Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology: The Impact of Nutrition and Lifestyle

In recent years, tryptophan metabolism emerged as a central hub for the metabolic control of immunological and neuropsychological processes. Several kynurenine downstream metabolites are neuroactive, and some are even able to cross the blood-brain barrier (BBB) [1]. A deeper insight into the relationship between tryptophan availability and systemic responses may not only be helpful for disease monitoring or therapeutic interventions, but also for the better understanding of the “immune-brain” loop, and thus how immunological status impacts behavior, stress, mood and thought, cognition, and, moreover, the development of psychiatric illness.

The breakdown of tryptophan along the kynurenine axis is accelerated in a variety of inflammation-associated disorders. Chronic inflammatory disorders, in particular, are frequently accompanied by a decreased quality of life, mood-lowering, and depression, but also neurocognitive symptoms [2, 3]. In addition, proinflammatory mechanisms contribute to the pathophysiology of major depression, including cell-mediated responses. Alterations of the serotonergic, noradrenergic, and glutamatergic neurotransmission may be provoked by the direct effects of cytokines on neurotransmitter storage and/or release, but also by indirect mechanisms such as changes of metabolite concentrations as reported, e.g. for several tryptophan catabolites [4, 5]. Changes in kynurenine and downstream metabolites have also been observed in a variety of central nervous system (CNS) disorders, including AIDS-dementia complex, Huntington’s disease, Alzheimer’s disease (AD), and CNS infections [6-8].

Moreover, the modulation of the tryptophan-kynurenine pathway by immunological activation and stress is recognized as a mediator of environmental factors on cognition and behavior [9]. It becomes more and more evident that several lifestyle parameters influence these metabolic circuits. Importantly, the enzyme indoleamine 2,3-dioxygenase-1 (IDO-1), which catalyzes the first and rate-limiting step in tryptophan breakdown along the kynurenine axis, has been shown to be susceptible to modulation by dietary components, microbiome composition, and physical exercise [10-13].

The aromatic amino acid tryptophan is 1 of 9 essential amino acids, and is the least available of all proteinogenic amino acids. As such, tryptophan availability is an important factor in the control of protein biosynthesis. This may be one important reason why the immune system utilizes tryptophan starvation to restrict the unwanted proliferation of pathogens and malignant cells [14]. Activation of the tryptophan-degrading enzyme IDO-1 is an integral defense mechanism in the cell-mediated immune response, whereby the T helper type 1 (Th1) cytokine, interferon (IFN)-γ, is the main activating factor [15, 16]. IDO catalyzes the first and rate-limiting step of tryptophan breakdown to kynurenine, and the kynurenine-to-tryptophan ratio (Kyn/Trp) was proposed as an estimate of IDO enzyme activity in the early 1990s [17].

In addition to its function as a defense strategy, tryptophan metabolism plays a pivotal role in the regulation of the immune response, by slowing down T cell proliferation. Moreover, kynurenine triggers regulatory T cell (Treg) development, and some of the tryptophan catabolites such as 3-hydroxyanthranilic and quinolinic acid have been shown to selectively drive Th1 cells (but not Th2 cells) into apoptosis [18]. In this way, a negative feedback loop is established that prevents overwhelming immune reactions, and a status of immunotolerance can be achieved. Accordingly, in patients with an activated immune system, IDO activity can contribute to immunosuppression, especially in chronic conditions. Indeed, enhanced IDO-1 activity has been observed in the blood of patients suffering from infections like HIV-1, autoimmune pathologies like systemic lupus erythematosus, several malignancies, and cardiovascular (CV) and neurodegenerative disorders [2]. Furthermore, low tryptophan concentrations together with high levels of neopterin, a biomarker of oxidative stress and immune activation, were associated with shorter survival in patients suffering from cancer (e.g., colorectal cancer and malignant melanoma) [19, 20], and enhanced overall and disease-specific mortality in CV disease [21, 22].

Despite being so important for protein synthesis, most dietary tryptophan (> 95%) is fed into the kynurenine pathway [23], giving rise to a number of downstream metabolites, the absolute and relative concentrations of which vary among cell types due to different enzymatic repertoires [16]. Further changes occur in disease conditions [7, 24]. The importance of tryptophan in depressive disorders was already being promoted in the 1960s and treatment possibilities were explored [25, 26]. Further studies accumulated, reporting on the correlation of accelerated tryptophan breakdown with neurologic/neuropsychiatric symptoms in conditions of activated cellular immunity, e.g., in HIV-1-infected patients [27].

After the first and rate-limiting step of tryptophan conversion to kynurenine, the downstream catabolism may divide into different branches, leading to the formation of 3-hydroxykynurenine, anthranilic acid, or kynurenic acid (Fig. 1). Catabolism of 3-hydroxykynurenine can lead to the generation of picolinic acid, quinolinic acid, and nicotinamide.

Several of these metabolites are neuroactive. Kynurenic acid is able to block ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate glutamate receptors [28]. Quinolinic acid is excitotoxic due to its NMDA receptor agonistic effects [29, 30]. While the neuroprotective kynurenic acid is present mainly in astrocytes, neurotoxic 3-hydroxykynurenine and excitotoxic quinolinic acid are found in microglial cells [31]. Besides directly targeting neurotransmitter receptors, the tryptophan metabolites, in particular 3-hydroxykynurenine and 3-hydroxyanthranilic acid, are redox active, leading to further effects that impact brain physiology [31, 32]. Not surprisingly, several enzymes are considered as important druggable targets, also for CNS-related disorders (comprehensively reviewed elsewhere [7]).

Besides the manifold biological activities of tryptophan catabolites, activation of this pathway contributes to a nicotinamide nucleotide pool which is considered important in situations of dietary shortage, as under normal conditions food is the main source of this metabolite in mammals. Furthermore, kynurenine metabolites are interlinked with other metabolic pathways, e.g., picolinic acid is involved in the intestinal absorption of zinc and quinolinic acid regulates gluconeogenesis by blocking phosphoenolpyruvate [33]. Thus, the modulation of the tryptophan-kynurenine pathway can be suggested as an indicator for a coherent metabolic shift.

CNS concentrations of tryptophan derivatives are not isolated but linked to peripheral metabolite concentrations. For the transport of tryptophan into the brain, the leucine-preferring system L1 large amino acid transporter (LAT1) is utilized in competition with the large neutral amino acids (LNAAs) [34]. Fukui et al. [1] reported on the uptake of several tryptophan metabolites in rat brains: L-kynurenine is also transported by the L-system, and the same carrier mediates the uptake of 3-hydroxykynurenine, both competing with the brain transfer of L-leucine. Anthranilic acid is taken up by passive diffusion; this has also been shown for 3-hydroxykynurenine, kynurenic acid, and quinolinic acid, though less pronounced. While plasma protein-binding plays a role for several of the metabolites, this is not the case for quinolinic acid.

Tryptophan, L-kynurenine, and 3-hydroxykynurenine efficiently cross the BBB whereas serum concentrations of the more polar compounds quinolinic acid, kynurenic acid, and 3-hydroxyanthranilic acid are less relevant for brain pools in conditions with an intact BBB [1, 31]. A LAT1 independent efflux transport for kynurenine has only recently been described, although the transporter responsible here is not yet known [35]. Thus, kynurenine concentrations are not only controlled by influencing the metabolic rate (which is limited because the downstream processing machinery may be saturated, or the accumulating catabolites can become too toxic), but also through clearance mechanisms. The origin of tryptophan metabolites in a compartment may change in the presence of inflammatory stimuli, as was observed in gerbils with systemic or CNS inflammation by using labeled metabolites and comparing local formation and transport [36]. In addition to cytokine-mediated induction of enzymatic activity, it is hypothesized that there is a major impact of systemic inflammation on the function of the BBB.

Tryptophan is also the precursor of 5-hydroxytryptamine (serotonin), which is involved in the physiological regulation of several behavioral and neuroendocrine functions. In this way, enhanced IDO-1 activity may contribute to mood-lowering when tryptophan availability becomes low during periods of immune activation [37]. In addition, serotonin is accepted as a substrate by IDO-1. In conditions that provoke prolonged high IDO-1 activity, not only brain tryptophan but also serotonin may become destroyed. Unlike tryptophan, serotonin itself cannot pass the BBB. If the immune activation process takes place primarily outside the brain, decreased tryptophan availability due to the accelerated breakdown may contribute to serotonin deficiency in the brain. The effects on serotonergic neurotransmission may be somewhat retarded when compared to the decrease of plasma tryptophan, and then become more severe when the pool of stored serotonin is exhausted. However, special attention must be paid to immune activation processes that develop directly in the brain, e.g., viral infections with encephalitis, Guillain-Barré syndrome [38], and neuroborreliosis, or brain tumors.

The pineal gland-derived hormone melatonin is an end-product of the serotonin pathway, and it is important for the regulation of the circadian rhythm. Circadian malfunction is associated with seasonal affective disorder and mood disturbances, and treatment options based on the modulation of melatonin concentrations have been a topic of discussion [39]. Melatonin itself can promote IDO-1 activity [40], which may represent a negative-feedback loop probably involved in the regulation of the circadian rhythm.

Of note, serotonin was first discovered in the gut which is the major source for this neurotransmitter in the periphery. About 95% of serotonin is synthesized and stored in the gastrointestinal tract, where it acts as a paracrine messenger to modulate sensation, secretion, and motility, and is also involved in appetite control [41, 42].

Physiological concentrations of tryptophan and kynurenine are usually kept in a relatively narrow range by hepatic tryptophan dioxygenase (TDO). So far, little is known about the TDO regulation, besides its substrate activation and stabilization by tryptophan, hormonal induction by glucocorticoids, cofactor activation by heme, and feedback inhibition by NADPH [43]. Serum concentrations of tryptophan are in the range of 70 ± 10 µmol/L for males and 65 ± 10 µmol/L for females, as reported for a cohort of human healthy blood donors [44]. Gender-specific differences of about 15% are in agreement with earlier reports [45]. Kynurenine concentrations are around 1.8 ± 0.4 µM and do not differ between genders, most likely due to the hepatic responses which stabilize the circulating concentrations of the metabolites. Ageing, which is associated with an increase of immune activation, also in otherwise-healthy individuals, affects tryptophan metabolism, giving rise to higher kynurenine and lower tryptophan concentrations that are often associated with neuropsychiatric symptoms [46].

During cellular immune activation with IFN-γ as the major stimulus, enzyme GTP-cyclohydrolase (GTP-CH-I) is induced, which synthesizes 7,8-dihydroneopterin triphosphate from GTP. Further enzymatic conversion by 6-pyruvoyl-tetrahydropterin synthase leads to the formation of 5,6,7,8-tetrahydrobiopterin (BH₄), a cofactor for several mono-oxygenases [47].

While most cell types produce BH₄ when GTP-CH-I is activated, in human monocytes/macrophages, the metabolic route is directed towards the formation of neopterin and 7,8-dihydroneopterin [48] (Fig. 1). Neopterin and 7,8-dihydroneopterin interfere with a variety of redox-regulated intracellular signaling pathways. Moreover, neopterin has emerged as an important diagnostic marker of cellular immune activation in a variety of disorders associated with oxidative stress including CV, neurodegenerative, and tumor diseases, viral infections, and during allograft rejection [48]. In the course of a Th1-type immune reaction, neopterin formation parallels IDO-1 activity [27, 49].

Serum concentrations of neopterin are in the range of 5.9 ± 1.6 nmol/L in human healthy blood donors [44]. Like kynurenine and tryptophan concentrations, neopterin levels increase in the elderly [46].

BH₄-dependent enzymes include tryptophan 5-hydroxylase (TPH), phenylalanine 4-hydroxylase (PAH), tyrosine 3-mono-oxygenase (alternative name: tyrosine 3-hydroxylase; TH), nitric oxide synthase (NOS), and alkylglycerol mono-oxygenase [47, 50, 51] (Fig. 1, 2). BH₄ is sensitive to the oxidative condition that arises during immune activation and inflammation, and the activity of dependent enzymes is therefore reduced under oxidative stress (Fig. 1). Furthermore, xanthurenic acid, a metabolite formed from 3-hydroxykynurenine [52], has been shown to inhibit sepiapterin reductase, the final enzyme in de novo BH₄ synthesis [53].

Such interactions have important consequences for the generation of serotonergic neurotransmitters and catecholamines. Dopamine, noradrenaline, and adrenaline are synthesized from tyrosine-derived L-DOPA. Both the conversion of phenylalanine to tyrosine and the following reaction to L-DOPA are BH₄-dependent steps. The direct measurement of BH₄ in clinical samples is somewhat hampered due to the oxidation-sensitive nature of this molecule. The phenylalanine-to-tyrosine ratio (Phe/Tyr) has been proposed as an estimate of BH₄ levels [54], because phenylalanine and tyrosine can be regarded as more stable analytes than BH₄. Serum concentrations of phenylalanine and tyrosine are in the range of 53–79 and 61–116 µmol/L, respectively [44]. Of note, Phe/Tyr is also often increased in the elderly [55].

The cross-talk involving the different isoforms of NOS present in different cell types, the activating nature of IFN-γ signaling, and the suppressing nature of reactive oxygen species (ROS) provide a variety of interactions that are important for the temporal and spatial regulation of NO concentrations. NO is a gaseous signaling molecule implicated in a broad range of processes, endothelial, neuronal, and immunological (reviewed elsewhere [56]). Importantly, it is able to inhibit IDO activity by reversibly binding to heme at the active site [57].

In light of the above-described consequences of altered tryptophan and neopterin metabolism, it becomes obvious that the treatments or conditions which affect these metabolic routes may result in altered CNS function with mood-related, behavioral, and/or cognitive effects. Moreover, several in vitro and in vivo studies involving human primary cells and cell lines show that these pathways are highly susceptible to modulation by dietary constituents including phytochemicals, preservatives, colorants, and probiotics as well as by other lifestyle-related factors [11, 58-60]. Both direct interfering activities as well as upstream regulatory events may be relevant. Already in 2013, tryptophan metabolism was discussed due to its role as a mediator of environmental factors on cognition and behavior [9]. In line with this, the following summary on the modulation of the abovementioned pathway by a variety of nutritional and lifestyle-related factors further underlines the role of IDO-mediated tryptophan catabolism as a pathway that is particular sensitive to environmental influences [61].

As mentioned, for the transport of tryptophan into the brain, the leucine-preferring L1-system is important, in competition with LNAAs. In addition, there is evidence that eating carbohydrates along with protein can increase the tryptophan available to the brain [62]. When carbohydrates are consumed, the body produces insulin which directs other amino acids to muscle tissue, but tryptophan remains in the bloodstream. Thus, competing amino acids in the circulation decline and tryptophan more freely enters the brain. Taking pure tryptophan works in a qualitatively different way than when it is obtained from a food source [63].

Under inflammatory conditions, where peripheral tryptophan concentrations are low anyway, the kynurenine transport via LAT1 becomes even more relevant. -L-leucine was shown to efficiently interfere with kynurenine transport into the brain of lipopolysaccharide-challenged mice, which could efficiently counteract depressive-like behavior [35]. Another possibility is that the tryptophan concentration in the blood stream may increase when the breakdown of the amino acid is counteracted. This can take place when the intake of compounds slows down inflammation and IDO-1 activity [59].

Food rich in antioxidant compounds could improve both serotonin and tryptophan status in the brain. These compounds counteract immune response and tryptophan breakdown by IDO, e.g., compounds like vitamin C and E, and also stilbene resveratrol and coffee flavonoids, were observed to slow down T cell activation and IFN-γ production in vitro in mitogen-stimulated human peripheral blood mononuclear cells (PBMC) from healthy donors, followed by lower activity of the downstream biochemical pathways (like tryptophan breakdown) by IDO-1 or neopterin production [64]. In CV disease, elevated neopterin concentrations were found to correlate with a decrease of the plasma antioxidants lycopene, lutein, and zeaxanthin, and the vitamins ascorbic acid and α-to-copherol [65], so several metabolites could benefit from decreasing oxidative stress. An antioxidative milieu stabilizes the oxidation-sensitive molecule BH₄, thus affecting the activity of BH₄-dependent enzymes.

Though the prediction of the net effects of dietary components of phytochemicals in humans based on in vitro data only is somewhat limited due to sometimes missing ADME (absorption, distribution, metabolism, and excretion) data, individual susceptibility, interferences with the microbiome, or interactions with other food components, some of the effects on tryptophan metabolism and related pathways have been reported. In a pilot study with healthy volunteers who received a single dose of resveratrol administered orally after overnight fasting, the Kyn/Trp was found to be slightly but significantly elevated, and tryptophan concentrations were decreased up to 5 h after the intervention [66]. Of note, resveratrol treatment in PBMC in vitro suppressed IDO-1 activity dose-dependently under inflammatory conditions; at low concentrations, a nonmonotonic response provoked an increased activity in otherwise-untreated PBMC [67]. Similar results were obtained when investigating the effect of the intake of regular black tea over a 6-month period: plasma Kyn/Trp and kynurenine -concentrations increased in volunteers compared to the placebo group, while tryptophan and neopterin concentrations were not affected [68]. The tea-drinkers were healthy individuals, with no major illnesses and normal-to--mildly elevated systolic blood pressure. In vitro, the stimulating effects of black tea were also shown on otherwise-unstimulated PBMC, reflected by the elevation of neopterin concentrations [69].

Though polyphenol-rich food/beverages and phytochemicals such as resveratrol are generally considered to act as antioxidants, the data suggest that the net effect depends on an individual’s immune status, being immunostimulatory in healthy individuals while a dampening of responses may occur on an inflammatory background.

The importance of tryptophan metabolism in the cross-talk of gut and microbiome was addressed in a -recent study by Laurans et al. [70], who reported ameliorating effects on obesity, liver steatosis, and insulin sensitivity in the absence of IDO-1 activity in mice, which were mediated by microbiota-dependent production of interleukin 22. In addition, microbiota can be a source of tryptophan and tryptophan-derived metabolites, some of which can be transported across membranes [71], and of neurotransmitters and precursors such as noradrenalin, γ-aminobutyric acid (GABA), and other neuroactive substances [72]. Thus, interferences with the microbiome are likely to influence the gut-brain axis.

No major effects regarding exercise-induced Kyn/Trp and neopterin concentrations were reported in a study with trained athletes receiving probiotics compared to those receiving placebo [73]. Though tryptophan degradation rates were somewhat lower in subjects supplemented with probiotics, this effect was not significant; however, there was a reduced incidence of upper respiratory tract infections compared to the placebo group [73]. However, probiotic supplementation provoked an increase in neopterin concentrations and a subclinical increase in neutrophil resting burst compared to treatment with placebo in patients with liver cirrhosis who suffered from intestinal dysbiosis and pro-inflammatory conditions [74]. Serum kynurenine concentrations increased slightly but significantly in AD patients treated with probiotics [75]. The influence of gut microbiome composition on neuropsychiatric conditions like anxiety, depression, cognition, and -autism spectrum disorder is largely accepted, likewise that there is a link between gut-derived signals and healthy brain development but also with the progression of neurological disorders [76]. The leaky gut syndrome, an increase of the intestinal barrier permeability allowing the entry of microbes and metabolites into the bloodstream, is associated with AD pathogenesis and provides a mechanistic explanation for this connection [77].

Though the abovementioned studies are limited due to small samples, these preliminary data indicates that, particularly in patients likely suffering from leaky gut syndrome on probiotic treatments, personalized monitoring is required, as the consequences of the observed immunostimulatory effects have not yet been fully clarified. Like with phytochemicals, the effects seem to be highly dependent on an individual’s immune status and epithelial barrier function. The type of probiotic and the treatment duration also play a role here.

In line with an augmentation of oxidative metabolism, an increase of tryptophan catabolism and neopterin formation has been observed with different types of exercise [11, 78]. Trying to explain the beneficial effects of physical exercise on a metabolic level, Lewis et al. [79] generated a metabolic signature of exercise detectable in the plasma, which indicated an exercise-induced metabolic shift towards glycogenolyis, lipolysis, effects on tricarboxylic acid, insulin sensitivity, and fatty acid oxidation. In addition to the expected catabolic consequences seen with a decreased tryptophan concentration, marathon running resulted in an increased kynurenate concentration [79]. Exercise-induced increased expression of kynurenine aminotransferase, which is mediated by the peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α (a key transcriptional coactivator in energy metabolism), was shown to contribute to the lowering of the plasma kynurenine concentration in mice [80].

Phenylalanine catabolism may also be driven by -exercise, and increased substrate availability for dopaminergic neurotransmission could counteract negative consequences on mood resulting from accelerated tryptophan breakdown, though such effects may depend on the type and duration of the training [11]. It is well established that prolonged exhaustive/endurance exercise can be associated with immunosuppression as well as low mood and depression, which may be explained that the short time lowering of neurotransmitter precursors can be -counterregulated, while the exercise-driven continuous catabolic reaction will negatively impact psychoneuroimmunological circuits.

It is important to take into account that, under certain conditions, the interpretation of changes in Kyn/Trp and neopterin concentrations may differ. For example, in children with persistent IgE-mediated food allergy, tryptophan concentration was higher and Kyn/Trp lower than in healthy, age-matched controls, but kynurenine concentrations were not different [81]. This may relate to the loss of tolerance due to lowered IDO-1 activity. Furthermore, cultures of PBMC from patients with different phenotypes of cow’s milk allergy showed distinct cytokine responses after treatment with casein and β-lactoglobulin [81].

A higher tryptophan concentration despite a minor -affected Kyn/Trp has also been reported in patients suffering from allergic rhinitis [82]. An increased concentration of NO, as observed in asthma and allergic rhinitis patients, may be responsible here and is due to the specific blockage of IDO-1 activity [83]. Interestingly, an elevated serotonin concentration, associated with behavioral symptoms, has been reported in pollinosis patients [84].

In a study on obese/overweight juveniles and a normal-weight, age-matched control population, it was -observed that in the obese juveniles, early vascular burden and chronic low-grade inflammation were already present and concentrations of C-reactive protein were increased, but there was a decrease of neopterin compared to in the healthy population [85]. In addition, a lower Kyn/Trp has been reported in overweight/obese juvenile males but not in females aged ≤18 years. This is a major difference when compared to overweight adults and adult patients with metabolic syndrome who show elevated Kyn/Trp [86], or adults at a risk of CV disease in whom Kyn/Trp and neopterin concentrations are elevated [65, 87]. The reason for the lower neopterin and Kyn/Trp levels in obese (male) juveniles has not yet been determined on the molecular level, although the potential implications of an excessive uptake of food antioxidants has been discussed. An influence of elevated nitrite concentrations might also provide a reasonable explanation in such -patients because it is well known that NO is increased in certain allergies and inhibits IDO-1 [88].

These examples further highlight that individual immune status varies substantially in the general population, which adds another degree of complexity when -trying to interpret personalized tryptophan metabolite concentrations in clinical settings.

Dietary interventions to increase tryptophan have been used to study the metabolism for a long time, and nutritional interventions to modulate these pathways hold great therapeutic potential, particularly for long-term treatment. Supplementation of tryptophan is suggested to be less effective as the net effect of the high -tryptophan is widely lost when it must compete with LNAAs for BBB transport. However, as discussed above, the modulation of serum tryptophan breakdown rates by nutritional constituents or probiotics may be a feasible way to attain long-term changes.

Moreover, specific interventions can also be used for diagnostic purposes, e.g., for acute tryptophan depletion (ADT), a neurodietary, short-term, physiological serotonin precursor-related challenge test, consisting of the administration of a cocktail of LNAAs and a lack of tryptophan, results in a decreased tryptophan concentration in the circulation and brain a few hours after treatment. The antidepressant action of ADT was the aim of studies in the 1980s and 1990s and is currently again in focus [89-91].

Maintenance of the tryptophan-kynurenine balance seems to be critical for the physiological homeostasis. The same is true for neopterin concentration. Both are indicators of individual immunological status. How-ever, a variety of physiological, lifestyle, nutritional, and environmental factors affects tryptophan metabolism and the related metabolic pathways. Though the organism can balance slight and temporarily limited increases or decreases in these metabolites, long-term perturbation may be associated with more severe symptoms. The observations reported in this review are limited because the main focus was the effect of metabolic changes, observable in the plasma or urine. However, the connection of peripheral and brain metabolite concentrations has been explained. Other drug-induced changes were not included in the discussion. Indeed, several enzymes in the tryptophan-kynurenine pathway are under investigation as promising drug targets with potential application for the treatment of metabolic, neurodegenerative, and psychiatric disorders as well as cancer. Susceptibility to the modulation of tryptophan breakdown and the related pathways, due to a variety of different factors, is a further challenge for these drug-targeting approaches as, most likely, such interventions require a profound knowledge of disease development combined with a strict personalized monitoring so as not to risk a complete blocking of activities that are potentially necessary to reobtain homeostasis. However, this high susceptibility also holds great potential for less specific interventions, such as dietary and physical (exercise-based) interventions.

This work was supported by the Austrian Science Funds (FWF T703).

The authors declare no conflicts of interest.