Cell Host & Microbe

Review

Gut Microbiota Regulation of Tryptophan

Metabolism in Health and Disease
Allison Agus,1,3 Julien Planchais,1,3 and Harry Sokol1,2,*
1INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France
2Sorbonne Université, École normale supérieure, PSL Research University, CNRS, INSERM, AP-HP, Gastroenterology Department, Hôpital
Saint-Antoine, Laboratoire de biomolécules, LBM, 184 rue du Faubourg Saint-Antoine, Paris 75005, France
3These authors contributed equally

*Correspondence: [email protected]
https://doi.org/10.1016/j.chom.2018.05.003

The gut microbiota is a crucial actor in human physiology. Many of these effects are mediated by metabolites
that are either produced by the microbes or derived from the transformation of environmental or host
molecules. Among the array of metabolites at the interface between these microorganisms and the host is
the essential aromatic amino acid tryptophan (Trp). In the gut, the three major Trp metabolism pathways
leading to serotonin (5-hydroxytryptamine), kynurenine (Kyn), and indole derivatives are under the direct
or indirect control of the microbiota. In this review, we gather the most recent advances concerning the
central role of Trp metabolism in microbiota-host crosstalk in health and disease. Deciphering the complex
equilibrium between these pathways will facilitate a better understanding of the pathogenesis of human
diseases and open therapeutic opportunities.

Introduction mon canonical amino acids, Trp is the largest by molecular

The intestine is a complex ecosystem harboring a dense and weight. Although Trp is the least abundant amino acid in protein
diverse microbial community called the gut microbiota, which and cells, it is a biosynthetic precursor of a large number of
co-evolved with the host to develop a mutualistic relationship. It microbial (Alkhalaf and Ryan, 2015) and host metabolites.
is increasingly obvious that loss of the fragile equilibrium within The ability of specific bacteria to produce Trp has been known
this complex ecosystem, termed dysbiosis, is implicated in for a century and has been significantly exploited in industry.
numerous human diseases. The intestinal microbiota has an Although some members of the bacterial microbiota, such as
important impact on several key physiological host functions, Escherichia coli, are able to produce Trp, no data support the
including metabolic and nutritional homeostasis, immune system significant contribution of bacteria-derived Trp in human physi-
maturation and stimulation, and even brain activity. These effects ology. Since Trp is not produced by animal cells, humans rely
are mediated by direct cell-to-cell interactions and by metabolites on exogenous, mostly dietary, intake. Common natural food
that are either produced by the microbes or derived from the trans- sources of Trp include oats, bananas, dried prunes, milk, tuna
formation of environmental or host molecules. The gut microbiota fish, cheese, bread, poultry, peanuts, and chocolate. The
is considered a virtual endocrine organ, producing molecules that World Health Organization set the recommended Trp intake to
are able to interact with the host physiology and trigger responses 4 mg/kg/day, and, to date, no adverse effects of excess Trp in
at the local and distant levels (Zhang and Davies, 2016). Any the diet have been reported.
perturbation in host-microbiota crosstalk can be an initiating or re-
inforcing factor in disease pathogenesis. A large array of metabo- Intestinal Tryptophan Metabolism: Pathways and
lites drives the crosstalk between the host and its microbiome. The Physiology
three currently most studied categories of metabolites involved in Trp metabolism follows three major pathways in the gastrointes-
host-microbiota interactions are (1) short-chain fatty acids tinal tract (Figure 1): (1) the direct transformation of Trp into
(SCFAs), produced by bacteria from the fermentation of fibers; several molecules, including ligands of the aryl hydrocarbon re-
(2) bile acids produced in the liver and transformed by the gut mi- ceptor (AhR), by the gut microbiota (Zelante et al., 2013); (2) the
crobiota before re-affecting the host; and (3) tryptophan (Trp) me- kynurenine pathway (KP) in both immune and epithelial cells via
tabolites, which are the topic of this review (Blacher et al., 2017). indoleamine 2,3-dioxygenase (IDO) 1 (Clarke et al., 2013); and (3)
In this article, we review the most recent insights regarding the the serotonin (5-hydroxytryptamine [5-HT]) production pathway
role of the gut microbiota in Trp metabolism, with a focus on the in enterochromaffin cells via Trp hydroxylase 1 (TpH1) (Yano
consequences on both physiology and diseases. In addition to et al., 2015).
the direct transformation of Trp into bioactive molecules by the Direct Metabolism of Trp by Microorganisms
gut microbiota, we discuss the way in which the gut microbiota Trp metabolism in the gut includes the direct transformation of
controls host Trp metabolism in the gut. Trp by intestinal microorganisms into several molecules, such
as indole and its derivatives. Many indole derivatives, such as
Tryptophan: Origin and Production indole-3-aldehyde (IAld), indole-3-acid-acetic (IAA), indole-
Trp is an essential aromatic amino acid composed of a b carbon 3-propionic acid (IPA), indole-3-acetaldehyde (IAAld), and
connected to the 3 position of an indole group. Of the 20 com- indoleacrylic acid, are ligands for AhR (Alexeev et al., 2018;

716 Cell Host & Microbe 23, June 13, 2018 ª 2018 Elsevier Inc.
Cell Host & Microbe

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Figure 1. Integrated Trp Metabolism under the Control of the Gut Microbiota in Host Physiology
Dietary Trp can be directly converted by gut microbiota into AhR ligands that are able to tune local and distant host functions, including immune homeostasis and
barrier physiology. Gut microbiota also influence the kynurenine-producing IDO pathway, which plays a critical role in inflammatory mechanisms, immune
responses, and neurobiological functions. Peripheral production of serotonin by enterochromaffin cells is also under the influence of the gut microbiota.
Gut-produced serotonin has many local effects, such as stimulating gut motility, and, even if it does not cross the blood-brain barrier, gut microbiota indirectly
affects central serotoninergic pathways by modulating Trp and tryptamine availability. 5-HTP, 5-hydroxytryptophan; IL, interleukin; QA, quinolinic acid.

Hubbard et al., 2015). AhR signaling is considered a key compo- identified in some members of the human gut microbiota such
nent of the immune response at barrier sites and is thus crucial as Clostridium sporogenes, which is able to decarboxylate Trp
for intestinal homeostasis by acting on epithelial renewal, barrier leading to the production of the neurotransmitter tryptamine
integrity, and many immune cell types, such as intraepithelial (Williams et al., 2014). In addition, oxidative and reductive path-
lymphocytes, Th17 cells, innate lymphoid cells, macrophages, ways have also been described in this species and lead to the
dendritic cells (DCs), and neutrophils (Lamas et al., 2018). AhR production of indoleacetic acid (IAA) and indolepropionic acid
is directly activated by dietary molecules and xenobiotics. In (IPA), two Trp metabolites known to affect intestinal permeability
addition, many AhR ligands are processed and inactivated by and host immunity (Dodd et al., 2017; Galligan, 2018; Lamas
cytochrome p450 family proteins, such as Cyp1A1, which is a et al., 2016) (Figure 2). Trp and indole active transporters have
direct AhR transcriptional target constituting a feedback loop been identified in E. coli. Tryptophanase, which converts Trp
for AhR signaling (Schiering et al., 2017). into indole, is expressed in E. coli and lactobacilli, but the precise
However, the role of microbial metabolism is preponderant in microbial enzymatic pathways involved in further indole pro-
intestinal AhR activity. Indeed, the intestinal contents of germ- cessing, as well as their existence and activity in other
free or dysbiotic mice are deficient for AhR agonists (Lamas commensal species, have yet to be described (Hubbard et al.,
et al., 2016). Only a few commensal species able to produce 2015). Indole is also an interspecies signaling molecule that is
AhR ligands, such as Peptostreptococcus russellii (Wlodarska able to control aspects of bacterial physiology such as antibiotic
et al., 2017) and Lactobacillus spp (Lamas et al., 2016; Zelante resistance, sporulation, and biofilm formation. In non-indole-
et al., 2013), have been characterized, and many likely remain producing bacteria, indole and its derivatives notably inhibit
to be discovered. Trp-metabolizing pathways have been quorum sensing and modulate virulence factors (Lee et al.,

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SEROTONIN

ASMT AANAT MAO

MELATONIN N-acetyserotonin SEROTONIN 5-HIAA

AAAD

5-HTP

TpH TNA

KYNURENIC ACID
ArAT fldH fldBC acdA
KAT IDO TRYPTOPHAN IPYA ILA IA* IPA
XANTHURENIC
KYNURENINE** TDO porB,C
ACID IDO TMO
KAT KMO TrD
KYNU
3H-KYN IAM TRYPTAMINE*
KYNU KMO INDOLE
3-HAA PICOLINIC ACID
IAA* IAAld*
INDOLE-SULFONIC ACID

QUINOLINIC ACID IAld* TRYPTOPHOL

NAD
INDOLE/AHR
KYNURENINE/IDO
* AhR ligands
** Potential AhR ligand but in supraphysiological concentrations
Host pathway
Microbial pathway
IDO : Indoleamine 2,3-Dioxygenase
3-HAA : 3-Hydroxyanthranilic Acid ILA : Indole-3-Lactic Acid
3H-KYN : 3-Hydroxykynurenine IPA : Indole-3-Propionic Acid
5-HTP : 5-Hydroxytryptophan IPYA : Indole-3-Pyruvate
AAAD : Aromatic Amino Acid Decarboxylase KAT : Kynurenine aminotransferase
AANAT : Aralkylamine N-Acetyltransferase KMO : Kynurenine 3-Monooxygenase
acdA : acyl-CoA dehydrogenase
KYNU : Kynureninase
AraT : Aromatic amino acid aminotransferase
MAO : Monoamine Oxydase
ASMT : Acetylserotonin O-Methyltransferase
NAD : Nicotinamide Adenine Dinucleotide
fldBC : phenyllactate dehydratase
fldH : phenyllactate dehydrogenase porB, C : pyruvate : ferredoxin oxidoreductase B and C
IA : Indole Acrylic Acid TDO : Tryptophan 2,3-Dioxygenase
IAA : Indole Acetic Acid TMO : Tryptophan 2-Monooxygenase
IAAld : Indole-3-Acetaldehyde TNA : Tryptophanase
IAld : Indole-3-Aldehyde TpH : Tryptophan Hydroxylase
IAM : Indole-3-Acetamide TrD : Tryptophan Decarboxylase

Figure 2. Pathways of Trp Metabolism through the 5-HT, Kyn, and Indole/AhR Pathways
Overview of Trp metabolic fate through eukaryotic and bacterial pathways to major products and derivatives.

2015). However, the importance of these complex phenomena in of a number of host biological processes involving neurotrans-
the gut ecosystem has not yet specifically been addressed. mission, inflammation, and the immune response. Moreover,
Kynurenine Pathway some metabolites appear to exert specific effects in the gut.
Trp metabolism through the KP in the gut is mediated by the This is the case for Kna, whose concentration increases gradu-
rate-limiting enzyme IDO1 and leads to the production of kynur- ally along the gastrointestinal tract. Kna exhibits mucosal
enine (Kyn) and downstream products such as quinolinic acid protective and immunoregulatory effects, probably through its
(QA), niacin, nicotinamide adenine dinucleotide, and kynurenic G protein-coupled receptor, GPR35, which is mostly expressed
acid (Kna) (Cervenka et al., 2017; Kennedy et al., 2017). The in epithelial and immune cells (Gao et al., 2018). Two other
key role of the gut microbiota in stimulating IDO1 activity has enzymes, Trp 2,3-dioxygenase (TDO) and IDO2, metabolize
been clearly demonstrated, notably in germ-free and antibiotic- Trp to Kyn, but these enzymes are not expressed in the gut
treated mice. KP end products are implicated in the regulation and are not discussed here. In addition, several intestinal

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bacteria encode enzymes homologous to those of the eukaryotic influenced by genetic factors (Lamas et al., 2016), and AhR
KP and are thus also able to produce Kyn and downstream expression in intestinal tissues was decreased compared with
metabolites such as 3-hydroxyanthranilic acid (Vujkovic- that in healthy subjects (Monteleone et al., 2011). Moreover,
Cvijin et al., 2013), which has neurotoxic effects (O’Farrell and IPA is decreased in the serum of patients with UC (Alexeev
Harkin, 2017). et al., 2018). Overactivation of IDO1 is observed both locally in
Serotonin Pathway the gut (Lamas et al., 2016) and systemically, likely reflecting
The neurotransmitter 5-HT is produced in the brain through the immune system activation. This hypothesis is supported by
Trp hydroxylase 2 enzyme (TpH2), where it plays an important higher IDO1 activity in active compared with nonactive IBD
role. However, more than 90% of the body’s 5-HT is produced patients and by the negative correlation between serum levels
in the gut and particularly in enterochromaffin cells (ECs), a of Trp and C-reactive protein, a commonly used biomarker
specialized subtype of intestinal epithelial cell. This process increased in response to inflammation (Nikolaus et al., 2017).
occurs through the Trp hydroxylase 1 enzyme (TpH1), which The state of 5-HT pathway activation in IBD is controversial.
produces 5-hydroxytryptophan (5-HTP), which is further Increased expression of the rate-limiting enzyme TpH1 and
metabolized into 5-HT. Under physiological conditions, periph- elevated intestinal 5-HT levels have been reported in Crohn
eral 5-HT does not cross the blood-brain barrier. disease, while most studies have found the opposite in UC (Man-
Peripheral 5-HT triggers numerous functions in the gastroin- ocha and Khan, 2012).
testinal tract and is implicated in a wide range of human physio- These alterations in Trp metabolism have a potential role in
logical functions by activating specific 5-HT receptors (Mawe IBD pathogenesis.
and Hoffman, 2013). Specifically, 5-HT is an important gastroin- Murine studies have also shown that, in mice, AhR deficiency
testinal signaling molecule that conveys signals from the gut to increases the severity of experimental colitis that is driven either
intrinsic or extrinsic neurons and influences intestinal peristalsis by T cell transfer or chemically via administration of dextran
and motility, secretion, vasodilatation, and the absorption of sulfate sodium (DSS). In these models, the AhR deficiency drives
nutrients. In addition, the serotonin-selective reuptake trans- colitis partially through the altered production of interleukin
porter (SERT; encoded by SLC6A4 gene), expressed in the (IL)-22, a cytokine with a well-known effect on intestinal homeo-
apical and basolateral membrane of intestinal epithelial cells, stasis (Qiu et al., 2012; Zelante et al., 2013). Our group demon-
acts as a sponge to remove 5-HT from the interstitial space after strated that the dysbiotic gut microbiota of mice deficient in
production by ECs. This pivotal molecule involved in the local caspase recruitment domain 9 (Card9), an IBD susceptibility
regulation of 5-HT availability is also responsible for 5-HT reup- gene, fails to catalyze Trp into AhR ligands, leading to reduced
take in the brain. IL-22 release and ultimately to higher susceptibility of Card9 /
The gut microbiota is a major actor in intestinal 5-HT produc- mice to DSS-induced colitis (Lamas et al., 2016). Some func-
tion (Yano et al., 2015). Its role has been demonstrated in germ- tional relevance is also seen in humans, as pharmacological acti-
free mice that exhibit impaired 5-HT production in the colon vation of AhR reduces the production of the proinflammatory
(but not in the small intestine) and low 5-HT concentrations in cytokine interferon (IFN) g and increases the production of
the blood. The mechanisms by which the gut microbiota mod- IL-22 in lamina propria mononuclear cells from IBD patients
ulates 5-HT production are not fully understood, but the role of (Monteleone et al., 2011). In addition, as observed in humans
SCFAs in the stimulation of TpH1 expression has been sug- with UC, IPA and indole are decreased in serum of mice with
gested (Reigstad et al., 2015). Moreover, some secondary DSS-induced colitis with additional evidence indicating that
bile acids, such as deoxycholate produced by microbial oral administration of IPA has protective properties in this model
biotransformation of cholate, can also stimulate 5-HT biosyn- system (Alexeev et al., 2018).
thesis (Yano et al., 2015). Alterations in the KP may also be mechanistically involved in
IBD pathogenesis. IDO1 / mice are more susceptible to colitis,
Perturbations in Tryptophan Metabolism demonstrating that IDO1 is a negative regulator of intestinal
In the last few decades, the role of the gut microbiota has been inflammation. The pathological damage associated with IDO1
suggested in many diseases associated with Western lifestyles, deficiency is partially due to the activation of proinflammatory
such as inflammatory bowel diseases (IBDs; regrouping Crohn cytokines and a decreased number of CD4+ Foxp3+ regulatory
disease and ulcerative colitis [UC]), irritable bowel syndrome T cells in the colon. However, the precise mechanisms and
(IBS), metabolic syndrome and associated complications (dia- metabolites involved remain unknown (Takamatsu et al., 2013).
betes, obesity, nonalcoholic fatty liver disease [NAFLD], insulin Kyn is known to be an AhR agonist, but the concentration
resistance, and atherosclerosis), and neuropsychiatric traits required to elicit reporter AhR activity in a hepatoma cell line
(notably anxiety, depression, and autism). Many of these dis- casts doubt on its relevance as an AhR activator under physio-
eases are also affected by end products of Trp metabolism logical conditions (Hubbard et al., 2015). Alterations to
(Figure 3), suggesting that the effects of the microbiota are at downstream metabolic pathways leading to deficiency in anti-
least partially mediated by impaired Trp metabolism. inflammatory metabolites, such as Kna, might be involved,
IBD and Intestinal Immunity but this remains to be demonstrated. In the context of IBD,
The role of an altered gut microbiota is clearly demonstrated in abnormal signals from a dysbiotic microbiota may be drivers of
IBD, and several seminal publications have highlighted alter- a skewed KP.
ations in gut Trp metabolism with potential links to intestinal The severity of chemically induced colitis is attenuated in
microorganisms. We recently uncovered the decreased produc- TpH1 / mice and in mice treated with the 5-HT synthesis
tion of AhR ligands by the microbiota of IBD patients, which was inhibitor parachlorophenylalanine, suggesting that 5-HT

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Figure 3. Perturbations to Trp Metabolism
in Diseases
AhR agonists AhR agonists
Ahr-activating probiotics Ahr-activating probiotics The three major pathways of Trp metabolism,
differentially affected in diseases, remain tightly
interconnected. Diagrams indicate repartitioning
of Trp fluxes in diseases based on the available
CD
UC clinical data. Weights of arrows indicate strength of
pathway activation. The restoration of disrupted
equilibrium using molecules or probiotics repre-
IDO1 sents a promising therapeutic strategy. AhR, aryl
hydrocarbon receptor; IDO1, indoleamine 2,3-di-
oxygenase 1; TpH1, tryptophan hydroxylase 1;
5-HT4 receptors 5-HT3 receptors
5-HT, 5-hydroxytryptamine; CD, Crohn disease;
agonists antagonists
UC, ulcerative colitis; IBS-C, irritable bowel syn-
Trp drome with constipation; IBS-D, irritable bowel
syndrome with diarrhea.
IBS-C Health IBS-D
H1
Ah

Tp
R

respectively (Manocha and Khan, 2012).

The pleiotropic effects of 5-HT are related
to the diversity of its receptors that are
? ? able to trigger specific functions in spe-
Autism Metabolic cific organs. 5-HT3 and 5-HT4 subtypes,
syndrome which are the most expressed in the
gastrointestinal tract, link 5-HT to visceral
nociception and motility disorders. The
TpH1 pathway
role of 5-HT has already been exploited
AhR pathway
as a therapeutic target with the use of
IDO1 pathway
5-HT3 receptor antagonists and 5-HT4
receptor agonists showing some efficacy
worsens intestinal inflammation (Ghia et al., 2009). Moreover, in diarrhea- and constipation-predominant IBS, respectively
deletion of SERT, leading to increased 5-HT availability, induces (Binienda et al., 2017).
the exacerbation of experimental colitis (Spohn and Mawe, However, perturbed central serotonin action, which is also
2017). These proinflammatory effects might be partly driven by potentially modulated by gut microbiota (Figure 1), may partici-
the activation of 5-HT7 receptors on DCs. However, new clues pate in IBS pathogenesis as well (Stasi et al., 2014). The effects
suggest that 5-HT also exerts anti-inflammatory effects by of the gut microbiota on 5-HT production and gut motility have
acting on the 5-HT4 receptor, with positive consequences on been demonstrated in mice (Yano et al., 2015) and suggest
intestinal epithelial cell barrier functions (Spohn and that IBS pathogenesis is partly related to the dysfunctional
Mawe, 2017). control of 5-HT production by the microbiota.
Taken together, these data suggest that the alterations in Trp Metabolic Syndrome and Obesity
metabolism observed in IBD might have an active role in dis- In human patients with metabolic syndrome, overactivation of
ease pathogenesis. The involvement of the microbiota is IDO1 has been reported with increased serum Kyn levels and a
obvious in terms of the impaired ability of these microorgan- correlation between the Kyn/Trp ratio and obesity, metabolic
isms to produce AhR agonists but might also account for the syndrome, BMI, and blood triglycerides (Mallmann et al.,
exacerbated local activation of IDO and TpH1 that occurs 2018). Increased gene expression of IDO1, and of downstream
under the direct influence of the microbiota under physiological enzymes of the KP such as kynureninase (KYNU), kynurenine
conditions. aminotransferase (KAT), and kynurenine 3-monooxygenase
Irritable Bowel Syndrome (KMO) (Figure 2), has been observed in the adipose tissues of
Although the etiology of IBS is largely unknown, the role of a dys- obese patients, suggesting the local activation of IDO1 (Faven-
biotic gut microbiota in its pathogenesis is suspected, at least for nec et al., 2015). However, circulating 5-HT levels are decreased
some subgroups of patients (Fan et al., 2017; Hyland et al., in metabolic syndrome and are negatively correlated with BMI
2014). In addition, there might be connections with impaired and body fat (Hodge et al., 2012). Several indole derivatives pro-
Trp metabolism. Kyn is increased in the serum of IBS patients duced via Trp transformation by the microbiota may have a role
(Clarke et al., 2012), and peripheral IDO1 activity is positively in metabolic syndrome pathogenesis. Indole itself has been
correlated with IBS severity (Fitzgerald et al., 2008). Alterations shown to stimulate enteroendocrine L cells to produce
in gut motility, one of the key features in IBS, are linked to glucagon-like peptide-1 (GLP-1), an incretin stimulating the
5-HT dysmetabolism. TpH1 and SERT expression levels were secretion of insulin by pancreatic b cells. This mechanism in-
found to be decreased in rectal biopsies from IBS patients volves the rapid inhibition of voltage-gated K+ channels stimu-
compared with those from healthy controls (Kerckhoffs et al., lating GLP-1 secretion but is controlled by longer-term effects
2012). In addition, 5-HT colon contents are decreased and on ATP synthesis inhibition, reducing GLP-1 secretion (Chimerel
increased in constipation- and diarrhea-predominant IBS, et al., 2014). Indole is also absorbed and metabolized to indoxyl

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sulfate in the liver. During kidney failure, this metabolite accumu- metabolism in intestinal homeostasis and the response to infec-
lates, and its proinflammatory and oxidant effects are implicated tion. Independent of the production of AhR ligands, local Trp
in the pathogenesis of atherosclerosis, arteriosclerosis, conges- metabolism might be an adaptive component of the interactions
tive heart failure, and other cardiovascular complications that are between the host and microorganisms. Trp auxotrophy by
particularly over-represented in patients with chronic kidney certain pathogens, such as the intracellular bacteria Chlamydia
failure (Hung et al., 2017). The role of indoxyl sulfate in subjects and parasite Leishmania, is a flaw that CD4+ T cells exploit to
with normal kidney function remains to be determined. The KP limit infection by overactivating IDO1, hijacking Trp to the KP
has also been implicated in atherosclerosis. In a mouse model, and thus starving bacteria. Some bacteria, such as Mycobacte-
IDO1 deficiency reduced the development of atherosclerosis rium tuberculosis, escape CD4-mediated defense by synthesiz-
lesions through the dysregulation of IL-10 production, a pheno- ing their own Trp under stress conditions (Zhang et al., 2013).
type reversed by the administration of Kna. In humans, high Kna Such a mechanism has not yet been described in the gut but
levels are correlated with an unstable plaque phenotype (Met- could be relevant for both pathogen- and microbiota-host inter-
ghalchi et al., 2015). The low-grade chronic inflammation that actions.
has been described in these pathologies may contribute to Neuropsychiatric Disorders
IDO1 activation. Overactivation of the KP is also likely to partic- The gut microbiota influences the brain and may be involved in
ipate in the onset of insulin resistance in low-grade inflammatory neuropsychiatric disorders, partly by modulating circulating
situations such as obesity, depression, hepatitis C virus infec- Trp availability. Although the blood-brain barrier is highly selec-
tion, and cardiovascular diseases. Human and experimental tive, Trp and Kyn cross it and have notable effects on the meta-
data suggest that xanthurenic acid and other products of the bolism of neurotransmitters. Kna and QA, produced in the brain
KP have deleterious effects on insulin production and release from Trp or directly from Kyn, affect brain chemistry differently by
and consequences on target tissues (Oxenkrug, 2013). acting on glutamate receptors such as the N-methyl-D-aspartate
Serotonin produced in the brain induces satiety, but gut- receptor, important in memory function. Indeed, Kna and QA act
derived 5-HT produced under the direct influence of the micro- respectively by decreasing or increasing extracellular levels of
biota does not cross the blood-brain barrier. However, Trp and glutamate (Schwarcz et al., 2012), which has been shown to
the direct 5-HT precursor 5-HTP do cross the blood-brain barrier be involved in anxiety and stress-related disorders. In this
and thus indirectly modulate central 5-HT production and func- context, IDO1 activation in the periphery, notably in the case of
tion. Moreover, peripheral 5-HT affects host metabolism inflammation, may remotely affect these cerebral processes,
independent of any central effect: gut-derived 5-HT is able to although the mechanisms involved remain unclear (Schwarcz
induce hypophagia and satiety (Voigt and Fink, 2015), and its et al., 2012). Recently, the pathogenesis of autism spectrum
level increases during fasting and stimulates lipolysis in adipose disorder (ASD), one of the most serious neurodevelopmental
tissue and gluconeogenesis in hepatocytes, favoring impaired conditions worldwide, has been suggested to involve an altered
glycemic control (Sumara et al., 2012). Subsequently, mice gut microbiota. Moreover, patients with ASD display altered Trp
with genetic or chemical ablation of TpH1 given a high-fat diet metabolism characterized by reduced plasma and urine levels of
are protected against obesity, insulin resistance, and nonalco- _
Trp (Ka1uzna-Czapli ska et al., 2017), high IDO1 activity (as-
n
holic fatty liver disease (NAFLD) by a mechanism involving sessed by Kyn/Trp ratio) (Lim et al., 2016), and high 5-HT blood
greater energy expenditure by thermogenic brown adipose levels (Muller et al., 2016).
tissue (Crane et al., 2015). However, these results might not be An experimental survey in mice mimicking autism syndrome
applicable to adult humans in whom the abundance of brown reported a 50% reduction in small and large intestine mucosal
adipose tissue is low and decreases with age. In addition, 5-HT with some correlations among 5-HT levels, intestinal transit
obesity in humans has been associated with decreased time, and the abundance of certain bacterial taxa such as Blautia
peripheral 5-HT, suggesting a complex role in pathogenesis (Golubeva et al., 2017). These results are in line with the frequent
(Hodge et al., 2012). The role of AhR has been investigated in constipation observed in patients with ASD. Thus, if low intesti-
metabolic syndrome using mouse models, but no clear conclu- nal production of 5-HT is confirmed in humans with ASD, the
sion has been reached. This might be related to the multiple origin of the increased 5-HT blood levels observed in these
effects of AhR, which is expressed in various cell types (entero- patients must be identified outside of the gut. In addition to
cytes, hepatocytes, and immune cells) involved in metabolic 5-HT, other Trp metabolism pathways might participate. Total
syndrome pathogenesis. neuroprotective metabolites such as picolinic acid (PA), a
Infectious Diseases metabolite of the KP, are decreased in ASD patients despite
The production of Trp-derived AhR agonists, such as IAld, by the an excess of QA production (Lim et al., 2016). Moreover, AhR
gut microbiota plays an important role in the protection against signaling might also be involved, as polymorphisms in the gene
mucosal candidiasis, a fungal infection caused by Candida spe- encoding AhR nuclear translocator (ARNT), which binds and
cies. The underlying mechanisms involve the production of facilitates AhR functions, are associated with ASD severity (Fuji-
IL-22, a key cytokine in colonization resistance against fungi (Ze- sawa et al., 2016).
lante et al., 2013). Similarly, the degradation of AhR ligands in Emerging evidence implicates the microbiome-gut-brain axis
response to Cyp1A1 dysregulation as well as the deletion of in depression as well. Decreased availability of 5-HT in the brain
AhR lead to increased susceptibility to Citrobacter rodentium is a key feature in the pathogenesis of depression. In the case of
infection (Qiu et al., 2012; Schiering et al., 2017). Susceptibility IDO1 pathway overactivation, such as that occurring in chronic
to these two pathogens is reversed by the restoration of intesti- inflammatory diseases or in patients treated with interferon for
nal AhR activity, highlighting the importance of balanced Trp hepatitis C, Trp is massively diverted to the production of Kyn,

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causing a deficiency in brain Trp and in 5-HT production, subse- can be addressed with high-sensitivity and/or high-throughput
quently leading to depression. A similar hypothesis exists methods, which are constantly under development. Combining
regarding depression in obesity, a condition also characterized different methods, particularly metabolomics, with metagenom-
by chronic inflammation and IDO1 activation (Chaves Filho ics and/or metatranscriptomics seems a particularly promising
et al., 2018). A comparable effect is observed in the case of strategy to identify microbes and microbial genes involved in
Trp deficiency due to low dietary intake, supporting the role of the modulation of Trp metabolism. Once identified, one can ima-
Trp pool depletion in depression. gine using natural microbes; genetically engineered bacteria; or,
more directly, microbial products to modulate Trp metabolism in
Tryptophan Metabolism: From a Disrupted Equilibrium a therapeutic context. This type of intervention might be used
to Clinical Opportunities either alone or more likely in combination to target several path-
Since Trp metabolism is affected in pathological situations, the ways and with concomitant modulation of Trp intake.
use of Trp and its metabolites as biomarkers to support diag-
nosis and prognosis and to orientate therapeutic choices is Concluding Remarks
attractive. For example, plasma levels of Trp and Kna predict Trp metabolism has a central role in physiology and physiopa-
adverse cardiovascular outcomes in patients hospitalized for thology. The major pathways described above, specifically the
acute myocardial infarction (Metghalchi et al., 2015). This 5-HT, Kyn, and AhR pathways, are differentially affected in
approach can likely be expanded and applied to the other dis- diseases but remain tightly interconnected. Moreover, intestinal
eases described above. Trp metabolism in these pathways is directly or indirectly
In addition to being biomarkers, the biological effects of Trp controlled by the microbiota (Figure 3). Trp metabolism in the
metabolites and their alterations in disease suggest that they gut is therefore an actionable actor from a therapeutic perspec-
may be therapeutic targets. This is directly achieved by the use tive, using either molecules targeting a specific pathway or
of Trp metabolites, or by targeting their receptors, or by indirectly exploiting microorganisms manipulating Trp metabolism as
manipulating the gut microbiota. For example, the administration probiotics. However, the complexity of microbiota-host interac-
of Lactobacillus, which naturally produces AhR agonists, im- tions and the sophistication of the diseases and models studied
proves colitis severity in mice with genetically induced dysbiosis, demand further investigation to refine targets and therapeutic
suggesting potential therapeutic applications in IBD (Lamas interventions.
et al., 2016). Similarly, Lactobacillus reuteri, through the produc-
tion of the AhR agonist indole-3-lactic acid, is able to reprogram ACKNOWLEDGMENTS
intraepithelial CD4+ T cells into immunoregulatory CD4+CD8aa+
T cells (Cervantes-Barragan et al., 2017). H.S. received funding from the European Research Council (ERC) under the
European Union’s Horizon 2020 Research and Innovation Programme
In situations where IDO is over-activated, decreased gastroin- (ERC-2016-StG-71577) and from JPI HDHL Intestinal Microbiomics
testinal Trp availability may contribute to lower production of (ANR-15-HDIM-0001-1).
AhR agonists by the gut microbiota. This is the case in settings
of intestinal inflammation, such as DSS-induced colitis in mice DECLARATION OF INTERESTS
in which dietary Trp supplementation alleviates colitis severity
Patents related to this work (H.S.): EP 15306303.7; EP16306300.1. H.S. is a
through restoration of AhR ligand production by the gut micro- co-founder of Nextbiotix.
biota (Islam et al., 2017). Similar protective effects have been re-
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