the issue stress through the dual strategy of combatting anxiety symptoms and stimulating relaxation. The formulas developed through this approach therefore focus on GABAergic actions (Benzodiazepine-like), and sometimes on the inhibition of serotonin reuptake (SSRI-like). While these methods offer consumers a short-term solution with quickly perceptible benefits, using the metabolic approach would lead to a sustained resilience to stressful conditions. The two approaches could therefore be complementary.

According to an IPSOS study, nearly one in every four women suffers from daily excessive mental load [21]. Our modern lifestyles require resilience, whether it is in terms of stress management, maintenance of cognitive performance or general dynamism. Ensuring the balance of tryptophan metabolism can limit the risk of neuroinflammation while promoting serotonin "availability"; two key elements of mental endurance.

Such a formula would be particularly interesting for seasonal depression, a common phenomenon associated with decreased photoperiod during cold seasons. The lack of luminosity leads to a higher production of melatonin which, in turn, tends to deplete serotonin stocks and increases the risk of developping mood disorders.

To address this, the following combination could be considered; NEURACTIVIN, a Korean red ginseng with a specific molecular profile clinically demonstrated to support mental endurance, with melon (Cucumis melo) superoxide dismutase - a clinically demonstrated ingredient for stress management (Extramel / BIONOV / Robertet Group ) - and a 5-HTP-rich Griffonia extract (Griffonia simplicifolia).

3.2. The concept of "Inflammatory Fatigue"

Periods of illness and surgeries carry a significant risk of "inflammatory fatigue", which can can then lead to a form of asthenia. Promoting a balanced tryptophan metabolism could be a great (although partial) solution to support the body's recovery, and mental recovery in particular.

Once again, the use of NEURACTIVIN could be considered, but this time in combination with a pomegranate (Punica granatum) extract, rich in ellagic acid, and another from Lake Baikal skullcap (Scutellaria baicalensis), rich in baicalein, both of which would allow an emphasis on the inflammatory dimension.

4. CONCLUSION

Tryptophan is an essential amino acid and a key component to the proper functioning of our body, in particular for the production of peripheral or cerebral serotonin. Tryptophan supplementation should therefore lead to significant well-being benefits for people suffering from serotonin deficiency. However, as is often the case when it comes to Human Health, things are not so simple and numerous factors come into play. Like many other physiological mechanisms, tryptophan metabolism is a subtle and complex system, the intricacies of which are still being uncovered.

For this reason should the elaboration of a nutraceutical formula require a thourough consideration of all (or at least a maximum) involved factors. Only this way can we guarantee optimal efficiency to the consumer and be part of an innovative cutting-edge approach, regardless of the product's health objective.

5. SCIENTIFIC REFERENCES

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[21] https://www.ipsos.com/sites/default/files/ct/news/documents/2018-02/o2_chargementale_infographie.pdf