REVIEW SUMMARY◥

METABOLISM

Kynurenines: Tryptophan’s metabolitesin exercise, inflammation, andmental healthIgor Cervenka, Leandro Z. Agudelo, Jorge L. Ruas*

BACKGROUND:Theessential aminoacid tryp-tophan is a substrate for the generationof severalbioactive compounds with important physiolog-ical roles. Only a small fraction of ingested tryp-tophan is used in anabolic processes, whereasthe largemajority is metabolized along the kyn-urenine pathway of tryptophan degradation.This pathway generates a range ofmetabolites,collectively known as kynurenines, involved ininflammation, immune response, and excitatoryneurotransmission.Kynurenines have been linkedto several psychiatric andmental healthdisorderssuch as depression and schizophrenia. In addi-tion, due to the close relationship between kyn-ureninemetabolismand inflammatory responses,kynurenines are emerging as recognized play-ers in a variety of diseases such as diabetes andcancer. Because the levels of enzymes of the kyn-urenine pathway in peripheral tissues tend to bemuch higher than in the brain, their contrib-ution to the kynurenine pathway can have bothlocal and systemic consequences. Due to theircharacteristics, kynurenine and its metaboliteshave the right profile to fill the role of media-tors of interorgan communication.

ADVANCES:Understandinghowthe tryptophan-kynurenine pathway is regulated in different

tissues, and the diverse biological activitiesof its metabolites, has become of interest tomany areas of science. The bioavailability oftryptophan can be affected by factors that rangefrom gut microbiome composition to systemicinflammatory signals. Gut-resident bacteria candirectly absorb tryptophan and thus limit itsavailability to the host organism. The resultingmetabolites can have local effects on both mi-crobiome and host cells and even mediate in-terspecies communication. In addition, thebiochemical fate of absorbed tryptophan willbe affected by cross-talk with other nutrientsand even by individual fitness, because skele-tal muscle has recently been shown to contrib-ute to kynurenine metabolism. With exercisetraining, skeletal muscle increases the expres-sion of kynurenine aminotransferase enzymesand shifts peripheral kynurenine metabolismtoward the production of kynurenic acid. As aconsequence, alleviating the accumulation ofkynurenine in the central nervous system canpositively 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 inflammationor infection. Kynurenine reduces the activity of

natural killer cells, dendritic cells, or proliferat-ing T cells, whereas kynurenic acid promotesmonocyte extravasation and controls cytokinerelease. Perturbations in the kynurenine path-way have been linked to several diseases. Highkynurenine levels can increase the prolifera-

tion and migratory capac-ity of cancer cells and helptumors escape immunesurveillance. Kynureninemetabolites have been pro-posed as markers of type2 diabetes and may inter-

fere at some level with either insulin secretionor its action on target cells. Kynurenines cansignal through different tissue-specific extra-and intracellular receptors in a network of eventsthat integrates nutritional and environmentalcues with individual health and fitness.

OUTLOOK: The modulation of tryptophan-kynureninemetabolismusing lifestyle andphar-macological interventions could help preventand treat several diseases with underlying in-flammatorymechanisms, includingmetabolic,oncologic, andmental health disorders. In thiscontext, and considering the substantial effectthat the gutmicrobiome can have on preabsorp-tive tryptophan metabolism, it is tempting toenvision the use of probiotic-based therapies.The discovery that aerobic exercise training canreduce kynurenine levels in circulation and inthe central nervous system could have importantimplications for the development of future gen-erationsofantidepressantmedications.This againstresses the many advantages of remaining phys-ically active throughout life. Understanding themultiple levels of control of the kynurenine path-way could help predict susceptibility to diseaselinked to environmental and dietary signals.▪

RESEARCH

Cervenka et al., Science 357, 369 (2017) 28 July 2017 1 of 1

The list of author affiliations is available in the full article online.*Corresponding author. Email: jorge.ruas@ki.seCite this article as I. Cervenka et al., Science 357, eaaf9794(2017). DOI: 10.1126/science.aaf9794

The kynurenine pathway generates tryptophan metabolites withdiverse biological activities throughout the body. Although mainlystudied in relation to the brain and mental health, the action ofkynurenine metabolites on peripheral tissues might be even more

profound. They serve as important mediators of interorgan andinterkingdom cross-talk, connecting seemingly diverse processessuch as the effects of exercise training and pathologies such asinflammatory diseases, cancer, and depression.

ON OUR WEBSITE◥

Read the full articleat http://dx.doi.org/10.1126/science.aaf9794..................................................

on June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

REVIEW◥

METABOLISM

Kynurenines: Tryptophan’s metabolitesin exercise, inflammation, andmental healthIgor Cervenka, Leandro Z. Agudelo, Jorge L. Ruas*

Kynurenine metabolites are generated by tryptophan catabolism and regulate biologicalprocesses that include host-microbiome signaling, immune cell response, and neuronalexcitability. Enzymes of the kynurenine pathway are expressed in different tissues and celltypes throughout the body and are regulated by cues, including nutritional and inflammatorysignals. As a consequence of this systemic metabolic integration, peripheral inflammationcan contribute to accumulation of kynurenine in the brain, which has been associated withdepression and schizophrenia. Conversely, kynurenine accumulation can be suppressed byactivating kynurenine clearance in exercised skeletal muscle.The effect of exercise trainingon depression through modulation of the kynurenine pathway highlights an importantmechanism of interorgan cross-talk mediated by these metabolites. Here, we discussperipheral mechanisms of tryptophan-kynurenine metabolism and their effects oninflammatory, metabolic, oncologic, and psychiatric disorders.

Tryptophan (Trp) is an essential amino acidcritical for protein synthesis, but it also servesas 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 nervoussystem (CNS) and linked to alterations inmood,anxiety, or cognition (1). Serotonin can be furtherconverted to N-acetylserotonin (NAS) and mela-tonin, adding control over circadian rhythmicityto the list of biological roles for Trp metabolites(2). However, in mammals, the majority of freeTrp is degraded through the kynurenine pathway(KP) (Fig. 1) and generates a range of metabolitesinvolved in inflammation, immune response, andexcitatory neurotransmission (3). The final prod-uct of theKP is nicotinamide adenine dinucleotide(NAD+), an important cofactor in cellular reactionslinked to energymetabolism (4) that is emergingas an attractive therapeutic target for several dis-eases. Here, we focus on peripheralmechanismsthat contribute to Trp-KP metabolism.Kynurenine (Kyn) and its metabolites (all with

defined chemical identities but often collectivelycalled “kynurenines”) are known for their effectson the CNS and have been linked to several psy-chiatric and mental health disorders such as de-pression and schizophrenia (5). The CNS receivesabout 60%ofKyn from the periphery by transportacross the blood-brain barrier (BBB), and the re-maining is produced locally. Kyn degradation in

the CNS is divided between different cell types,amongwhich astrocytes andmicroglia play impor-tant roles with antagonizing actions (6). Microgliaproduce quinolinic acid (Quin), anN-methyl-D-aspartate receptor (NMDAR) agonist, whereas as-trocytes are equipped to generate kynurenic acid(Kyna), anNMDARand a7 nicotinic acetylcholinereceptor (a7nAChR) antagonist. The levels of thesetwo Kyn metabolites have hence been associatedwith neuronal excitotoxicity (Quin) or protection(Kyna) and are found to be dysregulated inmajordepressive disorders and schizophrenia (7).Like Trp andKyn, 3-hydroxykynurenine (3-HK)

crosses the BBB and contributes to Quin gener-ation in microglia but is also able to exert moredirect deleterious effects linked to oxidative stressand apoptosis (8, 9). Defects inKyn signaling havealso been seen inmousemodels of neurodegenera-tive diseases such as Alzheimer’s andHuntington’s(10, 11). The underlying feature of these differentpathologies seem to converge on neuroinflamma-tion andassociated events, includingbrain infiltra-tionof circulating immunecells,microglia activation,and high levels of proinflammatory cytokines (12).The levels of enzymes of the KP in peripheral

tissues tend to bemuch higher than in the brain.For example, macrophages have a 20-fold highercapacity to produceQuin thanmicroglial cells. Thisis particularly important in situations of macro-phage infiltration across the BBB. Immune cellsare both important sources and targets for Kynmetabolites as they express high levels of severalenzymes of the pathway [e.g., indoleamine 2,3-dioxygenase (IDO) and kynurenine aminotrans-ferases (KATs)] and also of receptors such as Gprotein–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

for the transcription factor aryl hydrocarbon re-ceptor (AhR) (similar activity has been shown forKyn) (14, 15). IDO, together with tryptophan 2,3-dioxygenase (TDO) and AhR are present in sometumor cells, so it has been proposed that Kyn canhave a double role in promoting cancer invasionand immune escape. On one hand, activation ofcancer cell AhR by Kyn increases the expressionof genes that promote cell migration (16, 17). Onthe other hand, activated immune cell AhR sup-presses effector T cells and increases immune tol-erance by targeting dendritic and regulatory Bcells (18).The gastrointestinal tract (GIT) has an impor-

tant role in Trp metabolism. The upper GIT is re-sponsible for the majority of serotonin synthesis(19). It also absorbs and is directly influenced byKynmetabolites such as Kyna that are present infood and can act locally on GPR35 (20). The lowerportion of the GIT is home to substantial num-bers ofmicrobiota, which are affected by Trp avail-ability and in turn act on gutmucosal tissues andresident immunepopulation through the produc-tion of indole compounds that bind to AhR (21).Skeletalmuscle has recently been added to the

list of tissues that contribute to Kyn metabolism(22). This happens in the setting of exercise train-ing anddepends on the transcriptional coactivatorperoxisomeproliferator–activated receptor (PPAR)gamma coactivator-1a1 (PGC-1a1), which enhancesKAT gene expression andKyn to Kyna conversion.This links peripheral and central Kyn metabolismandprovides amechanism for someof the benefitsof 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 arequired daily dose of 3.5mg per kg ofweight (23).The highest concentration of Trp can be found inchocolate, eggs, fish, dairy products, legumes, andmeat. Less than 1% of ingested Trp is used forprotein synthesis because, under conditions of un-altered nitrogen balance, the demand for proteinsynthesis is met by protein breakdown (24). Themajority of Trp is thus metabolized along one offour known pathways, giving rise to a variety ofbiologically active compounds (e.g., serotonin, trypt-amine, indoles, kynurenines, andNAD+) (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 toavoid competition, with the notable exceptionof the BBB (26). The majority of Trp is importedinto the gut, where only a fraction is used,whereasthe rest enters portal circulation and undergoesliver metabolism. The remaining Trp, togetherwith its liver degradation products, is distributedto peripheral circulation and transported to tissuessuch as the brain, heart, and skeletal muscle. Trpnot taken up by the upper GIT ismetabolized byresidentmicrobiota to indole compounds (27), im-portant interspecies signaling molecules (28).Trp is the only amino acid transported bound

to albumin. However, degradation pathways canonly use Trp in its free form, which corresponds

RESEARCH

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 1 of 8

Department of Physiology and Pharmacology, Molecular andCellular Exercise Physiology, Karolinska Institutet, SE-17177Stockholm, Sweden.*Corresponding author. Email: jorge.ruas@ki.se

on June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

to 5 to 10% of total Trp (29). The mode of Trpdegradation and concentration of its end productsis a function of free Trp concentration, which is inturn 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 aconsequence, increasing NEFA levels by, for ex-ample, adrenaline or phosphodiesterase inhib-itors, increases free Trp. Conversely, antilipolyticagents such as insulin are able to decrease Trpconcentration by the same mechanism (25).The gut microbiota numbers are estimated to

outnumber cells in our body by a factor of 10 andtend to increase distally along the intestine (31).Due to their sheernumber, theyhavenonnegligibleeffects on Trp metabolism. Gut microbiota candirectly absorb Trp and thus limit its availabilityto the host organism. This can be seen in germ-free (GF) mice, which have high circulating Trplevels that normalize postcolonization. Bacteriallyproduced indoles interactwith pregnaneX recep-tors (PXRs) and mediate a range of effects, in-cluding improvedmucosal homeostasis and barrierfunction, and as such represent a fascinating ex-ampleof interkingdomcommunication (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, serotoninwas identified as a player in the peristaltic reflex ofthe gut and has since been shown to influence co-lonicmorphology,maintenance of entericmucosa,pellet formation, and propulsive motility. Cur-rently, the role of serotonin in the brain-gut axisthrough the activity of the microbiota is beingavidly explored (21). Thus, the extent of Trp use bybacteria, its dietary supply, and local turnover bythe GIT can have far-reaching implications in thedevelopment and proper functioning of both theenteric nervous system (ENS) and CNS.

The kynurenine pathway of tryptophandegradation

Decarboxylation of Trp to tryptamine, transam-ination to indol-3-yl pyruvic acid, and hydroxyl-ation to serotonin are minor Trp degradationpathways. Although serotonin is usually associ-ated with the brain, the majority of its produc-tion is localized in the gut. Asmuch as 90% of totalserotoninproduction (stored in secretory granules)comes from enterochromaffin cells and, to a lesserextent, from serotonergic neurons of the ENS (34).More than 95%of Trp ismetabolized along the

KP to yield nicotinamide and NAD+ (24) (Fig. 1).The rate-limiting step of the KP is the conversionof Trp toN-formylkynurenine, which ismediatedby two spatially segregatedmembers of this path-way. In the liver, the first step in Trp degradationis mediated by TDO, which under normal condi-tions is responsible for the majority of this con-version (35). TDO is the main determinant of Trpavailability to extrahepatic tissues and is induc-ible by Trp itself, glucocorticoids, and estrogens(36, 37). The extrahepatic branch of the KP is

under the control of two IDO enzymes (IDO1 andthemore recently discovered IDO2), whose activityis negligible under basal conditions but dramat-ically inducible by several stimuli, such as inflam-matory signals (e.g., interferon-g). IDOs aremostlyactive in the immune system and mucosal tissuessuch as gut (38, 39). Conversely, IDO can be inhi-bited by elevated levels of Trp, which results inchanneling the flux of Trp degradation back toTDO (40). Interestingly, the TDO and IDO genesdo 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 onwhich enzyme tips the conversion scales (5).Undernormal conditions, the majority of Kyn is excretedin the urine, so its bioavailability only increaseswhen the flux of Trp down the KP exceeds renalclearance (42). Kyn is usually hydroxylated to 3-HKand then further converted to 3-hydroxyanthranilicacid (3-HAA). 3-HAA is rapidly converted to Quinby the nonenzymatic reaction of an intermediaryproduct and proceeds with conversion to NAD+,a preferred end product of the KP (43). Underspecific conditions, picolinic acid (PA) is formedinstead. The other branch of the pathway, leadingto the production of Kyna and xanthurenic acid(XA) fromKyn isminor under normal conditionsbut increases under Trp orKyn loading (Fig. 1) (44).

These ratios change dramatically under differentTrp loads and are also influenced by vitamin B6availability (45). Our understanding of how theproportions of different Kynmetabolites changewith environmental context is incomplete, andmany contradictory results have been reported.Interestingly, this has prompted the developmentof mathematical models to help us understandmetabolite flux through the KP (46).

Conservation of kynurenine metabolismthroughout evolution

In bacteria, fungi, and plants, the biosynthesis ofaromatic amino acids such as Trp is provided bythe shikimate pathway. Whereas bacteria spendthemajority of theirmetabolic energy on proteinsynthesis, plants use this pathway to generate alarge variety of secondarymetabolites (47). Regard-ing the conservation of the KP, the TDO enzymecanbe found in themajority of bacterial species andin almost all metazoan species but has probablybeen lost in fungi during the course of evolution(Fig. 2) (48). IDO enzymes have been discoveredin vertebrates, and—even though its homologshavebeen confirmed in other species, such asmolluscs,yeasts, or deuterostomian invertebrates—they re-main poorly characterized. On the other hand,arthropods and nematodes generally lack IDOenzymes. The analysis ofmore downstream com-ponents of KP shows that vertebrates, yeasts, andsome invertebrates can generate NAD+ throughthe KP, with TDO serving as a main supplier ofprecursors and IDO having a different role. Insectsand invertebrates lack someof the downstreamKPenzymes, suggesting that alternatemeans ofNAD+

generation have prevailed throughout evolution(Fig. 2). TDO is regarded as a “high catalytic activity”enzyme in contrast to IDO; however, this seemsto be different in fungi where IDO assumed thelost TDO functionality. In vertebrates, IDO1 ac-quired high affinity for Trp after IDO1/IDO2diver-gence. The biological importance of “low-catalyticactivity” IDOs remains unclear and controversial,although they have been well conserved through-out evolution. KAT enzymes have also been some-what conservedduring evolution and canbe foundinprokaryotes, insects, nematodes, andvertebrates.However, some species contain multiple genes(nematodes, 2; humans, 4),which couldhave arisenduring 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 specializedwith time. Plants possess the enzyme tryptophanaminotransferase–related (TAR1) that plays a rolein 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, Kynahas been studied most. It was originally discov-ered in canine urine, but higher concentrationshave beenmeasured in the gut (increasing grad-ually along its length), bile, pancreatic juice of ratsand pigs, and, to a lesser extent, in human salivaand synovial and amniotic fluid (20). Its presenceinmany food products has also beendetermined.

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 2 of 8

Fig. 1. Overview of the kynurenine pathwayof tryptophan degradation. 3HAO,3-hydroxyanthranilic acid oxygenase; NAPRT1,nicotinate phosphoribosyltransferase.

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

Thehighest concentrations are found inhoneybeeproducts, broccoli, and some potatoes (50). Manymedicinal herbs contain high concentrations ofKyna, indicating therapeutic potential for the gas-trointestinal system (51). In addition to the Kynaingested in food or synthesized along the KP inthe GIT, the gut microflora possesses the enzymeaspartate aminotransferase, which is analogous tomitochondrial KAT4 and produces Kyna by trans-amination of Kyn. The action of Kyna on the GITis several fold. Early reports suggested that Kynaisable toprotect the intestinalmucosa in the settingsof obstructive jaundice andprotect fromethanol- ortoxin-inducedulcers (52). In addition,Kyna canalsomodulate local inflammation,most likely throughactivation of GPR35, which is highly expressed inthe immune cells of the GIT.

Liver control of tryptophan-kynureninemetabolism

Amongthemanycell types that expressKPenzymes,hepatocytes contain all the machinery requiredfor Trp degradation toward any branch of the KP(53). Most important, they are the sole cell typewith high TDO activity and thus have a centralrole in themodulation of systemic Trp levels (35).Because TDO has low affinity for Trp, it remainsactive even when Trp exceeds the levels requiredfor serotonin and protein synthesis (54). If the re-quirements for protein synthesis are surpassed, theliver metabolizes excess Trp to NAD+, oxidizingthe rest via the glutarate pathway (Fig. 3). If Trpconcentration is low, the liverwill clear andmetab-olize circulating Trp to NAD+ for energy demands(53). Interestingly, when Trp requirements aremetand liver TDO activity is increased by glucocorti-coids, saturation of thepathwaywill lead to leakageof some of its metabolites, such as Kyn.Of note, factors that are detrimental tomental

health, such as stress, social isolation, sleep depri-vation, and lack of physical activity, elevate circu-lating glucocorticoid levels in both humans andnonhuman socialmammals (55, 56). Thiswill leadto a feed-forward loop in which liver Kynmetab-olism increases the output of KP substrates fromthe 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 ofglucocorticoid receptor (GR) resistance, which inturn fails to dampen the inflammatory response.The reduction in GR activity leads to suppressedliver TDO expression and a shift to extrahepaticTrp andKynmetabolism (42). One reason for thisshift in Trp degradation could be to promote theimmunomodulatory roles of kynurenines and re-duce inflammation.

Immune system

In immune cells, as inmost extrahepatic tissues,the KP is initiated by IDO. This enzyme is ubiq-uitously expressed and has affinity for substratesother thanTrp, including 5-hydroxytryptophanandserotonin. IDO is highly regulated in the im-mune system, where its expression is increased byinterferon-g (IFN-g), tumornecrosis factora (TNFa),and pathogenic infections (57, 58). IDO-mediated

Trp catabolism in the host microenvironmentsurrounding parasites, viruses, and bacteria wasseen as away 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 ofactivity on immune cell regulation (60). An un-restrained immune responsewould bedetrimental,so cells have developed metabolic pathways tocontrol immuneactivation (61). Thus, IDOactivity isstimulated by type 1 or proinflammatory cytokines(62) and inhibited by type 2 or anti-inflammatorycytokines (63). Trpdegradationby IDOhas emergedas a rate-limiting step for metabolic immune reg-ulation, according to two proposed mechanisms:first, by the generation of Trp metabolites withimmuneactivity, suchasKynandKyna (64); second,by triggering an amino acid–sensing signal in cellsundergoingTrpdepletion (65). Initial observationsshowed that Kyn metabolites, in particular Kynitself, suppress the activity of natural killer cells(NKT) (66) and antigen-presenting cells (APC) suchas dendritic cells (DC), monocytes, and macro-phages inmice (67, 68). Furthermore, Kyn blocksT cell proliferation and induces T cell death (69),and IDO-mediated Kyn production in DC leads tothe proliferation of regulatory T cells (Tregs) (67, 70).These effects are, at least in part, mediated by Kynactivation of AhR (Fig. 3) (15, 71), a ligand-activatedtranscription factor involved inxenobiotic responseto foreign substances. It is expressed in cells ofboth innate and adaptive immune systems, andit has been shown to have anti-inflammatory ac-tivity inmice (72, 73).Given theKyn-AhR–mediateddecrease in immune surveillance, regulating theKyn pathway has become an attractive target forcancer therapy. Interestingly, the Kyn-AhR axishas been postulated to constitute one of the linksbetween chronic inflammation and tumor pro-gression (15). Similarly, Kyna was also found toactivate AhR (14), butwhether this activation leadsto similar immune regulation remains unclear.Kynahas been recently shown to alsobe a ligand

for GPR35. This receptor is expressed in humanCD14+monocytes, T cells, neutrophils, DCs, eosino-phils, basophils and invariant NKT (iNKT) cells

(13, 74). Of those, circulating monocytes displaythe highest expression of GPR35, and its interac-tionwithKyna has been shown to promotemono-cyte extravasation (75). It was later confirmed thatKyna-GPR35 interaction reduces the inflamma-tory response induced by lipopolysaccharide (LPS)stimulation inmonocytes andmacrophages (76)and controls cytokine release in human iNKT cells(74). Taken together, the effects of Kyna on im-mune cell activationmight represent a direct anti-inflammatory mechanism that further reinforcesthe immunosuppressant function of Trp catabo-lism. Other metabolites of the KP, such as 3-HAAand Quin, have been shown to induce apoptosisof type 1 T helper (TH1) cells, while promoting pro-liferation of type 2 T helper (TH2) cells (67). Thisimmune shift would favor cell survival against thedeleteriouseffectofuncontrolled immuneactivation.Inflammatory conditions are characterized by

high levels of cellular stress and energy use, oftenaccompanied by increased rates of DNA damage.In macrophages, as in the liver, oxidation of Trpthrough theKP can replenishNAD+ levels tomeetenergy requirements (77). In addition,NAD+ is usedby poly (ADP-ribose) polymerase (PARP) inDNArepairmechanisms (78). Trp catabolism in immunecells is therefore a negative feedbackmechanismthat 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 theCNS. The discovery that skeletal muscle can con-tribute to the KP (22) is highlighted by the factthat sedentary lifestyles can lead to chronic low-grade inflammation in this organ. This adds a newregulatorynode toKynmetabolism in theperiphery.

Skeletal muscle

The effect of skeletal muscle and exercise on nu-trientmetabolism has been appreciated for a longtime. Aerobic exercise training elevates the levelsof PGC-1a1 in skeletalmuscle ofmice andhumans.PGC-1a1 is a transcriptional coactivator importantfor adaptive responses inmany tissues (79), mostnotably in skeletal muscle. When activated, PGC-1a1, togetherwithPPARa/d, increases skeletalmus-cle expressionofKATenzymesand shifts peripheralKynmetabolism toward the production of Kyna.Under these conditions, Kyna does not cross theBBB, so reducing Kyn levels in the brain can re-duce stress-mediated effects underlying depressivesymptoms. In fact, mice with transgenic expres-sion of PGC-1a1 in skeletalmuscle (and thereforehigher skeletal muscle KAT levels) are resilientto developing depressive-like behavior caused byelevated Kyn levels resulting from stress or exog-enous administration (Fig. 4) (22). This pathwayhas been shown to be active in both mouse andhumanmuscle (22, 80).Modulating PGC-1a1-PPARactivation in skeletalmuscle could become a newtherapeutic intervention to regulate Trp-Kynme-tabolism. In particular, this would preserve theimmunosuppressant actionofkynurenines viaKynaand decrease the neurotoxic effects associatedwithKyn during chronic inflammatory states.SkeletalmuscleKP is likely to be affected by other

amino acid metabolic pathways. For example,

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 3 of 8

Fig. 2. Evolutionary conservation of enzymesof the kynurenine pathway. KYNU,Kynureninase.

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

duringphysical exercise, skeletalmuscle canoxidizebranched-chain amino acids (BCAA) and Trp forenergy (81). Muscle fibers contain all the neces-sary transporters/carriers for amino acid clearance;however, circulating BCAA compete with Trp andkynurenines for the same transporters (82). More-over, BCAA inhibit some of the enzymes of theKP (83), especially KATs (84), which indicatesthat fuel availability (in particular, BCAA) canaffect skeletal muscle Trp metabolism and Kynclearance.

Kynurenine metabolites and disease

Trpmetabolism ismostwidely knownand studiedin relation to disorders of the nervous system. Itseffect on stress-related depression, schizophrenia,and Alzheimer’s and Parkinson’s diseases havebeen comprehensively reviewed elsewhere (85).The following sections summarize recent advancesin our understanding of how Kyn metabolismis dysregulated in peripheral tissue dysfunction.However, it is important to remember that themajority of defects of Trpmetabolism in peripheralorgans can also have a strong effect on the CNS,resulting in complications such as anxiety anddepression.

Irritable bowel syndrome and disease

Twomain diseases of the GIT are associatedwithTrp metabolism: irritable bowel syndrome (IBS)and irritable bowel disease (IBD). IBS is charac-terized by abdominal pain together with alteredbowel habits and affects a considerable portionof the adult population (15 to 20%) (86). Increasein serum-free Trp has been documented in IBSpatients. The etiology of IBS has been connectedto abnormal serotonergic neuronal signaling duringdevelopment and also to alterations in serotonin

production and signaling in enterochromaffincells (87, 88). One of the hallmarks of the disease,visceral hypersensitivity, is thought to occur as aresult of the sensitization of afferent neurons andto compromised epithelial integrity, which in turnmakes it possible for intraluminal compounds tocross the gut wall barrier (89).By contrast, IBD is a relapsing inflammatory

condition with complex etiology that affects 1 in500 individuals, peaking around the age of 20.The etiology of IBD lies at the intersection ofdysbiosis ofmicrobiota, host immunity, andgeneticpredisposition, with anxiety and depression ascommon comorbidities (90). In this context, it isnot unexpected that aberrant Trpmetabolism isa common denominator of these complications.IBD patients have increased plasma levels of Kynand Kyna, probably as a result of increased IDOexpression. IBD is also connected to microbiotahomeostasis, and IBDpatients also have increasedrisk of colorectal cancer (91). Recently, caspaserecruitmentdomain–containingprotein9 (CARD9)has been found to be an IBD susceptibility gene.CARD9 encodes a host adaptor protein criticalfor immune responses against microorganisms.Microbiota derived from CARD9 knockout (KO)mice have compromised Trp to indole conversionand cannot activate AhR. Furthermore, bacteriafrom CARD9 KO animals are sufficient to inducecolitis in wild-type germ-free animals. Coloniza-tion of CARD9 KO animals with bacteria capableof catabolizing Trp alleviates the disease (92). Dueto the tight regulation between microbiota andhost responses, individual contributionswill provechallenging to distinguish. Interestingly, plant-derived indole compounds have been used in tra-ditionalmedicine to treat IBD,which lends supportto the importance of the interactions of kynur-

enineswithAhR and their actions on the immunesystem (93).

Pancreatitis

One of the less-studied diseases with connectionto Trp metabolism is acute pancreatitis (AP). Itis a severe sterile inflammation of the pancreasconnected to gut dysfunction that can lead tomultiorgan failure with very highmortality rates(94). PlasmaKyn of AP patients seems to originatein the gut-associated lymphoid tissue (GALT), andits levels correlate with magnitude of injury andsystemic inflammatory burden (95). Kynurenine-3-monooxidase (KMO) is central to the patho-genesis of pancreatitis, and its genetic ablationor pharmacological inhibition conveys protectionfrom deleterious effects. The pathology of AP ismediated by 3-HK transported in the mesentericlymph to other organs such as the lungs, where itcauses near total cell death by oxidative stress,apoptosis, and pathological protein cross-linking(96). Decreasing 3-HK production from Kyn bydiverting it togeneratingKyna inhibitsLPS-inducedTNFa secretion and leads to increased survivalinrodentmodelsofacutepancreatitis (96).Melatonin,another Trp metabolite, has emerged as a treat-ment option of AP by reducing oxidative stressand protecting from inflammation (97).

Cancer

Cancer cells have amultifaceted relationshipwithalteredTrpmetabolism. Several tumor types showincreased Trp uptake [as evidenced by a-[11C]-methyl-L-tryptophan (AMT)–positron emissiontomography (PET) scanning of human patients],which in turn correlates with poor disease prog-nosis (98). Although the reason for this is not fullyunderstood, tumor cellsmight needhighTrp levels

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 4 of 8

Fig. 3. Activity, uptake, and conversion of tryptophan and its metabolites in peripheral tissues during unchallenged conditions. 5-HT, 5-hydroxytryptamine; ROS, reactive oxygen species.

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

to fuel an ever-increasing demand for proteinsynthesis. On the other hand, Trp starvationwillinduce general control nonderepressible 2 (GCN2)kinase that inhibits G1 to S transition, inducingcell cycle arrest (99). To prevent this, tumorsmightincrease their Trp supply by up-regulating LAT1expression. However, LAT1 has been shown towork in a bidirectional manner, exchanging gluta-mate for Trp. To counteract this shortcoming, ithas been shown that proliferating tumor cells,but not resting T cells, up-regulate expression ofthe glutamate transporter by the activating tran-scription factor 4 (ATF4) pathway after sensingTrp unavailability (100, 101). Moreover, tumorsshow enhanced IDO expression, with downstreammetabolites, such as Kyn, being able to activatebeta-catenin signaling, leading to increased coloncancer proliferation inmice (102). IDO expressionin mouse models of ovarian cancer, melanoma,and renal cell carcinoma correlateswith increasedangiogenesis (103). TDO, on the other hand, hasbeenpredominantly connected to the escape fromthe immune system surveillance and increasedmigratory capacity. Kyn generated in tumorsmightbe subsequently released into the surroundingmilieu, where it can affect a variety of immunecell populations by binding to AhR (Fig. 4). More-over, it can have autocrine effects and stimulateinvasiveness 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 intermediatescan also induce apoptosis in a variety of immunecells (67).NAD+ is an important cofactor involved in

genome stability, stress tolerance, and metab-olism (4). Probably for a combination of all thosereasons, tumor cells have broadly altered NAD+

use and production. It has been postulated that,in tumor cells, most NAD+ comes from salvagepathways. However, they also possess the abilityto shift to de novo production using Trp as asource. This becomes relevant in the setting ofNAD+-depleting anticancer drugs, irradiation, orinduction of oxidative stress by alkylating agents.For example, it has been shown that reducing Trpuptake leads to rapid NAD+ depletion by PARP,resulting in apoptotic cell death of lung cancercellsmediatedbyNAD(P)Hquinonedehydrogenase1 (NQO1) (106). On the other hand, tumors elevateexpression of quinolinate phosphoribosyltrans-ferase (QPRT),which protects them fromoxidativestress by converting Quin to NAD+. IncreasedQPRTexpression is generally associatedwith poordisease prognosis in humans (107). At the time ofwriting, several modulators of the KP or analogsof Trp metabolites are undergoing clinical trialsfor cancer treatment (108).

Diabetes

The main links between diabetes and Trp metab-olism are inflammation and immune suppression.Additionally, increased production of serotoninhasbeen implicated in thepathogenesis of diabetes(109). Glucocorticoid-mediated insulin resistance

elevates the synthesis of serotonin in the liver andadipose tissue ina tryptophanhydroxylase 1 (Tph1)–dependent manner. Serotonin binds to mecha-nistic target of rapamycin (mTOR), increasingliver lipogenesis and impairing insulin signalingin adipocytes. Accordingly, inhibition of serotonindegradation by monoamine oxidase A (MAOA)exacerbates the effects (110). Compounding theproblem, serotonin has well-documented effectson brain-mediated control of appetite. Despite itsanorexigenic effects, serotonin transporter (SERT)KO animals are obese and, conversely, Tph1 and2 KOmice lose body weight (111). Several studieshave highlighted the role of serotonin in the regu-lation of white and brown adipose tissue energystorage and expenditure. Serotonin can increasefat accumulation in humans and rodents, andthe activation of its receptors in hypertrophiedfat cells induces adiponectin production. Con-versely, Tph1 KO mice have significantly lowerweight, improved glycemic control, enhancedenergy expenditure, and lower adiposity whenon high-fat diets (112).In the Torii ratmodel of spontaneous diabetes,

decreases in Trp and Kyn production were iden-tified as biomarkers of aprediabetic state.Morbidlyobese patients have lower circulating levels ofTrp andhigherKyn/Trp ratios (113). Chronic stressand low-grade inflammation are major risk fac-tors in prediabetes to diabetes transition. Theycan skew the balance of Trpmetabolism towardKyn, 3-HK, and Kyna, both by activating TDO/IDO and by reducing the availability of pyridoxal-5-phosphate, a necessary cofactor for many KPenzymes. This diverts the system away fromNAD+

production and instead generates a compendiumof molecules with substantial biological effects(114, 115). Diabetic patients show increased levelsof XA and Kyna in urine, which have been con-sequently suggested as biomarkers for type 2 dia-betes mellitus (T2DM) (116, 117). Moreover, Trpmetabolites inhibit both proinsulin synthesis andglucose- and leucine-induced insulin release fromrat pancreatic islets, and XA in particular bindsto circulating insulin and prevents its action ontarget cells (118). Recently, Kyn-AhR signalingin mice has been suggested to play a role in theetiology of obesity stimulated by transforminggrowth factor–b1 and Toll-like receptor 2/4 sig-naling pathways (119).Trp supplementation in rats, on the other hand,

suppresses hyperglycemia and increases energyexpenditure and insulin secretion when admin-istered together with glucose (120). It also leadsto decreased glucose absorption from the intes-tine and increased glucose uptake to adipocytes(Fig. 4). Interestingly, oral Trp is more effectivethan intraperitoneal administration. Unlike sero-tonin, tryptamine has been shown to increaseinsulin-stimulated glucose uptake into adipocytes.In rats with hereditary T2DM, consumption ofTrp-rich chow at a young age protects beta cellsfrom exhaustion in old animals. However, sinceTrp 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 notbeen investigated.During the course of many of the aforemen-

tioned diseases and in the process of aging, theintracellular levels of Trp and NAD+ can fall ifthe KP is stressed by inflammation or imbalancebetween catabolic and anabolic substrates. How-ever, de novo synthesis from Trp is not a veryefficient way to boost NAD+ levels, because itrequires very high Trp to saturate other branchesof the catabolic pathway (4). Nevertheless, NAD+

boosting strategies seem to be successful in re-storingmitochondrial and stem cell function (121)and in ameliorating diseases such as musculardystrophy 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,immune response decline, or inflammation. Lowerlevels of Trp and TDO activity have been reportedin the brain of aged rodents; however, contraryto expectations, the amount of downstream KPmetabolites is increased (25). This could be inpart due to the activity of IDO, initiated by pro-inflammatory cytokines. Interestingly, depletionor inactivation of TDO in Caenorhabditis elegansor 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 betweenthe host, the microbiome, and the mycobiome.Fungal and bacterial commensals coexist in acomplex milieu, and their interactions can havefar-reaching implications for pathogenicity (127).To deal with fungal infection, immune responsesneed to be regulated in a way that limits tissuedamage and preserves the commensals. Over-active inflammation primes the gut for fungalcolonization, which leads to further inflamma-tion and propagation of this vicious cycle. Bacteriaproduce indole derivatives, which have been shownto activate interleukin-22 (IL-22)–producing innatelymphoid cells (ILC3) inmice. In turn, IL-22 canincrease mucosal protection by driving the pro-duction of antimicrobial peptides (18, 33). IL-22also seems to have an indirect effect bymediatingsurvival of mixed microbial populations, whichprevents colonization by opportunistic pathogens(128). Tolerogenic DCs convert Trp to Kyn, pro-moting immune tolerance through expansion ofTreg cells in humans (Fig. 4) (129). AhR activa-tion by Trp metabolites during development isrequired for proper formation of innate lymph-oid cells. Of note, fungi possess a constitutivelyactive IDO, although its importance in gut ho-meostasis has not been sufficiently addressed.In addition to inhibiting the growth of parasitesand bacteria, Trp depletion is also associatedwithantiviral properties. Serotonin depletion by the KPplays a role in neuroinflammation in conditionsassociatedwith chronic viral infections [e.g., humanimmunodeficiency virus (HIV)] (130). HIV, forexample, is able to alter mucosal permeability

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 5 of 8

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

in patients, facilitatingmicrobe invasion leadingto potentiated systemic immune activation (131).Enhanced Trp to Kyn metabolism during infec-tion contributes to both immune suppression andto the loss of memory T cells (132).

Conclusions and future perspectives

As the role of Kyn metabolites continues to beexplored 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 ofthe gut microbiome for controlling Trp availa-bility and Kyn metabolism could be crucial tobetter understanding interindividual variabilityin interpreting nutritional cues. In addition, re-cruiting skeletalmuscle through exercise trainingto enhance Kyn clearance and improve mentalhealth could have additional, still unknown, con-sequences. In this context, it is tempting to spec-ulate that situationswhere skeletalmuscle oxidativecapacity and PGC-1a1 are reduced (such as withaging ormetabolic disease) could negatively affectthe KP. Interestingly, there are several knownPPAR agonists, which could be explored as po-tential therapeutic agents to activate the KP inskeletalmuscle. This could have applications notonly in stress-induced depression but also in othersituations where reducing the Kyn burden wouldbe beneficial—for example, as cytostatic drugs,where the benefit would be several fold. Inhibitionof the KPwould allow for tumor cells that escapeimmune surveillance to be properly recognized.Additionally, the same intervention could inter-ferewith cell proliferation, angiogenesis, andmeta-static potential and at the same time deprive thetumor of energy by reducingNAD+ production. Itmay seem that inhibition of a single pathway ad-dresses themajorityof cancerprogressionhallmarks.As the interest in Kyn metabolites grows, it

becomes clear thatwhere you find themconditions

their biological activity. While exploring theirrole in the brain and processes affecting mentalhealth, kynurenines are being rediscovered inperipheral tissues where they induce local andsystemic adaptations in both health and disease.We expect the tales of these metabolites to growin the years to come.

REFERENCES AND NOTES

1. T. Canli, K. P. Lesch, Long story short: The serotonintransporter in emotion regulation and social cognition. Nat.Neurosci. 10, 1103–1109 (2007). doi: 10.1038/nn1964;pmid: 17726476

2. C. A. Yates, J. Herbert, Differential circadian rhythms inpineal and hypothalamic 5-HT induced by artificialphotoperiods or melatonin. Nature 262, 219–220 (1976).doi: 10.1038/262219a0; pmid: 934338

3. T. W. Stone, N. Stoy, L. G. Darlington, An expanding range oftargets for kynurenine metabolites of tryptophan. TrendsPharmacol. Sci. 34, 136–143 (2013). doi: 10.1016/j.tips.2012.09.006; pmid: 23123095

4. C. Cantó, K. J. Menzies, J. Auwerx, NAD+ metabolism and thecontrol of energy homeostasis: A balancing act betweenmitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).pmid: 26118927

5. Y. Chen, G. J. Guillemin, Kynurenine pathway metabolites inhumans: Disease and healthy states. Int. J. Tryptophan Res.2, 1–19 (2009). pmid: 22084578

6. G. J. Guillemin, G. Smythe, O. Takikawa, B. J. Brew,Expression of indoleamine 2,3-dioxygenase and productionof quinolinic acid by human microglia, astrocytes, andneurons. Glia 49, 15–23 (2005). doi: 10.1002/glia.20090;pmid: 15390107

7. N. Müller, M. J. Schwarz, The immune-mediated alteration ofserotonin and glutamate: Towards an integrated view ofdepression. Mol. Psychiatry 12, 988–1000 (2007).doi: 10.1038/sj.mp.4002006; pmid: 17457312

8. M. P. Heyes, C. Y. Chen, E. O. Major, K. Saito, Differentkynurenine pathway enzymes limit quinolinic acid formationby various human cell types. Biochem. J. 326, 351–356(1997). doi: 10.1042/bj3260351; pmid: 9291104

9. L. Amori, P. Guidetti, R. Pellicciari, Y. Kajii, R. Schwarcz, On therelationship between the two branches of the kynureninepathway in the rat brain in vivo. J. Neurochem. 109, 316–325(2009). doi: 10.1111/j.1471-4159.2009.05893.x; pmid: 19226371

10. M. F. Beal et al., Replication of the neurochemicalcharacteristics of Huntington’s disease by quinolinic acid.Nature 321, 168–171 (1986). doi: 10.1038/321168a0;pmid: 2422561

11. W. Wu et al., Expression of tryptophan 2,3-dioxygenase andproduction of kynurenine pathway metabolites in tripletransgenic mice and human Alzheimer’s disease brain.PLOS ONE 8, e59749 (2013). doi: 10.1371/journal.pone.0059749; pmid: 23630570

12. R. Dantzer, J. C. O’Connor, M. A. Lawson, K. W. Kelley,Inflammation-associated depression: From serotonin tokynurenine. Psychoneuroendocrinology 36, 426–436 (2011).doi: 10.1016/j.psyneuen.2010.09.012; pmid: 21041030

13. J. Wang et al., Kynurenic acid as a ligand for orphan Gprotein-coupled receptor GPR35. J. Biol. Chem. 281,22021–22028 (2006). doi: 10.1074/jbc.M603503200;pmid: 16754668

14. B. C. DiNatale et al., Kynurenic acid is a potentendogenous aryl hydrocarbon receptor ligand thatsynergistically induces interleukin-6 in the presence ofinflammatory signaling. Toxicol. Sci. 115, 89–97 (2010).doi: 10.1093/toxsci/kfq024; pmid: 20106948

15. C. A. Opitz et al., An endogenous tumour-promoting ligandof the human aryl hydrocarbon receptor. Nature 478,197–203 (2011). doi: 10.1038/nature10491;pmid: 21976023

16. N. C. D’Amato et al., A TDO2-AhR signaling axis facilitatesanoikis resistance and metastasis in triple-negative breastcancer. Cancer Res. 75, 4651–4664 (2015). doi: 10.1158/0008-5472.CAN-15-2011; pmid: 26363006

17. J.-Y. Chen et al., Cancer/stroma interplay viacyclooxygenase-2 and indoleamine 2,3-dioxygenasepromotes breast cancer progression. Breast Cancer Res. 16,410 (2014). doi: 10.1186/s13058-014-0410-1;pmid: 25060643

18. A. Bessede et al., Aryl hydrocarbon receptor control of adisease tolerance defence pathway. Nature 511, 184–190(2014). doi: 10.1038/nature13323; pmid: 24930766

19. G. M. Mawe, J. M. Hoffman, Serotonin signalling in thegut—functions, dysfunctions and therapeutic targets. Nat. Rev.Gastroenterol. Hepatol. 10, 473–486 (2013). doi: 10.1038/nrgastro.2013.105; pmid: 23797870

20. M. P. Turski, M. Turska, P. Paluszkiewicz, J. Parada-Turska,G. F. Oxenkrug, Kynurenic acid in the digestive system: Newfacts, new challenges. Int. J. Tryptophan Res. 6, 47–55(2013). pmid: 24049450

21. S. M. O’Mahony, G. Clarke, Y. E. Borre, T. G. Dinan,J. F. Cryan, Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav. Brain Res. 277, 32–48 (2015).pmid: 25078296

22. L. Z. Agudelo et al., Skeletal muscle PGC-1a1 modulateskynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014). doi: 10.1016/j.cell.2014.07.051; pmid: 25259918

23. N. R. Council, Recommended Dietary Allowances: 10th Edition(The National Academies Press, Washington, DC, 1989).

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 6 of 8

C - Blood-brain barrier

A - Liver

B - Skeletal muscle

Trp

Kyn KynaKATsPPARδ

PGC-1α1

Kyna

hyperglycemiasuppression

D - Adipose tissue - diabetes5-HT - fat accumulationdecreased Kyn production

Trp

mTOR

5-HT

β-catenin

E - Cancerescape from immune surveillanceincreased proliferation and invasivenessoxidative stress protection

Kyn

AhR LAT1

Trp

A - Liver

TrpTDOIDO

KynaXA

hepatocytesTrp kynurenines

glucocorticoid resistance - TDO inhibition

D - Adipose tissue

E - CancerTrp

IDOKyn

QuinQPRT

NAD+

Trp 5-HTTph1

kynurenines

Kyna

Trp

TrpTrp

TrpTrp

BCAA

Trp kynurenines

Trp

peripheral circulation

Trp Trp

Fig. 4. Activity, uptake, and conversion of tryptophan and its metabolites in peripheral tissues during disease states and challenges tohomeostasis.

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

24. D. A. Bender, Effects of a dietary excess of leucine onthe metabolism of tryptophan in the rat: A mechanismfor the pellagragenic action of leucine. Br. J. Nutr. 50,25–32 (1983). doi: 10.1079/BJN19830068; pmid: 6882730

25. A. A. B. Badawy, Tryptophan availability for kynureninepathway metabolism across the life span: Controlmechanisms and focus on aging, exercise, diet andnutritional supplements. Neuropharmacology 112 (Pt B),248–263 (2017). doi: 10.1016/j.neuropharm.2015.11.015;pmid: 26617070

26. R. J. Boado, J. Y. Li, M. Nagaya, C. Zhang, W. M. Pardridge,Selective expression of the large neutral amino acidtransporter at the blood-brain barrier. Proc. Natl. Acad.Sci. U.S.A. 96, 12079–12084 (1999). doi: 10.1073/pnas.96.21.12079; pmid: 10518579

27. L. S. Zhang, S. S. Davies, Microbial metabolism of dietarycomponents to bioactive metabolites: Opportunities for newtherapeutic interventions. Genome Med. 8, 46 (2016).doi: 10.1186/s13073-016-0296-x; pmid: 27102537

28. J.-H. Lee, T. K. Wood, J. Lee, Roles of indole as aninterspecies and interkingdom signaling molecule.Trends Microbiol. 23, 707–718 (2015). doi: 10.1016/j.tim.2015.08.001; pmid: 26439294

29. R. H. McMenamy, J. L. Oncley, The specific binding ofL-tryptophan to serum albumin. J. Biol. Chem. 233,1436–1447 (1958). pmid: 13610854

30. J. P. Bohney, R. C. Feldhoff, Effects of nonenzymaticglycosylation and fatty acids on tryptophan binding tohuman serum albumin. Biochem. Pharmacol. 43,1829–1834 (1992). doi: 10.1016/0006-2952(92)90717-W;pmid: 1575775

31. S. R. Gill et al., Metagenomic analysis of the human distal gutmicrobiome. Science 312, 1355–1359 (2006). doi: 10.1126/science.1124234; pmid: 16741115

32. M. Venkatesh et al., Symbiotic bacterial metabolites regulategastrointestinal barrier function via the xenobiotic sensorPXR and Toll-like receptor 4. Immunity 41, 296–310 (2014).doi: 10.1016/j.immuni.2014.06.014; pmid: 25065623

33. T. Zelante et al., Tryptophan catabolites from microbiotaengage aryl hydrocarbon receptor and balance mucosalreactivity via interleukin-22. Immunity 39, 372–385 (2013).doi: 10.1016/j.immuni.2013.08.003; pmid: 23973224

34. M. D. Gershon, 5-Hydroxytryptamine (serotonin) in thegastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes.20, 14–21 (2013). doi: 10.1097/MED.0b013e32835bc703;pmid: 23222853

35. M. Kanai et al., Tryptophan 2,3-dioxygenase is a keymodulator of physiological neurogenesis and anxiety-relatedbehavior in mice. Mol. Brain 2, 8 (2009). doi: 10.1186/1756-6606-2-8; pmid: 19323847

36. M. Civen, W. E. Knox, The independence of hydrocortisoneand tryptophan inductions of tryptophan pyrrolase.J. Biol. Chem. 234, 1787–1790 (1959). pmid: 13672965

37. O. Gbeengard, P. Feigelson, A difference between the modesof action of substrate and hormonal inducers of rat livertryptophan pyrrolase. Nature 190, 446–447 (1961).doi: 10.1038/190446a0; pmid: 13708323

38. M. T. Pallotta et al., Indoleamine 2,3-dioxygenase is asignaling protein in long-term tolerance by dendritic cells.Nat. Immunol. 12, 870–878 (2011). doi: 10.1038/ni.2077;pmid: 21804557

39. S. Yamamoto, O. Hayaishi, Tryptophan pyrrolase of rabbitintestine. D- and L-tryptophan-cleaving enzyme or enzymes.J. Biol. Chem. 242, 5260–5266 (1967). pmid: 6065097

40. A. W. S. Yeung, A. C. Terentis, N. J. C. King, S. R. Thomas,Role of indoleamine 2,3-dioxygenase in health anddisease. Clin. Sci. 129, 601–672 (2015). doi: 10.1042/CS20140392; pmid: 26186743

41. H. J. Ball, F. F. Jusof, S. M. Bakmiwewa, N. H. Hunt,H. J. Yuasa, Tryptophan-catabolizing enzymes: Party of three.Front. Immunol. 5, 485 (2014). doi: 10.3389/fimmu.2014.00485; pmid: 25346733

42. O. Takikawa, R. Yoshida, R. Kido, O. Hayaishi, Tryptophandegradation in mice initiated by indoleamine 2,3-dioxygenase. J. Biol. Chem. 261, 3648–3653 (1986).pmid: 2419335

43. Y. Nishizuka, O. Hayaishi, Enzymic synthesis of niacinnucleotides from 3-hydroxyanthranilic acid in mammalianliver. J. Biol. Chem. 238, 483–485 (1963). pmid: 13938817

44. D. A. Bender, Effects of a dietary excess of leucineand of the addition of leucine and 2-oxo-isocaproate on themetabolism of tryptophan and niacin in isolated rat liver cells.Br. J. Nutr. 61, 629–640 (1989). doi: 10.1079/BJN19890150;pmid: 2527060

45. G. Crepaldi, G. Allegri, A. De Antoni, C. Costa, M. Muggeo,Relationship between tryptophan metabolism and vitaminB6 and nicotinamide in aged subjects. Acta Vitaminol.Enzymol. 29, 140–144 (1975). pmid: 146412

46. L. Rios-Avila, H. F. Nijhout, M. C. Reed, H. S. Sitren,J. F. Gregory 3rd, A mathematical model of tryptophanmetabolism via the kynurenine pathway provides insightsinto the effects of vitamin B-6 deficiency, tryptophan loading,and induction of tryptophan 2,3-dioxygenase on tryptophanmetabolites. J. Nutr. 143, 1509–1519 (2013). doi: 10.3945/jn.113.174599; pmid: 23902960

47. K. M. Herrmann, The Shikimate pathway: Early steps in thebiosynthesis of aromatic compounds. Plant Cell 7, 907–919(1995). doi: 10.1105/tpc.7.7.907; pmid: 12242393

48. H. J. Yuasa, H. J. Ball, Efficient tryptophan-catabolizingactivity is consistently conserved through evolution of TDOenzymes, but not IDO enzymes. J. Exp. Zool. B Mol. Dev. Evol.324, 128–140 (2015). doi: 10.1002/jez.b.22608;pmid: 25702628

49. W. He et al., A small-molecule screen identifies L-kynurenineas a competitive inhibitor of TAA1/TAR activity in ethylene-directed auxin biosynthesis and root growth in Arabidopsis.Plant Cell 23, 3944–3960 (2011). doi: 10.1105/tpc.111.089029; pmid: 22108404

50. M. P. Turski, M. Turska, W. Zgrajka, D. Kuc, W. A. Turski,Presence of kynurenic acid in food and honeybee products.Amino Acids 36, 75–80 (2009). doi: 10.1007/s00726-008-0031-z; pmid: 18231708

51. M. P. Turski et al., Distribution, synthesis, and absorption ofkynurenic acid in plants. Planta Med. 77, 858–864 (2011).doi: 10.1055/s-0030-1250604; pmid: 21157681

52. G. B. Glavin, R. Bose, C. Pinsky, Kynurenic acid protectsagainst gastroduodenal ulceration in mice injected withextracts from poisonous Atlantic shellfish. Prog.Neuropsychopharmacol. Biol. Psychiatry 13, 569–572 (1989).doi: 10.1016/0278-5846(89)90148-6; pmid: 2748881

53. J. R. Moffett, M. A. Namboodiri, Tryptophan and the immuneresponse. Immunol. Cell Biol. 81, 247–265 (2003).doi: 10.1046/j.1440-1711.2003.t01-1-01177.x; pmid: 12848846

54. M. F. Murray, Tryptophan depletion and HIV infection: Ametabolic link to pathogenesis. Lancet Infect. Dis. 3, 644–652(2003). doi: 10.1016/S1473-3099(03)00773-4;pmid: 14522263

55. L. C. Hawkley, S. W. Cole, J. P. Capitanio, G. J. Norman,J. T. Cacioppo, Effects of social isolation on glucocorticoidregulation in social mammals. Horm. Behav. 62, 314–323(2012). doi: 10.1016/j.yhbeh.2012.05.011; pmid: 22663934

56. R. J. Liu, G. K. Aghajanian, Stress blunts serotonin- andhypocretin-evoked EPSCs in prefrontal cortex: Role ofcorticosterone-mediated apical dendritic atrophy. Proc. Natl.Acad. Sci. U.S.A. 105, 359–364 (2008). doi: 10.1073/pnas.0706679105; pmid: 18172209

57. Y. Suzuki et al., Serum indoleamine 2,3-dioxygenase activitypredicts prognosis of pulmonary tuberculosis. Clin. VaccineImmunol. 19, 436–442 (2012). doi: 10.1128/CVI.05402-11;pmid: 22219312

58. S. Divanovic et al., Opposing biological functions oftryptophan catabolizing enzymes during intracellularinfection. J. Infect. Dis. 205, 152–161 (2012). doi: 10.1093/infdis/jir621; pmid: 21990421

59. E. R. Pfefferkorn, P. M. Guyre, Inhibition of growth ofToxoplasma gondii in cultured fibroblasts by humanrecombinant gamma interferon. Infect. Immun. 44, 211–216(1984). pmid: 6425215

60. K. Schröcksnadel, B. Wirleitner, C. Winkler, D. Fuchs,Monitoring tryptophan metabolism in chronic immuneactivation. Clin. Chim. Acta 364, 82–90 (2006). doi: 10.1016/j.cca.2005.06.013; pmid: 16139256

61. R. G. Jones, C. B. Thompson, Revving the engine: Signaltransduction fuels T cell activation. Immunity 27, 173–178(2007). doi: 10.1016/j.immuni.2007.07.008; pmid: 17723208

62. H. H. Hassanain, S. Y. Chon, S. L. Gupta, Differentialregulation of human indoleamine 2,3-dioxygenase geneexpression by interferons-gamma and -alpha. Analysis of theregulatory region of the gene and identification of aninterferon-gamma-inducible DNA-binding factor.J. Biol. Chem. 268, 5077–5084 (1993). pmid: 8444884

63. A. C. Chaves et al., IL-4 and IL-13 regulate the induction ofindoleamine 2,3-dioxygenase activity and the control ofToxoplasma gondii replication in human fibroblasts activatedwith IFN-gamma. Eur. J. Immunol. 31, 333–344 (2001).doi: 10.1002/1521-4141(200102)31:2<333::AID-IMMU333>3.0.CO;2-X; pmid: 11180096

64. Y. Mándi, L. Vécsei, The kynurenine system andimmunoregulation. J. Neural Transm. 119, 197–209 (2012).doi: 10.1007/s00702-011-0681-y; pmid: 21744051

65. T. M. Aune, S. L. Pogue, Inhibition of tumor cell growth byinterferon-gamma is mediated by two distinct mechanismsdependent upon oxygen tension: Induction of tryptophandegradation and depletion of intracellular nicotinamideadenine dinucleotide. J. Clin. Invest. 84, 863–875 (1989).doi: 10.1172/JCI114247; pmid: 2503544

66. G. Frumento et al., Tryptophan-derived catabolites areresponsible for inhibition of T and natural killer cellproliferation induced by indoleamine 2,3-dioxygenase.J. Exp. Med. 196, 459–468 (2002). doi: 10.1084/jem.20020121; pmid: 12186838

67. F. Fallarino et al., T cell apoptosis by tryptophan catabolism.Cell Death Differ. 9, 1069–1077 (2002). doi: 10.1038/sj.cdd.4401073; pmid: 12232795

68. C. Orabona et al., Toward the identification of a tolerogenicsignature in IDO-competent dendritic cells. Blood 107,2846–2854 (2006). doi: 10.1182/blood-2005-10-4077;pmid: 16339401

69. M. L. Belladonna et al., Immunosuppression via tryptophancatabolism: The role of kynurenine pathway enzymes.Transplantation 84 (Suppl), S17–S20 (2007). doi: 10.1097/01.tp.0000269199.16209.22; pmid: 17632406

70. M. Hill et al., IDO expands human CD4+CD25high regulatoryT cells by promoting maturation of LPS-treated dendriticcells. Eur. J. Immunol. 37, 3054–3062 (2007). doi: 10.1002/eji.200636704; pmid: 17948274

71. J. D. Mezrich et al., An interaction between kynurenine andthe aryl hydrocarbon receptor can generate regulatoryT cells. J. Immunol. 185, 3190–3198 (2010). doi: 10.4049/jimmunol.0903670; pmid: 20720200

72. D. Wu et al., Eosinophils sustain adipose alternativelyactivated macrophages associated with glucose homeostasis.Science 332, 243–247 (2011). doi: 10.1126/science.1201475;pmid: 21436399

73. C. A. Beamer, B. P. Seaver, D. M. Shepherd, Aryl hydrocarbonreceptor (AhR) regulates silica-induced inflammation butnot fibrosis. Toxicol. Sci. 126, 554–568 (2012). doi: 10.1093/toxsci/kfs024; pmid: 22273745

74. S. Fallarini, L. Magliulo, T. Paoletti, C. de Lalla, G. Lombardi,Expression of functional GPR35 in human iNKT cells.Biochem. Biophys. Res. Commun. 398, 420–425 (2010).doi: 10.1016/j.bbrc.2010.06.091; pmid: 20599711

75. M. C. Barth et al., Kynurenic acid triggers firm arrest ofleukocytes to vascular endothelium under flow conditions.J. Biol. Chem. 284, 19189–19195 (2009). doi: 10.1074/jbc.M109.024042; pmid: 19473985

76. Z. Tiszlavicz et al., Different inhibitory effects of kynurenicacid and a novel kynurenic acid analogue on tumour necrosisfactor-a (TNF-a) production by mononuclear cells, HMGB1production by monocytes and HNP1-3 secretion byneutrophils. Naunyn Schmiedebergs Arch. Pharmacol. 383,447–455 (2011). doi: 10.1007/s00210-011-0605-2;pmid: 21336543

77. R. S. Grant, R. Passey, G. Matanovic, G. Smythe, V. Kapoor,Evidence for increased de novo synthesis of NAD in immune-activated RAW264.7 macrophages: A self-protectivemechanism? Arch. Biochem. Biophys. 372, 1–7 (1999).doi: 10.1006/abbi.1999.1381; pmid: 10562410

78. J. M. de Murcia et al., Requirement of poly(ADP-ribose)polymerase in recovery from DNA damage in mice and incells. Proc. Natl. Acad. Sci. U.S.A. 94, 7303–7307 (1997).doi: 10.1073/pnas.94.14.7303; pmid: 9207086

79. J. C. Correia, D. M. S. Ferreira, J. L. Ruas, Intercellular: Localand systemic actions of skeletal muscle PGC-1s. TrendsEndocrinol. Metab. 26, 305–314 (2015). doi: 10.1016/j.tem.2015.03.010; pmid: 25934582

80. M. Schlittler et al., Endurance exercise increases skeletalmuscle kynurenine aminotransferases and plasmakynurenic acid in humans. Am. J. Physiol. Cell Physiol. 310,C836–C840 (2016). doi: 10.1152/ajpcell.00053.2016;pmid: 27030575

81. B. Strasser et al., Effects of exhaustive aerobic exercise ontryptophan-kynurenine metabolism in trained athletes.PLOS ONE 11, e0153617 (2016). doi: 10.1371/journal.pone.0153617; pmid: 27124720

82. W. M. Pardridge, Blood-brain barrier carrier-mediatedtransport and brain metabolism of amino acids. Neurochem.Res. 23, 635–644 (1998). doi: 10.1023/A:1022482604276;pmid: 9566601

83. A. A.-B. Badawy, S. L. Lake, D. M. Dougherty, Mechanisms ofthe pellagragenic effect of leucine: Stimulation of hepatic

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 7 of 8

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

tryptophan oxidation by administration of branched-chainamino acids to healthy human volunteers and the role ofplasma free tryptophan and total kynurenines. Int. J.Tryptophan Res. 7, 23–32 (2014). doi: 10.4137/IJTR.S18231;pmid: 25520560

84. Q. Han, H. Robinson, T. Cai, D. A. Tagle, J. Li, Biochemicaland structural properties of mouse kynurenineaminotransferase III. Mol. Cell. Biol. 29, 784–793 (2009).doi: 10.1128/MCB.01272-08; pmid: 19029248

85. R. Schwarcz, T. W. Stone, The kynurenine pathway and thebrain: Challenges, controversies and promises.Neuropharmacology 112 (Pt B), 237–247 (2017).pmid: 27511838

86. G. F. Longstreth et al., Functional bowel disorders.Gastroenterology 130, 1480–1491 (2006). doi: 10.1053/j.gastro.2005.11.061; pmid: 16678561

87. D. M. Christmas et al., Increased serum free tryptophan inpatients with diarrhea-predominant irritable bowel syndrome.Nutr. Res. 30, 678–688 (2010). doi: 10.1016/j.nutres.2010.09.009; pmid: 21056283

88. S. P. Dunlop et al., Abnormalities of 5-hydroxytryptaminemetabolism in irritable bowel syndrome. Clin. Gastroenterol.Hepatol. 3, 349–357 (2005). doi: 10.1016/S1542-3565(04)00726-8; pmid: 15822040

89. A. Ait-Belgnaoui, S. Bradesi, J. Fioramonti, V. Theodorou,L. Bueno, Acute stress-induced hypersensitivity to colonicdistension depends upon increase in paracellularpermeability: Role of myosin light chain kinase. Pain 113,141–147 (2005). doi: 10.1016/j.pain.2004.10.002;pmid: 15621374

90. A. N. Ananthakrishnan, Epidemiology and risk factors for IBD.Nat. Rev. Gastroenterol. Hepatol. 12, 205–217 (2015).doi: 10.1038/nrgastro.2015.34; pmid: 25732745

91. N. K. Gupta et al., Serum analysis of tryptophan catabolismpathway: Correlation with Crohn’s disease activity. Inflamm.Bowel Dis. 18, 1214–1220 (2012). doi: 10.1002/ibd.21849;pmid: 21823214

92. B. Lamas et al., CARD9 impacts colitis by altering gutmicrobiota metabolism of tryptophan into aryl hydrocarbonreceptor ligands. Nat. Med. 22, 598–605 (2016).doi: 10.1038/nm.4102; pmid: 27158904

93. S. Sugimoto, M. Naganuma, T. Kanai, Indole compounds maybe promising medicines for ulcerative colitis. J. Gastroenterol.51, 853–861 (2016). doi: 10.1007/s00535-016-1220-2;pmid: 27160749

94. J. Granger, D. Remick, Acute pancreatitis: Models, markers,and mediators. Shock 24 (Suppl 1), 45–51 (2005).doi: 10.1097/01.shk.0000191413.94461.b0; pmid: 16374372

95. D. J. Mole et al., Tryptophan catabolites in mesenteric lymphmay contribute to pancreatitis-associated organ failure.Br. J. Surg. 95, 855–867 (2008). doi: 10.1002/bjs.6112;pmid: 18473343

96. D. J. Mole et al., Kynurenine-3-monooxygenase inhibitionprevents multiple organ failure in rodent models of acutepancreatitis. Nat. Med. 22, 202–209 (2016). doi: 10.1038/nm.4020; pmid: 26752518

97. A. Leja-Szpak et al., Melatonin precursor; L-tryptophanprotects the pancreas from development of acutepancreatitis through the central site of action. J. Physiol.Pharmacol. 55, 239–254 (2004). pmid: 15082881

98. C. Juhász et al., Quantitative pet imaging of tryptophanaccumulation in gliomas and remote cortex: Correlation withtumor proliferative activity. Clin. Nucl. Med. 37, 838–842(2013). doi: 10.1097/RLU.0b013e318251e458

99. D. H. Munn et al., GCN2 kinase in T cells mediatesproliferative arrest and anergy induction in response toindoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).doi: 10.1016/j.immuni.2005.03.013; pmid: 15894280

100. E. Timosenko et al., Nutritional stress induced by tryptophan-degrading enzymes results in ATF4-dependentreprogramming of the amino acid transporter profile in tumorcells. Cancer Res. 76, 6193–6204 (2016). doi: 10.1158/0008-5472.CAN-15-3502; pmid: 27651314

101. Y. D. Bhutia, E. Babu, V. Ganapathy, Interferon-g inducesa tryptophan-selective amino acid transporter inhuman colonic epithelial cells and mouse dendritic cells.Biochim. Biophys. Acta 1848, 453–462 (2015).doi: 10.1016/j.bbamem.2014.10.021; pmid: 25450809

102. A. I. Thaker et al., IDO1 metabolites activate b-cateninsignaling to promote cancer cell proliferation and colontumorigenesis in mice. Gastroenterology 145, 416–425(2013). doi: 10.1053/j.gastro.2013.05.002; pmid: 23669411

103. H. Nonaka et al., Indoleamine 2,3-dioxygenase promotesperitoneal dissemination of ovarian cancer through inhibitionof natural killercell function and angiogenesis promotion.Int. J. Oncol. 38, 113–120 (2011). pmid: 21109932

104. O. Novikov et al., An aryl hydrocarbon receptor-mediatedamplification loop that enforces cell migration in ER-/PR-/Her2- human breast cancer cells. Mol. Pharmacol. 90,674–688 (2016). doi: 10.1124/mol.116.105361;pmid: 27573671

105. D. H. Munn et al., Inhibition of T cell proliferation bymacrophage tryptophan catabolism. J. Exp. Med. 189,1363–1372 (1999). doi: 10.1084/jem.189.9.1363;pmid: 10224276

106. H. Liu et al., De-novo NAD+ synthesis regulates SIRT1-FOXO1apoptotic pathway in response to NQO1 substrates in lungcancer cells. Oncotarget 7, 62503–62519 (2016).pmid: 27566573

107. F. Sahm et al., The endogenous tryptophan metabolite andNAD+ precursor quinolinic acid confers resistance of gliomasto oxidative stress. Cancer Res. 73, 3225–3234 (2013).doi: 10.1158/0008-5472.CAN-12-3831; pmid: 23548271

108. E. Ananieva, Targeting amino acid metabolism in cancergrowth and anti-tumor immune response. World J. Biol.Chem. 6, 281–289 (2015). doi: 10.4331/wjbc.v6.i4.281;pmid: 26629311

109. J. D. Crane et al., Inhibiting peripheral serotonin synthesisreduces obesity and metabolic dysfunction by promotingbrown adipose tissue thermogenesis. Nat. Med. 21, 166–172(2015). doi: 10.1038/nm.3766; pmid: 25485911

110. T. Li et al., Important role of 5-hydroxytryptamine inglucocorticoid-induced insulin resistance in liver andintra-abdominal adipose tissue of rats. J. Diabetes Investig. 7,32–41 (2016). doi: 10.1111/jdi.12406; pmid: 26816599

111. K. Nonogaki, A. M. Strack, M. F. Dallman, L. H. Tecott,Leptin-independent hyperphagia and type 2 diabetes in micewith a mutated serotonin 5-HT2C receptor gene. Nat. Med. 4,1152–1156 (1998). doi: 10.1038/2647; pmid: 9771748

112. C.-M. Oh et al., Regulation of systemic energy homeostasisby serotonin in adipose tissues. Nat. Commun. 6, 6794(2015). doi: 10.1038/ncomms7794; pmid: 25864946

113. I. Wolowczuk et al., Tryptophan metabolism activation byindoleamine 2,3-dioxygenase in adipose tissue of obesewomen: An attempt to maintain immune homeostasis andvascular tone. Am. J. Physiol. Regul. Integr. Comp. Physiol.303, R135–R143 (2012). doi: 10.1152/ajpregu.00373.2011;pmid: 22592557

114. G. F. Oxenkrug, Increased plasma levels of xanthurenic andkynurenic acids in type 2 diabetes. Mol. Neurobiol. 52,805–810 (2015). doi: 10.1007/s12035-015-9232-0;pmid: 26055228

115. M. Favennec et al., The kynurenine pathway is activated inhuman obesity and shifted toward kynureninemonooxygenase activation. Obesity (Silver Spring) 23,2066–2074 (2015). doi: 10.1002/oby.21199; pmid: 26347385

116. M. Hattori, Y. Kotake, Y. Kotake, Studies on the urinaryexcretion of xanthurenic acid in diabetics. Acta Vitaminol.Enzymol. 6, 221–228 (1984). pmid: 6524581

117. A. D. Patterson et al., Metabolomics reveals attenuation ofthe SLC6A20 kidney transporter in nonhuman primate andmouse models of type 2 diabetes mellitus. J. Biol. Chem.286, 19511–19522 (2011). doi: 10.1074/jbc.M111.221739;pmid: 21487016

118. K. S. Rogers, S. J. Evangelista, 3-Hydroxykynurenine,3-hydroxyanthranilic acid, and o-aminophenol inhibit leucine-

stimulated insulin release from rat pancreatic islets.Proc. Soc. Exp. Biol. Med. 178, 275–278 (1985). doi: 10.3181/00379727-178-42010; pmid: 3881773

119. B. J. Moyer et al., Inhibition of the aryl hydrocarbon receptorprevents Western diet-induced obesity. Model for AHRactivation by kynurenine via oxidized-LDL, TLR2/4, TGFb, andIDO1. Toxicol. Appl. Pharmacol. 300, 13–24 (2016).doi: 10.1016/j.taap.2016.03.011; pmid: 27020609

120. T. Inubushi et al., L-tryptophan suppresses rise in bloodglucose and preserves insulin secretion in type-2 diabetesmellitus rats. J. Nutr. Sci. Vitaminol. (Tokyo) 58, 415–422(2012). doi: 10.3177/jnsv.58.415; pmid: 23419400

121. H. Zhang et al., NAD+ repletion improves mitochondrial andstem cell function and enhances life span in mice. Science352, 1436–1443 (2016). doi: 10.1126/science.aaf2693;pmid: 27127236

122. D. Ryu et al., NAD+ repletion improves muscle function inmuscular dystrophy and counters global PARylation.Sci. Transl. Med. 8, 361ra139 (2016). doi: 10.1126/scitranslmed.aaf5504; pmid: 27798264

123. S. A. Trammell et al., Nicotinamide riboside opposes type2 diabetes and neuropathy in mice. Sci. Rep. 6, 26933(2016). doi: 10.1038/srep26933; pmid: 27230286

124. L. Mouchiroud et al., The NAD+/sirtuin pathway modulateslongevity through activation of mitochondrial UPR and FOXOsignaling. Cell 154, 430–441 (2013). doi: 10.1016/j.cell.2013.06.016; pmid: 23870130

125. G. F. Oxenkrug, V. Navrotskaya, L. Voroboyva,P. Summergrad, Extension of life span of Drosophilamelanogaster by the inhibitors of tryptophan-kynureninemetabolism. Fly (Austin) 5, 307–309 (2011). doi: 10.4161/fly.5.4.18414; pmid: 22041575

126. A. T. van der Goot et al., Delaying aging and the aging-associated decline in protein homeostasis by inhibition oftryptophan degradation. Proc. Natl. Acad. Sci. U.S.A. 109,14912–14917 (2012). doi: 10.1073/pnas.1203083109;pmid: 22927396

127. L. Romani et al., Microbiota control of a tryptophan-AhRpathway in disease tolerance to fungi. Eur. J. Immunol. 44,3192–3200 (2014). doi: 10.1002/eji.201344406;pmid: 25256754

128. S. Oh, G. W. Go, E. Mylonakis, Y. Kim, The bacterial signallingmolecule indole attenuates the virulence of the fungalpathogen Candida albicans. J. Appl. Microbiol. 113, 622–628(2012). doi: 10.1111/j.1365-2672.2012.05372.x;pmid: 22726313

129. D. H. Munn et al., Potential regulatory function of humandendritic cells expressing indoleamine 2,3-dioxygenase.Science 297, 1867–1870 (2002). doi: 10.1126/science.1073514; pmid: 12228717

130. V. Mehraj, J.-P. Routy, Tryptophan catabolism in chronicviral infections: Handling uninvited guests. Int. J.Tryptophan Res. 8, 41–48 (2015). doi: 10.4137/IJTR.S26862; pmid: 26309411

131. M. A. Jenabian et al., Immunosuppressive tryptophancatabolism and gut mucosal dysfunction following early HIVinfection. J. Infect. Dis. 212, 355–366 (2015). doi: 10.1093/infdis/jiv037; pmid: 25616404

132. X. Dagenais-Lussier et al., Kynurenine reduces memory CD4T-cell survival by interfering with interleukin-2 signaling earlyduring HIV-1 infection. J. Virol. 90, 7967–7979 (2016).doi: 10.1128/JVI.00994-16; pmid: 27356894

ACKNOWLEDGMENTS

The authors acknowledge members of the Ruas laboratory forcritical reading of the manuscript and funding from the SwedishResearch Council, the Novo Nordisk Foundation (Denmark),Karolinska Institutet, the Lars Hierta Memorial Foundation, theStrategic Research Program (SRP) in Diabetes, and the SRP inRegenerative Medicine at Karolinska Institutet.

10.1126/science.aaf9794

Cervenka et al., Science 357, eaaf9794 (2017) 28 July 2017 8 of 8

RESEARCH | REVIEWon June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from

Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental healthIgor Cervenka, Leandro Z. Agudelo and Jorge L. Ruas

DOI: 10.1126/science.aaf9794 (6349), eaaf9794.357Science 

, this issue p. eaaf9794Sciencecommunicate with the microbiota.to cancer progression. Further, they can mediate the effects of exercise, mood, and neuronal excitability and, ultimately, physiological context, kynurenines influence health and disease states ranging from intestinal conditions to inflammationmetabolites distribute into homeostatic networks that integrate diverse aspects of mammalian physiology. Depending on

review the many pathways taken by dietary tryptophan as it is metabolized into kynurenines. Theseet al.Cervenka Our gut hurts and we feel miserable. Such disparate phenomena are mechanistically connected, but how?

From stomach ache to depression

ARTICLE TOOLS http://science.sciencemag.org/content/357/6349/eaaf9794

CONTENTRELATED http://stm.sciencemag.org/content/scitransmed/5/193/193ra91.full

REFERENCES

http://science.sciencemag.org/content/357/6349/eaaf9794#BIBLThis article cites 131 articles, 35 of which you can access for free

PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions

Terms of ServiceUse of this article is subject to the

is a registered trademark of AAAS.ScienceScience, 1200 New York Avenue NW, Washington, DC 20005. The title (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement ofScience

Science. No claim to original U.S. Government WorksCopyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of

on June 1, 2020

http://science.sciencemag.org/

Dow

nloaded from