R ES E A RC H
◥ natural killer cells, dendritic cells, or proliferat-
REVIEW SUMMARY
METABOLISM
Kynurenines: Tryptophan’s metabolites
in exercise, inflammation, and
mental health
Igor Cervenka, Leandro Z. Agudelo, Jorge L. Ruas*
BACKGROUND: The essential amino acid tryp-
tophan is a substrate for the generation of several
bioactive compounds with important physiolog-
ical roles. Only a small fraction of ingested tryp-
tophan is used in anabolic processes, whereas
the large majority is metabolized along the kyn-
urenine pathway of tryptophan degradation.
This pathway generates a range of metabolites,
collectively known as kynurenines, involved in
inflammation, immune response, and excitatory
neurotransmission. Kynurenines have been linked
to several psychiatric and mental health disorders
such as depression and schizophrenia. In addi-
tion, due to the close relationship between kyn-
urenine metabolism and inflammatory responses,
kynurenines are emerging as recognized play-
ers in a variety of diseases such as diabetes and
cancer. Because the levels of enzymes of the kyn-
urenine pathway in peripheral tissues tend to be
much higher than in the brain, their contrib-
ution to the kynurenine pathway can have both
local and systemic consequences. Due to their
characteristics, kynurenine and its metabolites
have the right profile to fill the role of media-
tors of interorgan communication.
ADVANCES: Understanding how the tryptophan-
kynurenine pathway is regulated in different
The kynurenine pathway generates tryptophan metabolites with
diverse biological activities throughout the body. Although mainly
studied in relation to the brain and mental health, the action of
kynurenine metabolites on peripheral tissues might be even more
Cervenka et al., Science 357, 369 (2017) 28 July 2017
tissues, and the diverse biological activities
of its metabolites, has become of interest to
many areas of science. The bioavailability of
tryptophan can be affected by factors that range
from gut microbiome composition to systemic
inflammatory signals. Gut-resident bacteria can
directly absorb tryptophan and thus limit its
availability to the host organism. The resulting
metabolites can have local effects on both mi-
crobiome and host cells and even mediate in-
terspecies communication. In addition, the
biochemical fate of absorbed tryptophan will
be affected by cross-talk with other nutrients
and even by individual fitness, because skele-
tal muscle has recently been shown to contrib-
ute to kynurenine metabolism. With exercise
training, skeletal muscle increases the expres-
sion of kynurenine aminotransferase enzymes
and shifts peripheral kynurenine metabolism
toward the production of kynurenic acid. As a
consequence, alleviating the accumulation of
kynurenine in the central nervous system can
positively affect mental health, such as reduc-
ing stress-induced depressive symptoms.
The kynurenine pathway is highly regulated
in the immune system, where it promotes im-
munosuppression in response to inflammation
or infection. Kynurenine reduces the activity of
profound. They serve as important mediators of interorgan and
interkingdom cross-talk, connecting seemingly diverse processes
such as the effects of exercise training and pathologies such as
inflammatory diseases, cancer, and depression.
ing T cells, whereas kynurenic acid promotes
monocyte extravasation and controls cytokine
release. Perturbations in the kynurenine path-
way have been linked to several diseases. High
kynurenine levels can increase the prolifera-
ON OUR WEBSITE
◥ tion and migratory capac-
ity of cancer cells and help
Read the full article
at http://dx.doi.
org/10.1126/
tumors escape immune
surveillance. Kynurenine
metabolites have been pro-
science.aaf9794
..................................................
posed as markers of type
2 diabetes and may inter-
fere at some level with either insulin secretion
or its action on target cells. Kynurenines can
signal through different tissue-specific extra-
and intracellular receptors in a network of events
that integrates nutritional and environmental
cues with individual health and fitness.
Downloaded from http://science.sciencemag.org/ on September 16, 2019
OUTLOOK: The modulation of tryptophan-
kynurenine metabolism using lifestyle and phar-
macological interventions could help prevent
and treat several diseases with underlying in-
flammatory mechanisms, including metabolic,
oncologic, and mental health disorders. In this
context, and considering the substantial effect
that the gut microbiome can have on preabsorp-
tive tryptophan metabolism, it is tempting to
envision the use of probiotic-based therapies.
The discovery that aerobic exercise training can
reduce kynurenine levels in circulation and in
the central nervous system could have important
implications for the development of future gen-
erations of antidepressant medications. This again
stresses the many advantages of remaining phys-
ically active throughout life. Understanding the
multiple levels of control of the kynurenine path-
way could help predict susceptibility to disease
linked to environmental and dietary signals.
▪
The list of author affiliations is available in the full article online.
*Corresponding author. Email: jorge.ruas@ki.se
Cite this article as I. Cervenka et al., Science 357, eaaf9794
(2017). DOI: 10.1126/science.aaf9794
1 of 1
R ES E A RC H

◥ for the transcription factor aryl hydrocarbon re-

REVIEW ceptor (AhR) (similar activity has been shown for
Kyn) (14, 15). IDO, together with tryptophan 2,3-
dioxygenase (TDO) and AhR are present in some
METABOLISM tumor cells, so it has been proposed that Kyn can
have a double role in promoting cancer invasion

Kynurenines: Tryptophan’s metabolites and immune escape. On one hand, activation of

cancer cell AhR by Kyn increases the expression
of genes that promote cell migration (16, 17). On
in exercise, inflammation, and the other hand, activated immune cell AhR sup-
presses effector T cells and increases immune tol-

mental health erance by targeting dendritic and regulatory B

cells (18).
The gastrointestinal tract (GIT) has an impor-
Igor Cervenka, Leandro Z. Agudelo, Jorge L. Ruas* tant role in Trp metabolism. The upper GIT is re-
sponsible for the majority of serotonin synthesis
Kynurenine metabolites are generated by tryptophan catabolism and regulate biological (19). It also absorbs and is directly influenced by
processes that include host-microbiome signaling, immune cell response, and neuronal Kyn metabolites such as Kyna that are present in
excitability. Enzymes of the kynurenine pathway are expressed in different tissues and cell food and can act locally on GPR35 (20). The lower
types throughout the body and are regulated by cues, including nutritional and inflammatory portion of the GIT is home to substantial num-

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signals. As a consequence of this systemic metabolic integration, peripheral inflammation bers of microbiota, which are affected by Trp avail-
can contribute to accumulation of kynurenine in the brain, which has been associated with ability and in turn act on gut mucosal tissues and
depression and schizophrenia. Conversely, kynurenine accumulation can be suppressed by resident immune population through the produc-
activating kynurenine clearance in exercised skeletal muscle. The effect of exercise training tion of indole compounds that bind to AhR (21).
on depression through modulation of the kynurenine pathway highlights an important Skeletal muscle has recently been added to the
mechanism of interorgan cross-talk mediated by these metabolites. Here, we discuss list of tissues that contribute to Kyn metabolism
peripheral mechanisms of tryptophan-kynurenine metabolism and their effects on (22). This happens in the setting of exercise train-
inflammatory, metabolic, oncologic, and psychiatric disorders. ing and depends on the transcriptional coactivator

T
ryptophan (Trp) is an essential amino acid
critical for protein synthesis, but it also serves
as substrate for the generation of several bio-
active compounds with important physiolog-
ical roles. Probably the best-known fate of Trp
is its conversion to serotonin (5-hydroxytryptamine),
an important neurotransmitter involved in the con-
trol of adaptive responses in the central nervous
system (CNS) and linked to alterations in mood,
anxiety, or cognition (1). Serotonin can be further
converted to N-acetylserotonin (NAS) and mela-
tonin, adding control over circadian rhythmicity
to the list of biological roles for Trp metabolites
(2). However, in mammals, the majority of free
Trp is degraded through the kynurenine pathway
(KP) (Fig. 1) and generates a range of metabolites
involved in inflammation, immune response, and
excitatory neurotransmission (3). The final prod-
uct of the KP is nicotinamide adenine dinucleotide
(NAD+), an important cofactor in cellular reactions
linked to energy metabolism (4) that is emerging
as an attractive therapeutic target for several dis-
eases. Here, we focus on peripheral mechanisms
that contribute to Trp-KP metabolism.
Kynurenine (Kyn) and its metabolites (all with
defined chemical identities but often collectively
called “kynurenines”) are known for their effects
on the CNS and have been linked to several psy-
chiatric and mental health disorders such as de-
pression and schizophrenia (5). The CNS receives
about 60% of Kyn from the periphery by transport
across the blood-brain barrier (BBB), and the re-
maining is produced locally. Kyn degradation in
Department of Physiology and Pharmacology, Molecular and
Cellular Exercise Physiology, Karolinska Institutet, SE-17177
Stockholm, Sweden.
*Corresponding author. Email: jorge.ruas@ki.se
the CNS is divided between different cell types,
among which astrocytes and microglia play impor-
tant roles with antagonizing actions (6). Microglia
produce quinolinic acid (Quin), an N-methyl-D-
aspartate receptor (NMDAR) agonist, whereas as-
trocytes are equipped to generate kynurenic acid
(Kyna), an NMDAR and a7 nicotinic acetylcholine
receptor (a7nAChR) antagonist. The levels of these
two Kyn metabolites have hence been associated
with neuronal excitotoxicity (Quin) or protection
(Kyna) and are found to be dysregulated in major
depressive disorders and schizophrenia (7).
Like Trp and Kyn, 3-hydroxykynurenine (3-HK)
crosses the BBB and contributes to Quin gener-
ation in microglia but is also able to exert more
direct deleterious effects linked to oxidative stress
and apoptosis (8, 9). Defects in Kyn signaling have
also been seen in mouse models of neurodegenera-
tive diseases such as Alzheimer’s and Huntington’s
(10, 11). The underlying feature of these different
pathologies seem to converge on neuroinflamma-
tion and associated events, including brain infiltra-
tion of circulating immune cells, microglia activation,
and high levels of proinflammatory cytokines (12).
The levels of enzymes of the KP in peripheral
tissues tend to be much higher than in the brain.
For example, macrophages have a 20-fold higher
capacity to produce Quin than microglial cells. This
is particularly important in situations of macro-
phage infiltration across the BBB. Immune cells
are both important sources and targets for Kyn
metabolites as they express high levels of several
enzymes of the pathway [e.g., indoleamine 2,3-
dioxygenase (IDO) and kynurenine aminotrans-
ferases (KATs)] and also of receptors such as G
protein–coupled receptor 35 (GPR35). The expres-
sion of IDO and KATs allow Trp to be metabo-
lized to Kyna, a GPR35 agonist (13) and a ligand
peroxisome proliferator–activated receptor (PPAR)
gamma coactivator-1a1 (PGC-1a1), which enhances
KAT gene expression and Kyn to Kyna conversion.
This links peripheral and central Kyn metabolism
and provides a mechanism for some of the benefits
of physical exercise for mental health.
The many fates of tryptophan
Humans lack the biochemical pathways to synthe-
size Trp, which must be acquired from diet with a
required daily dose of 3.5 mg per kg of weight (23).
The highest concentration of Trp can be found in
chocolate, eggs, fish, dairy products, legumes, and
meat. Less than 1% of ingested Trp is used for
protein synthesis because, under conditions of un-
altered nitrogen balance, the demand for protein
synthesis is met by protein breakdown (24). The
majority of Trp is thus metabolized along one of
four known pathways, giving rise to a variety of
biologically active compounds (e.g., serotonin, trypt-
amine, indoles, kynurenines, and NAD+) (25). Trp,
together with other neutral amino acids, is trans-
ported by large neutral amino acid transporters
(LAT) 1 to 4. These are widely distributed through-
out the body, and their capacity is sufficient to
avoid competition, with the notable exception
of the BBB (26). The majority of Trp is imported
into the gut, where only a fraction is used, whereas
the rest enters portal circulation and undergoes
liver metabolism. The remaining Trp, together
with its liver degradation products, is distributed
to peripheral circulation and transported to tissues
such as the brain, heart, and skeletal muscle. Trp
not taken up by the upper GIT is metabolized by
resident microbiota to indole compounds (27), im-
portant interspecies signaling molecules (28).
Trp is the only amino acid transported bound
to albumin. However, degradation pathways can
only use Trp in its free form, which corresponds

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to 5 to 10% of total Trp (29). The mode of Trp
degradation and concentration of its end products
is a function of free Trp concentration, which is in
turn readily influenced by nutritional, hormonal,
and pharmacological cues. For example, nones-
terified fatty acids (NEFA) directly affect Trp avail-
ability by displacing it from albumin (30). As a
consequence, increasing NEFA levels by, for ex-
ample, adrenaline or phosphodiesterase inhib-
itors, increases free Trp. Conversely, antilipolytic
agents such as insulin are able to decrease Trp
concentration by the same mechanism (25).
The gut microbiota numbers are estimated to
outnumber cells in our body by a factor of 10 and
tend to increase distally along the intestine (31).
Due to their sheer number, they have nonnegligible
effects on Trp metabolism. Gut microbiota can
directly absorb Trp and thus limit its availability
to the host organism. This can be seen in germ-
free (GF) mice, which have high circulating Trp
levels that normalize postcolonization. Bacterially
produced indoles interact with pregnane X recep-
tors (PXRs) and mediate a range of effects, in-
cluding improved mucosal homeostasis and barrier
function, and as such represent a fascinating ex-
ample of interkingdom communication (32). More-
over, indoles act as hydroxyl radical scavengers,
neuroprotectants, and human AhR selective ago-
nists attenuating inflammation (33). Conversely,
some bacteria are susceptible to selective sero-
tonin reuptake inhibitors (SSRIs) such as sertra-
line, fluoxetine, and paroxetine. Initially, serotonin
was identified as a player in the peristaltic reflex of
the gut and has since been shown to influence co-
lonic morphology, maintenance of enteric mucosa,
pellet formation, and propulsive motility. Cur-
rently, the role of serotonin in the brain-gut axis
through the activity of the microbiota is being
avidly explored (21). Thus, the extent of Trp use by
bacteria, its dietary supply, and local turnover by
the GIT can have far-reaching implications in the
development and proper functioning of both the
enteric nervous system (ENS) and CNS.
The kynurenine pathway of tryptophan
degradation
Decarboxylation of Trp to tryptamine, transam-
ination to indol-3-yl pyruvic acid, and hydroxyl-
ation to serotonin are minor Trp degradation
pathways. Although serotonin is usually associ-
ated with the brain, the majority of its produc-
tion is localized in the gut. As much as 90% of total
serotonin production (stored in secretory granules)
comes from enterochromaffin cells and, to a lesser
extent, from serotonergic neurons of the ENS (34).
More than 95% of Trp is metabolized along the
KP to yield nicotinamide and NAD+ (24) (Fig. 1).
The rate-limiting step of the KP is the conversion
of Trp to N-formylkynurenine, which is mediated
by two spatially segregated members of this path-
way. In the liver, the first step in Trp degradation
is mediated by TDO, which under normal condi-
tions is responsible for the majority of this con-
version (35). TDO is the main determinant of Trp
availability to extrahepatic tissues and is induc-
ible by Trp itself, glucocorticoids, and estrogens
(36, 37). The extrahepatic branch of the KP is
Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017
under the control of two IDO enzymes (IDO1 and
the more recently discovered IDO2), whose activity
is negligible under basal conditions but dramat-
ically inducible by several stimuli, such as inflam-
matory signals (e.g., interferon-g). IDOs are mostly
active in the immune system and mucosal tissues
such as gut (38, 39). Conversely, IDO can be inhi-
bited by elevated levels of Trp, which results in
channeling the flux of Trp degradation back to
TDO (40). Interestingly, the TDO and IDO genes
do not share a common ancestor but are an ex-
ample of functional convergence (41).
The KP can yield metabolites with neurotoxic
and neuroprotective properties, depending on
which enzyme tips the conversion scales (5). Under
normal conditions, the majority of Kyn is excreted
in the urine, so its bioavailability only increases
when the flux of Trp down the KP exceeds renal
clearance (42). Kyn is usually hydroxylated to 3-HK
and then further converted to 3-hydroxyanthranilic
acid (3-HAA). 3-HAA is rapidly converted to Quin
by the nonenzymatic reaction of an intermediary
product and proceeds with conversion to NAD+,
a preferred end product of the KP (43). Under
specific conditions, picolinic acid (PA) is formed
instead. The other branch of the pathway, leading
to the production of Kyna and xanthurenic acid
(XA) from Kyn is minor under normal conditions
but increases under Trp or Kyn loading (Fig. 1) (44).
Fig. 1. Overview of the kynurenine pathway
of tryptophan degradation. 3HAO,
3-hydroxyanthranilic acid oxygenase; NAPRT1,
nicotinate phosphoribosyltransferase.
These ratios change dramatically under different
Trp loads and are also influenced by vitamin B6
availability (45). Our understanding of how the
proportions of different Kyn metabolites change
with environmental context is incomplete, and
many contradictory results have been reported.
Interestingly, this has prompted the development
of mathematical models to help us understand
metabolite flux through the KP (46).
Conservation of kynurenine metabolism
throughout evolution
In bacteria, fungi, and plants, the biosynthesis of
aromatic amino acids such as Trp is provided by
the shikimate pathway. Whereas bacteria spend
the majority of their metabolic energy on protein
synthesis, plants use this pathway to generate a
large variety of secondary metabolites (47). Regard-
ing the conservation of the KP, the TDO enzyme
can be found in the majority of bacterial species and
Downloaded from http://science.sciencemag.org/ on September 16, 2019
in almost all metazoan species but has probably
been lost in fungi during the course of evolution
(Fig. 2) (48). IDO enzymes have been discovered
in vertebrates, and—even though its homologs have
been confirmed in other species, such as molluscs,
yeasts, or deuterostomian invertebrates—they re-
main poorly characterized. On the other hand,
arthropods and nematodes generally lack IDO
enzymes. The analysis of more downstream com-
ponents of KP shows that vertebrates, yeasts, and
some invertebrates can generate NAD+ through
the KP, with TDO serving as a main supplier of
precursors and IDO having a different role. Insects
and invertebrates lack some of the downstream KP
enzymes, suggesting that alternate means of NAD+
generation have prevailed throughout evolution
(Fig. 2). TDO is regarded as a “high catalytic activity”
enzyme in contrast to IDO; however, this seems
to be different in fungi where IDO assumed the
lost TDO functionality. In vertebrates, IDO1 ac-
quired high affinity for Trp after IDO1/IDO2 diver-
gence. The biological importance of “low-catalytic
activity” IDOs remains unclear and controversial,
although they have been well conserved through-
out evolution. KAT enzymes have also been some-
what conserved during evolution and can be found
in prokaryotes, insects, nematodes, and vertebrates.
However, some species contain multiple genes
(nematodes, 2; humans, 4), which could have arisen
during evolution by means of gene duplication.
Because the individual KAT enzymes display dif-
ferent tissue profiles, it might be that their func-
tions and localizations have become specialized
with time. Plants possess the enzyme tryptophan
aminotransferase–related (TAR1) that plays a role
in the synthesis of auxin but is also able to trans-
aminate Kyn to Kyna (49).
Kynurenic acid
Of all the different by-products of the KP, Kyna
has been studied most. It was originally discov-
ered in canine urine, but higher concentrations
have been measured in the gut (increasing grad-
ually along its length), bile, pancreatic juice of rats
and pigs, and, to a lesser extent, in human saliva
and synovial and amniotic fluid (20). Its presence
in many food products has also been determined.
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The highest concentrations are found in honeybee
products, broccoli, and some potatoes (50). Many
medicinal herbs contain high concentrations of
Kyna, indicating therapeutic potential for the gas-
trointestinal system (51). In addition to the Kyna
ingested in food or synthesized along the KP in
the GIT, the gut microflora possesses the enzyme
aspartate aminotransferase, which is analogous to
mitochondrial KAT4 and produces Kyna by trans-
amination of Kyn. The action of Kyna on the GIT
is several fold. Early reports suggested that Kyna
is able to protect the intestinal mucosa in the settings
of obstructive jaundice and protect from ethanol- or
toxin-induced ulcers (52). In addition, Kyna can also
modulate local inflammation, most likely through
activation of GPR35, which is highly expressed in
the immune cells of the GIT.
Liver control of tryptophan-kynurenine
metabolism
Among the many cell types that express KP enzymes,
hepatocytes contain all the machinery required
for Trp degradation toward any branch of the KP
(53). Most important, they are the sole cell type
with high TDO activity and thus have a central
role in the modulation of systemic Trp levels (35).
Because TDO has low affinity for Trp, it remains
active even when Trp exceeds the levels required
for serotonin and protein synthesis (54). If the re-
quirements for protein synthesis are surpassed, the
liver metabolizes excess Trp to NAD+, oxidizing
the rest via the glutarate pathway (Fig. 3). If Trp
concentration is low, the liver will clear and metab-
olize circulating Trp to NAD+ for energy demands
(53). Interestingly, when Trp requirements are met
and liver TDO activity is increased by glucocorti-
coids, saturation of the pathway will lead to leakage
of some of its metabolites, such as Kyn.
Of note, factors that are detrimental to mental
health, such as stress, social isolation, sleep depri-
vation, and lack of physical activity, elevate circu-
lating glucocorticoid levels in both humans and
nonhuman social mammals (55, 56). This will lead
to a feed-forward loop in which liver Kyn metab-
olism increases the output of KP substrates from
the periphery to the CNS. As mentioned before,
these compounds can be degraded locally to me-
tabolites with deleterious effects to the CNS (7).
Chronically high cortisol levels create a state of
glucocorticoid receptor (GR) resistance, which in
turn fails to dampen the inflammatory response.
The reduction in GR activity leads to suppressed
liver TDO expression and a shift to extrahepatic
Trp and Kyn metabolism (42). One reason for this
shift in Trp degradation could be to promote the
immunomodulatory roles of kynurenines and re-
duce inflammation.
Immune system
In immune cells, as in most extrahepatic tissues,
the KP is initiated by IDO. This enzyme is ubiq-
uitously expressed and has affinity for substrates
other than Trp, including 5-hydroxytryptophan and
serotonin. IDO is highly regulated in the im-
mune system, where its expression is increased by
interferon-g (IFN-g), tumor necrosis factor a (TNFa),
and pathogenic infections (57, 58). IDO-mediated
Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017
Fig. 2. Evolutionary conservation of enzymes
of the kynurenine pathway. KYNU,
Kynureninase.
Trp catabolism in the host microenvironment
surrounding parasites, viruses, and bacteria was
seen as a way to curb their proliferation (59). How-
ever, immune cells can also contribute to Trp deg-
radation during nonpathogenic inflammation,
indicating that IDO has a broader spectrum of
activity on immune cell regulation (60). An un-
restrained immune response would be detrimental,
so cells have developed metabolic pathways to
control immune activation (61). Thus, IDO activity is
stimulated by type 1 or proinflammatory cytokines
(62) and inhibited by type 2 or anti-inflammatory
cytokines (63). Trp degradation by IDO has emerged
as a rate-limiting step for metabolic immune reg-
ulation, according to two proposed mechanisms:
first, by the generation of Trp metabolites with
immune activity, such as Kyn and Kyna (64); second,
by triggering an amino acid–sensing signal in cells
undergoing Trp depletion (65). Initial observations
showed that Kyn metabolites, in particular Kyn
itself, suppress the activity of natural killer cells
(NKT) (66) and antigen-presenting cells (APC) such
as dendritic cells (DC), monocytes, and macro-
phages in mice (67, 68). Furthermore, Kyn blocks
T cell proliferation and induces T cell death (69),
and IDO-mediated Kyn production in DC leads to
the proliferation of regulatory T cells (Tregs) (67, 70).
These effects are, at least in part, mediated by Kyn
activation of AhR (Fig. 3) (15, 71), a ligand-activated
transcription factor involved in xenobiotic response
to foreign substances. It is expressed in cells of
both innate and adaptive immune systems, and
it has been shown to have anti-inflammatory ac-
tivity in mice (72, 73). Given the Kyn-AhR–mediated
decrease in immune surveillance, regulating the
Kyn pathway has become an attractive target for
cancer therapy. Interestingly, the Kyn-AhR axis
has been postulated to constitute one of the links
between chronic inflammation and tumor pro-
gression (15). Similarly, Kyna was also found to
activate AhR (14), but whether this activation leads
to similar immune regulation remains unclear.
Kyna has been recently shown to also be a ligand
for GPR35. This receptor is expressed in human
CD14+ monocytes, T cells, neutrophils, DCs, eosino-
phils, basophils and invariant NKT (iNKT) cells
(13, 74). Of those, circulating monocytes display
the highest expression of GPR35, and its interac-
tion with Kyna has been shown to promote mono-
cyte extravasation (75). It was later confirmed that
Kyna-GPR35 interaction reduces the inflamma-
tory response induced by lipopolysaccharide (LPS)
stimulation in monocytes and macrophages (76)
and controls cytokine release in human iNKT cells
(74). Taken together, the effects of Kyna on im-
mune cell activation might represent a direct anti-
inflammatory mechanism that further reinforces
the immunosuppressant function of Trp catabo-
lism. Other metabolites of the KP, such as 3-HAA
and Quin, have been shown to induce apoptosis
of type 1 T helper (TH1) cells, while promoting pro-
liferation of type 2 T helper (TH2) cells (67). This
immune shift would favor cell survival against the
deleterious effect of uncontrolled immune activation.
Inflammatory conditions are characterized by
high levels of cellular stress and energy use, often
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accompanied by increased rates of DNA damage.
In macrophages, as in the liver, oxidation of Trp
through the KP can replenish NAD+ levels to meet
energy requirements (77). In addition, NAD+ is used
by poly (ADP-ribose) polymerase (PARP) in DNA
repair mechanisms (78). Trp catabolism in immune
cells is therefore a negative feedback mechanism
that suppresses ongoing inflammatory response.
However, situations such as chronic low-grade in-
flammation can lead to a robust elevation of cir-
culating Kyn levels, which will also increase in the
CNS. The discovery that skeletal muscle can con-
tribute to the KP (22) is highlighted by the fact
that sedentary lifestyles can lead to chronic low-
grade inflammation in this organ. This adds a new
regulatory node to Kyn metabolism in the periphery.
Skeletal muscle
The effect of skeletal muscle and exercise on nu-
trient metabolism has been appreciated for a long
time. Aerobic exercise training elevates the levels
of PGC-1a1 in skeletal muscle of mice and humans.
PGC-1a1 is a transcriptional coactivator important
for adaptive responses in many tissues (79), most
notably in skeletal muscle. When activated, PGC-
1a1, together with PPARa/d, increases skeletal mus-
cle expression of KAT enzymes and shifts peripheral
Kyn metabolism toward the production of Kyna.
Under these conditions, Kyna does not cross the
BBB, so reducing Kyn levels in the brain can re-
duce stress-mediated effects underlying depressive
symptoms. In fact, mice with transgenic expres-
sion of PGC-1a1 in skeletal muscle (and therefore
higher skeletal muscle KAT levels) are resilient
to developing depressive-like behavior caused by
elevated Kyn levels resulting from stress or exog-
enous administration (Fig. 4) (22). This pathway
has been shown to be active in both mouse and
human muscle (22, 80). Modulating PGC-1a1-PPAR
activation in skeletal muscle could become a new
therapeutic intervention to regulate Trp-Kyn me-
tabolism. In particular, this would preserve the
immunosuppressant action of kynurenines via Kyna
and decrease the neurotoxic effects associated with
Kyn during chronic inflammatory states.
Skeletal muscle KP is likely to be affected by other
amino acid metabolic pathways. For example,
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Fig. 3. Activity, uptake, and conversion of tryptophan and its metabolites in peripheral tissues during unchallenged conditions. 5-HT, 5-hydroxy
tryptamine; ROS, reactive oxygen species.
during physical exercise, skeletal muscle can oxidize
branched-chain amino acids (BCAA) and Trp for
energy (81). Muscle fibers contain all the neces-
sary transporters/carriers for amino acid clearance;
however, circulating BCAA compete with Trp and
kynurenines for the same transporters (82). More-
over, BCAA inhibit some of the enzymes of the
KP (83), especially KATs (84), which indicates
that fuel availability (in particular, BCAA) can
affect skeletal muscle Trp metabolism and Kyn
clearance.
Kynurenine metabolites and disease
Trp metabolism is most widely known and studied
in relation to disorders of the nervous system. Its
effect on stress-related depression, schizophrenia,
and Alzheimer’s and Parkinson’s diseases have
been comprehensively reviewed elsewhere (85).
The following sections summarize recent advances
in our understanding of how Kyn metabolism
is dysregulated in peripheral tissue dysfunction.
However, it is important to remember that the
majority of defects of Trp metabolism in peripheral
organs can also have a strong effect on the CNS,
resulting in complications such as anxiety and
depression.
Irritable bowel syndrome and disease
Two main diseases of the GIT are associated with
Trp metabolism: irritable bowel syndrome (IBS)
and irritable bowel disease (IBD). IBS is charac-
terized by abdominal pain together with altered
bowel habits and affects a considerable portion
of the adult population (15 to 20%) (86). Increase
in serum-free Trp has been documented in IBS
patients. The etiology of IBS has been connected
to abnormal serotonergic neuronal signaling during
development and also to alterations in serotonin
Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017
production and signaling in enterochromaffin
cells (87, 88). One of the hallmarks of the disease,
visceral hypersensitivity, is thought to occur as a
result of the sensitization of afferent neurons and
to compromised epithelial integrity, which in turn
makes it possible for intraluminal compounds to
cross the gut wall barrier (89).
By contrast, IBD is a relapsing inflammatory
condition with complex etiology that affects 1 in
500 individuals, peaking around the age of 20.
The etiology of IBD lies at the intersection of
dysbiosis of microbiota, host immunity, and genetic
predisposition, with anxiety and depression as
common comorbidities (90). In this context, it is
not unexpected that aberrant Trp metabolism is
a common denominator of these complications.
IBD patients have increased plasma levels of Kyn
and Kyna, probably as a result of increased IDO
expression. IBD is also connected to microbiota
homeostasis, and IBD patients also have increased
risk of colorectal cancer (91). Recently, caspase
recruitment domain–containing protein 9 (CARD9)
has been found to be an IBD susceptibility gene.
CARD9 encodes a host adaptor protein critical
for immune responses against microorganisms.
Microbiota derived from CARD9 knockout (KO)
mice have compromised Trp to indole conversion
and cannot activate AhR. Furthermore, bacteria
from CARD9 KO animals are sufficient to induce
colitis in wild-type germ-free animals. Coloniza-
tion of CARD9 KO animals with bacteria capable
of catabolizing Trp alleviates the disease (92). Due
to the tight regulation between microbiota and
host responses, individual contributions will prove
challenging to distinguish. Interestingly, plant-
derived indole compounds have been used in tra-
ditional medicine to treat IBD, which lends support
to the importance of the interactions of kynur-
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enines with AhR and their actions on the immune
system (93).
Pancreatitis
One of the less-studied diseases with connection
to Trp metabolism is acute pancreatitis (AP). It
is a severe sterile inflammation of the pancreas
connected to gut dysfunction that can lead to
multiorgan failure with very high mortality rates
(94). Plasma Kyn of AP patients seems to originate
in the gut-associated lymphoid tissue (GALT), and
its levels correlate with magnitude of injury and
systemic inflammatory burden (95). Kynurenine-
3-monooxidase (KMO) is central to the patho-
genesis of pancreatitis, and its genetic ablation
or pharmacological inhibition conveys protection
from deleterious effects. The pathology of AP is
mediated by 3-HK transported in the mesenteric
lymph to other organs such as the lungs, where it
causes near total cell death by oxidative stress,
apoptosis, and pathological protein cross-linking
(96). Decreasing 3-HK production from Kyn by
diverting it to generating Kyna inhibits LPS-induced
TNFa secretion and leads to increased survival
in rodent models of acute pancreatitis (96). Melatonin,
another Trp metabolite, has emerged as a treat-
ment option of AP by reducing oxidative stress
and protecting from inflammation (97).
Cancer
Cancer cells have a multifaceted relationship with
altered Trp metabolism. Several tumor types show
increased Trp uptake [as evidenced by a-[11C]-
methyl-L-tryptophan (AMT)–positron emission
tomography (PET) scanning of human patients],
which in turn correlates with poor disease prog-
nosis (98). Although the reason for this is not fully
understood, tumor cells might need high Trp levels
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to fuel an ever-increasing demand for protein
synthesis. On the other hand, Trp starvation will
induce general control nonderepressible 2 (GCN2)
kinase that inhibits G1 to S transition, inducing
cell cycle arrest (99). To prevent this, tumors might
increase their Trp supply by up-regulating LAT1
expression. However, LAT1 has been shown to
work in a bidirectional manner, exchanging gluta-
mate for Trp. To counteract this shortcoming, it
has been shown that proliferating tumor cells,
but not resting T cells, up-regulate expression of
the glutamate transporter by the activating tran-
scription factor 4 (ATF4) pathway after sensing
Trp unavailability (100, 101). Moreover, tumors
show enhanced IDO expression, with downstream
metabolites, such as Kyn, being able to activate
beta-catenin signaling, leading to increased colon
cancer proliferation in mice (102). IDO expression
in mouse models of ovarian cancer, melanoma,
and renal cell carcinoma correlates with increased
angiogenesis (103). TDO, on the other hand, has
been predominantly connected to the escape from
the immune system surveillance and increased
migratory capacity. Kyn generated in tumors might
be subsequently released into the surrounding
milieu, where it can affect a variety of immune
cell populations by binding to AhR (Fig. 4). More-
over, it can have autocrine effects and stimulate
invasiveness in an AhR-dependent manner (104).
Rapid Trp usage and its subsequent local deple-
tion results in proliferative block of T cells (99).
Of note, certain types of macrophages can sup-
press T cell proliferation in the same manner
(105). Production of NAD+ pathway intermediates
can also induce apoptosis in a variety of immune
cells (67).
NAD+ is an important cofactor involved in
genome stability, stress tolerance, and metab-
olism (4). Probably for a combination of all those
reasons, tumor cells have broadly altered NAD+
use and production. It has been postulated that,
in tumor cells, most NAD+ comes from salvage
pathways. However, they also possess the ability
to shift to de novo production using Trp as a
source. This becomes relevant in the setting of
NAD+-depleting anticancer drugs, irradiation, or
induction of oxidative stress by alkylating agents.
For example, it has been shown that reducing Trp
uptake leads to rapid NAD+ depletion by PARP,
resulting in apoptotic cell death of lung cancer
cells mediated by NAD(P)H quinone dehydrogenase
1 (NQO1) (106). On the other hand, tumors elevate
expression of quinolinate phosphoribosyltrans-
ferase (QPRT), which protects them from oxidative
stress by converting Quin to NAD+. Increased
QPRT expression is generally associated with poor
disease prognosis in humans (107). At the time of
writing, several modulators of the KP or analogs
of Trp metabolites are undergoing clinical trials
for cancer treatment (108).
Diabetes
The main links between diabetes and Trp metab-
olism are inflammation and immune suppression.
Additionally, increased production of serotonin
has been implicated in the pathogenesis of diabetes
(109). Glucocorticoid-mediated insulin resistance
Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017
elevates the synthesis of serotonin in the liver and
adipose tissue in a tryptophan hydroxylase 1 (Tph1)–
dependent manner. Serotonin binds to mecha-
nistic target of rapamycin (mTOR), increasing
liver lipogenesis and impairing insulin signaling
in adipocytes. Accordingly, inhibition of serotonin
degradation by monoamine oxidase A (MAOA)
exacerbates the effects (110). Compounding the
problem, serotonin has well-documented effects
on brain-mediated control of appetite. Despite its
anorexigenic effects, serotonin transporter (SERT)
KO animals are obese and, conversely, Tph1 and
2 KO mice lose body weight (111). Several studies
have highlighted the role of serotonin in the regu-
lation of white and brown adipose tissue energy
storage and expenditure. Serotonin can increase
fat accumulation in humans and rodents, and
the activation of its receptors in hypertrophied
fat cells induces adiponectin production. Con-
versely, Tph1 KO mice have significantly lower
weight, improved glycemic control, enhanced
energy expenditure, and lower adiposity when
on high-fat diets (112).
In the Torii rat model of spontaneous diabetes,
decreases in Trp and Kyn production were iden-
tified as biomarkers of a prediabetic state. Morbidly
obese patients have lower circulating levels of
Trp and higher Kyn/Trp ratios (113). Chronic stress
and low-grade inflammation are major risk fac-
tors in prediabetes to diabetes transition. They
can skew the balance of Trp metabolism toward
Kyn, 3-HK, and Kyna, both by activating TDO/
IDO and by reducing the availability of pyridoxal-
5-phosphate, a necessary cofactor for many KP
enzymes. This diverts the system away from NAD+
production and instead generates a compendium
of molecules with substantial biological effects
(114, 115). Diabetic patients show increased levels
of XA and Kyna in urine, which have been con-
sequently suggested as biomarkers for type 2 dia-
betes mellitus (T2DM) (116, 117). Moreover, Trp
metabolites inhibit both proinsulin synthesis and
glucose- and leucine-induced insulin release from
rat pancreatic islets, and XA in particular binds
to circulating insulin and prevents its action on
target cells (118). Recently, Kyn-AhR signaling
in mice has been suggested to play a role in the
etiology of obesity stimulated by transforming
growth factor–b1 and Toll-like receptor 2/4 sig-
naling pathways (119).
Trp supplementation in rats, on the other hand,
suppresses hyperglycemia and increases energy
expenditure and insulin secretion when admin-
istered together with glucose (120). It also leads
to decreased glucose absorption from the intes-
tine and increased glucose uptake to adipocytes
(Fig. 4). Interestingly, oral Trp is more effective
than intraperitoneal administration. Unlike sero-
tonin, tryptamine has been shown to increase
insulin-stimulated glucose uptake into adipocytes.
In rats with hereditary T2DM, consumption of
Trp-rich chow at a young age protects beta cells
from exhaustion in old animals. However, since
Trp conversion to tryptamine is very low, a sub-
stantial increase in dietary Trp is needed to in-
crease the biological availability of tryptamine
(120). How this influences the activity of other
Trp degradation pathways and the concentra-
tion of their biologically active products has not
been investigated.
During the course of many of the aforemen-
tioned diseases and in the process of aging, the
intracellular levels of Trp and NAD+ can fall if
the KP is stressed by inflammation or imbalance
between catabolic and anabolic substrates. How-
ever, de novo synthesis from Trp is not a very
efficient way to boost NAD+ levels, because it
requires very high Trp to saturate other branches
of the catabolic pathway (4). Nevertheless, NAD+
boosting strategies seem to be successful in re-
storing mitochondrial and stem cell function (121)
and in ameliorating diseases such as muscular
dystrophy and diabetes (122, 123) or even pro-
longing life span (124). Our understanding of age-
related effects of the KP is still largely incomplete.
However, there is a general notion that altera-
tions of the KP can bring about oxidative stress,
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immune response decline, or inflammation. Lower
levels of Trp and TDO activity have been reported
in the brain of aged rodents; however, contrary
to expectations, the amount of downstream KP
metabolites is increased (25). This could be in
part due to the activity of IDO, initiated by pro-
inflammatory cytokines. Interestingly, depletion
or inactivation of TDO in Caenorhabditis elegans
or Drosophila melanogaster increases life span
(125, 126).
Microbiome, mycobiome, and virome
In the GIT, there is a complex interkingdom regu-
latory network and cross-talk occurring between
the host, the microbiome, and the mycobiome.
Fungal and bacterial commensals coexist in a
complex milieu, and their interactions can have
far-reaching implications for pathogenicity (127).
To deal with fungal infection, immune responses
need to be regulated in a way that limits tissue
damage and preserves the commensals. Over-
active inflammation primes the gut for fungal
colonization, which leads to further inflamma-
tion and propagation of this vicious cycle. Bacteria
produce indole derivatives, which have been shown
to activate interleukin-22 (IL-22)–producing innate
lymphoid cells (ILC3) in mice. In turn, IL-22 can
increase mucosal protection by driving the pro-
duction of antimicrobial peptides (18, 33). IL-22
also seems to have an indirect effect by mediating
survival of mixed microbial populations, which
prevents colonization by opportunistic pathogens
(128). Tolerogenic DCs convert Trp to Kyn, pro-
moting immune tolerance through expansion of
Treg cells in humans (Fig. 4) (129). AhR activa-
tion by Trp metabolites during development is
required for proper formation of innate lymph-
oid cells. Of note, fungi possess a constitutively
active IDO, although its importance in gut ho-
meostasis has not been sufficiently addressed.
In addition to inhibiting the growth of parasites
and bacteria, Trp depletion is also associated with
antiviral properties. Serotonin depletion by the KP
plays a role in neuroinflammation in conditions
associated with chronic viral infections [e.g., human
immunodeficiency virus (HIV)] (130). HIV, for
example, is able to alter mucosal permeability
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peripheral circulation
Trp B - Skeletal muscle
BCAA
Trp
A - Liver
Trp PPARδ
Trp
Trp PGC-1α1
Trp
kynurenines
C - Blood-brain barrier
Trp
Trp
Kyna
Fig. 4. Activity, uptake, and conversion of tryptophan and its metabolites in peripheral tissues during disease states and challenges to
homeostasis.
in patients, facilitating microbe invasion leading
to potentiated systemic immune activation (131).
Enhanced Trp to Kyn metabolism during infec-
tion contributes to both immune suppression and
to the loss of memory T cells (132).
Conclusions and future perspectives
As the role of Kyn metabolites continues to be
explored in different physiologic and disease set-
tings, the relevance of these compounds as im-
portant integrators of environmental, metabolic,
and immune system signals continues to emerge.
In this context, understanding the importance of
the gut microbiome for controlling Trp availa-
bility and Kyn metabolism could be crucial to
better understanding interindividual variability
in interpreting nutritional cues. In addition, re-
cruiting skeletal muscle through exercise training
to enhance Kyn clearance and improve mental
health could have additional, still unknown, con-
sequences. In this context, it is tempting to spec-
ulate that situations where skeletal muscle oxidative
capacity and PGC-1a1 are reduced (such as with
aging or metabolic disease) could negatively affect
the KP. Interestingly, there are several known
PPAR agonists, which could be explored as po-
tential therapeutic agents to activate the KP in
skeletal muscle. This could have applications not
only in stress-induced depression but also in other
situations where reducing the Kyn burden would
be beneficial—for example, as cytostatic drugs,
where the benefit would be several fold. Inhibition
of the KP would allow for tumor cells that escape
immune surveillance to be properly recognized.
Additionally, the same intervention could inter-
fere with cell proliferation, angiogenesis, and meta-
static potential and at the same time deprive the
tumor of energy by reducing NAD+ production. It
may seem that inhibition of a single pathway ad-
dresses the majority of cancer progression hallmarks.
As the interest in Kyn metabolites grows, it
becomes clear that where you find them conditions
Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017
D - Adipose tissue - diabetes
5-HT - fat accumulation
Trp decreased Kyn production
Kyn Kyna
KATs
mTOR
hyperglycemia
suppression
5-HT
E - Cancer
escape from immune surveillance
kynurenines
increased proliferation and invasiveness
oxidative stress protection
AhR LAT1
Trp
Kyn
Kyna
β-catenin
their biological activity. While exploring their
role in the brain and processes affecting mental
health, kynurenines are being rediscovered in
peripheral tissues where they induce local and
systemic adaptations in both health and disease.
We expect the tales of these metabolites to grow
in the years to come.
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AC KNOWLED GME NTS
The authors acknowledge members of the Ruas laboratory for
critical reading of the manuscript and funding from the Swedish
Research Council, the Novo Nordisk Foundation (Denmark),
Karolinska Institutet, the Lars Hierta Memorial Foundation, the
Strategic Research Program (SRP) in Diabetes, and the SRP in
Regenerative Medicine at Karolinska Institutet.
10.1126/science.aaf9794
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Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health
Igor Cervenka, Leandro Z. Agudelo and Jorge L. Ruas

Science 357 (6349), eaaf9794.

DOI: 10.1126/science.aaf9794

From stomach ache to depression

Our gut hurts and we feel miserable. Such disparate phenomena are mechanistically connected, but how?
Cervenka et al. review the many pathways taken by dietary tryptophan as it is metabolized into kynurenines. These
metabolites distribute into homeostatic networks that integrate diverse aspects of mammalian physiology. Depending on

Downloaded from http://science.sciencemag.org/ on September 16, 2019

physiological context, kynurenines influence health and disease states ranging from intestinal conditions to inflammation
to cancer progression. Further, they can mediate the effects of exercise, mood, and neuronal excitability and, ultimately,
communicate with the microbiota.
Science, this issue p. eaaf9794

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