Tryptophan’s Journey Through Pregnancy: The Role of Serotonin

Abstract

Tryptophan is an essential amino acid required for protein synthesis and a precursor of key bioactive metabolites produced through the kynurenine, indole and serotonin pathways. Beyond its nutritional role, tryptophan metabolism critically regulates the nervous, immune and endocrine systems, coordinates circadian rhythms via melatonin, and exerts antioxidant effects. These processes are profoundly remodeled during pregnancy. Pregnancy represents a unique physiological state characterized by systemic adaptations, including changes in immunity and erythropoiesis, while the placenta emerges as a central organ coordinating fetal development, maternal–fetal exchanges, immune tolerance, and protection against external infections. Increasing evidence indicates that tryptophan availability and its downstream metabolites play key roles in maintaining maternal–fetal and placental homeostasis. In particular, serotonin, traditionally viewed as a neurotransmitter, has emerged as a locally produced signaling molecule in the placenta, impacting trophoblast development, placental vascularization, and immune modulation. Dysregulation of tryptophan metabolic pathways has been associated with pregnancy complications and adverse developmental outcomes. This review aims to provide an overview of tryptophan metabolism during gestation, with a specific focus on serotonin as a key factor in placental homeostasis. Targeting tryptophan-derived pathways may offer novel opportunities to improve maternal and neonatal health.

Keywords

kynurenine indole 5-HT melatonin placenta embryo

Overview of Tryptophan Metabolism

Tryptophan

In 1901, Hopkins and Cole identified a previously unknown substance: tryptophan. Its formula is C₁₁H₁₂N₂O₂, and its chemical structure was described 7 years later by Ellinger and Flamand.^1,2 Tryptophan, or L-tryptophan its active biological isomer, is known as 1 of the 8 essential amino acids, meaning that it is not synthesized by our body and can thus only be obtained from diet.³ Dietary sources of tryptophan include bananas, peanuts, chicken, turkey, eggs, and cheese.^4,5 The recommended daily intake ranges from 250 to 450 mg, depending on age, sex, and body weight – and 7 to 10 mg/kg/day during pregnancy. In mammalian, once ingested, tryptophan is absorbed through the intestinal epithelium and enters the bloodstream, where it circulates predominantly bound to albumin – even though around 10% to 20% of tryptophan remains free. The L-type amino acid transporters (LATs), notably LAT1 and LAT2, represent the main mechanism for cellular uptake of L-tryptophan. LAT1 is mainly expressed in tissues with high cellular proliferation, as well as in the testis, thymus and brain. LAT2 is mainly found in the kidney and intestine.^6,7 Both are expressed in the placenta.

Beyond its fundamental role in protein synthesis, tryptophan participates in several metabolic pathways (Figure 1) – as we will discuss below.³ A portion of tryptophan is also metabolized by the gut microbiota, influencing inflammation and intestinal barrier integrity.⁸

Figure 1.

Tryptophan and the kynurenine, indole and serotonin pathways.

Kynurenine Pathway

Tryptophan is primarily degraded via 3 major metabolic pathways: the kynurenine pathway (accounting for approximately 90% of tryptophan degradation), the indole pathway (~5%), and the serotonin pathway (~5%; Figure 1).

Among them, the kynurenine pathway stands out as the dominant route of tryptophan catabolism.⁹ For a long time, it was considered the unique metabolic pathway of tryptophan. This pathway plays a pivotal role in the immune system, notably by promoting immune tolerance and regulating inflammation.

The first step involves the degradation of tryptophan into N-formylkynurenine, by the enzymes indoleamine 2,3-dioxygenase (IDO) 1 and 2, or tryptophan 2,3-dioxygenase (TDO). IDO and TDO represent the rate-limiting enzymes of tryptophan catabolism via this pathway. IDO1 is a ubiquitous enzyme mainly found in the lung, intestines or placenta whereas IDO2 is produced in a limited type of organs, such as kidney, liver or antigen presenting cells.¹⁰ TDO is expressed in various organs, but is most abundantly found in liver where it is responsible for synthesizing the majority of global kynurenine.¹¹ Studies have shown that mice lacking TDO or IDO1 still produce kynurenine, suggesting the existence of alternative enzymes yet to be identified.^12,13 Analysis of double knock-out (KO) of IDO1 and TDO has shown that IDO1 mainly regulates systemic kynurenine production, whereas TDO alone can maintain physiological tryptophan levels.¹⁴ Another important difference between these enzymes is that TDO has a lower affinity but higher efficiency than IDO1 for tryptophan.¹³

N-formylkynurenine is then converted into kynurenine by the enzyme formamidase.⁹ From there, kynurenine can be further metabolized through 2 distinct branches, as illustrated in Figure 2.

Figure 2.

Overview of the kynurenine pathway. (3-HAO: kynurenine 3-monooxygénase; IDO: indoleamine 2,3 dioxygenase; KAT: kynurenine-amino transferase; KMO: Kynurenine 3-monooxygenase; NAD+: nicotinamide adenine dinucleotide; TDO: tryptophan 2,3-dioxygenase).

Under physiological conditions, kynurenine metabolites primarily play a role in the central nervous system (CNS). However, in peripheral organs, these metabolites may reflect a dysregulation of pathways such as inflammation or immune response.¹⁵ Several metabolites derived from the kynurenine exert important physiological functions:

- Kynurenine plays a key role in immune regulation. It acts as an agonist of the aryl hydrocarbon receptor (AhR) and its fixation on this receptor drives the differentiation of T cells into regulatory T cells (Tregs).¹⁶ In addition, AhR activation by kynurenine has been shown to upregulate Programed cell Death protein 1 (PD-1) expression, a critical immune checkpoint receptor, and to suppress CD8+ T cell activation, contributing to an immunosuppressive environment.¹⁷

- Quinolinic acid is primarily produced in the brain, where it undergoes a series of enzymatic reactions to ultimately generate nicotinamide adenine dinucleotide (NAD+).⁹ NAD⁺ is a vital pyridine nucleotide that acts both as a cofactor and a substrate in numerous essential cellular processes, including oxidative phosphorylation and ATP synthesis, DNA repair, epigenetic regulation, intracellular calcium signaling, and immune system regulation through modulation of macrophage function and polarization.¹⁸ Quinolinic acid also acts as an agonist of N-methyl-D-aspartate (NMDA) receptors, which are essential for synaptic plasticity – a fundamental process for learning and memory.¹⁹ However, excessive stimulation of these receptors can lead to a paradoxical phenomenon known as excitotoxicity, where heightened activation becomes detrimental to neuronal health. Indeed, too little activation is harmful, but too much is even worse. Such deregulation has been observed in an increasing number of neuropathological conditions.²⁰ Additionally, quinolinic acid may interact with iron metabolism by forming a complex with ferrous iron, thereby altering its bioavailability and further exacerbating its deleterious effects.^21,22 Overall, quinolinic acid acts as a neurotoxin, a gliotoxin, a pro-inflammatory mediator, a pro-oxidant agent, and can compromise the integrity and cohesion of the blood–brain barrier.

- Picolinic acid, a derivative produced of the same biosynthetic route than quinolinic acid, exerts a neuroprotective role, notably by shielding neurons from quinolinic acid-induced toxicity.^23,24

- Kynurenic acid is directly derived from kynurenine by the kynurenine-amino transferase (KAT). It plays a critical role in cerebral activity and mood regulation. Kynurenic acid exerts neuroprotective effects by acting as an antagonist of ionotropic glutamate receptors (which include NDMA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainite receptors – all involved in synaptic transmission and plasticity).²⁵ The balance between kynurenic acid and quinolinic acid, referred to as the K/Q ratio, is critical for neuronal health. The K/Q ratio, or ‘neuroprotective ratio”, reflects the equilibrium between excitotoxic and neuroprotective forces in the brain: an increase in kynurenic acid levels or a decrease in quinolinic acid can help reduce excitotoxicity and promote neuronal viability. Alterations in K/Q ratio has been associated with psychiatric disorders and neurodegenerative diseases.^9,26,27

- Xanthurenic acid role remains less well defined. However, emerging studies suggests that it may participate in neurotransmission.^28,29 A study has reported an interaction of xanthurenic acid with G protein-coupled receptors (GPCRs) leading to the accumulation of intracellular Ca²⁺. It also showed that xanthurenic acid can interact with glutamatergic receptors, specifically metabotropic glutamate receptors 2 and 3 (mGluR2/3), as well as with the vesicular glutamate transporter. These interactions are thought to contribute to analgesia, modulation of trans synaptic signaling and regulation of monoaminergic transmission.^30,31

Indole Pathway

Around 5% of tryptophan is metabolized by the gut microbiota into indole and its derivatives, such as indole-3-aldehyde, indole-3-acetic acid or indole-3-propionic acid, as illustrated in Figure 3.

Figure 3.

Overview of the indole pathway.

Certain bacterial species of the microbiota can convert tryptophan into tryptamine via the enzyme tryptophan decarboxylase.³² Recent discoveries on the importance of the microbiota for overall health have highlighted new insights into the indole pathway, linking gut microbiota and tryptophan metabolism. Metabolites from this microbial pathway play diverse immunological and physiological roles: they have been shown to inhibit macrophage activity,³³ enhance intestinal barrier integrity,^34,35 regulate inflammatory cytokines³⁶ and promote activation of intestinal lymphocytes.³⁷ Gut dysbiosis can alter tryptophan metabolization by the microbiota and increase the severity of diseases such as non-alcoholic fatty liver disease or chronic kidney disease.^38,39 Microbiota-targeted therapies have been suggested to attenuate symptoms associated with dysregulated tryptophan metabolism.^38-41

Serotonin Pathway

Approximately 5% of tryptophan is metabolized via the serotonin pathway, as shown in Figure 4. This pathway produces several key metabolites, including serotonin (5-hydroxytryptamine or 5-HT), 5-hydroxyindoleacetic (5-HIAA), and melatonin.

Figure 4.

Overview of the serotonin pathway.

Serotonin (5-HT)

Serotonin is a monoamine synthesized from tryptophan through a 2-step enzymatic process involving tryptophan hydroxylase (Tph, the rate limiting enzyme) and 5-hydroxytryptophan decarboxylase (also known as aromatic L-amino acid decarboxylase (AADC). First identified in 1948 by Maurice Rapport as a molecule involved in intestinal contractions, serotonin later gained significant attention for its role in the central nervous system as a neurotransmitter.

Once synthesized, serotonin is stored into synaptic vesicles by vesicular monoamine transporter (VMAT) and is released via calcium-dependent exocytosis into the synaptic cleft. Serotonin can then either be recaptured by its serotonin transporter (SERT or 5-HTT), bind to 1 of its 5-HT receptors (5-HTR), or be metabolized by the monoamine oxidase A (MAO A; Figure 5).

Figure 5.

Serotonin synthesis and metabolism.

Fifteen 5-HTRs have been identified, grouped into 7 families (5-HT₁ to 5-HT₇). All are GPCRs, also known as 7-transmembrane domain receptors, except for 5-HT₃, which is a ligand-gated ion channel. The activation of these receptors regulates a wide range of physiological and behavioral functions, depending on the receptor, tissue localization and cellular context.

In the brain, serotonin is primarily produced in the raphe nuclei by the neuronal isoform of Tph: Tph2. There, it acts as a neurotransmitter, influencing mood, anxiety, libido, cognition, and behavior through its binding to its receptors. Several antidepressant drugs target the serotonin system, such as selective serotonin reuptake inhibitors (SSRI) which inhibit SERT to increase serotonin availability in the synaptic cleft. The SSRI affects central but also peripheral serotonin levels, potentially leading to a side effect called serotonin syndrome. In some patients, SSRI use can indeed lead to neuropsychiatric symptoms (eg, confusion, hallucinations), vascular dysregulation (eg, hypertension, bleeding, tachycardia), and gastrointestinal disturbances (eg, diarrhea).^42,43

A second isoform of Tph, Tph1, is expressed in peripheral tissues – notably in enterochromaffin cells of the gastrointestinal tract where peripheral serotonin is mainly produced.⁴⁴ Peripheral serotonin is then predominantly stored in platelets. While research on its functions outside the central nervous system is relatively recent, the Tph1 knockout (KO) mouse model, where the mice are deficient in peripheral serotonin, has enabled significant progress. Peripheral serotonin is now increasingly recognized for its role in a wide range of physiological processes, including (Table 1):

Table 1.

Examples of Roles of Peripheral Serotonin.

Organ	Receptor	Function	References
Intestine	5-HT₃	Stimulates propulsive motility and extrinsic sensory signaling	Kendig and Grider⁴⁵, Terry and Margolis⁴⁶
Intestine	5-HT₄	Stimulates peristaltic reflex and secretion	Kendig and Grider⁴⁵, Terry and Margolis⁴⁶
Bone	5-HT_1B	Stimulates osteoclast differentiation and proliferation Inhibits osteoblast proliferation	Chabbi-Achengli et al⁴⁷, Martin et al⁴⁸
	5-HT_2A	Stimulates osteoclast differentiation and proliferation
	5-HT_2B	Stimulates osteoclast differentiation and proliferation
Bone marrow	5-HT_2A	Stimulates erythroid progenitors proliferation	Amireault et al⁴⁹, Amireault et al⁵⁰
Pancreas	5-HT_2A	Stimulates insulin secretion	Martin et al⁴⁸, Barradas et al⁵¹, Choi et al⁵², Iordanidou et al⁵³, Kivimäki et al⁵⁴, Raeder et al⁵⁵
	5-HT_2B	Stimulates pancreatic beta cell proliferation
	5-HT_1D	Inhibits insulin secretion
Blood vessel	5-HT_1B	Promotes vasoconstriction	Ayme-Dietrich et al⁵⁶, Fujita et al⁵⁷
	5-HT_2A	Promotes vasoconstriction
	5-HT₇	Promotes vasodilatation
Embryo	5-HT_2A	Participates in cardiac development (Its role during pregnancy is discussed below)	Côté et al⁴⁴, Côté et al⁵⁸, Maroteaux and Kilic⁵⁹

Melatonin

Melatonin is synthesized from serotonin through a 2-step enzymatic process involving N-acetylation followed by O-methylation. A key enzyme in this pathway is serotonin-N-acetyltransferase, also called aryalkylamine N-acetyltransferase (NAT or AANAT), whose activity is regulated by the pineal gland according to the circadian rhythm.^60,61 A second enzyme is involved in melatonin synthesis, the acetylserotonin O-methyltransferase (ASMT or HIOMT). Circadian melatonin is primarily produced in central nervous system structures such as the pineal gland, retina, and cerebellum. Once synthetized, circadian melatonin is released into the bloodstream and distributed throughout the body. It is mainly metabolized in the liver and excreted in the urine.^62,63 Melatonin exerts its biological effects through 2 main receptors, named MT1 and MT2, which are GPCRs. Melatonin has several functions in the central nervous system, listed in Table 2.

Table 2.

Roles of Melatonin in the Central Nervous System.

Context	Role of melatonin	References
Sleep regulation	Regulates sleep by influencing plasma melatonin levels, which are closely associated with the onset and duration of sleep. Considered one of the primary signals initiating the sleep process.	Cajochen et al⁶⁴
Thermoregulation	Contributes to nighttime thermoregulation by lowering core body temperature during sleep, in line with its circadian secretion rhythm. This effect may be mediated through melatonin-induced peripheral vasodilation.	Chang and Chiang⁶⁵, Strassman et al⁶⁶, van der Helm-van Mil et al⁶⁷
Antioxidant activity	Enhances the activity of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, and may upregulate the expression of genes encoding these enzymes.	Albarrán et al⁶⁸, Baydas et al⁶⁹, Liu and Ng⁷⁰, Pablos et al⁷¹, Mayo et al⁷²
Nociception regulation	Modulates pain by reducing cerebral hyperemia and enhancing the antinociceptive effects of opioids.	Hemati et al⁷³, le Grand et al⁷⁴

Several peripheral organs can also produce melatonin such as the skin, ovary, liver, pancreas, kidneys, bone marrow, lymphoid tissues, gastrointestinal tract,^75,76 and placenta.⁷⁷ Unlike central production, peripheral melatonin synthesis does not follow a circadian day/night cycle and its effects remain local.⁷⁸ It can exert a wide range of actions, listed in Table 3.

Table 3.

Roles of Melatonin in Peripheral Organs.

Context	Role of melatonin	References
Antioxidant activity	Exhibits antioxidant activity in many organs, including the liver, kidneys, muscles, gut, and placenta.	Galano et al⁷⁹
Anti-aging	Delays aging-related processes by reducing oxidative stress, improving mitochondrial function, and enhancing DNA repair mechanisms.	Hardeland⁸⁰
Cardiovascular regulation	Modulates vascular tone, reduces blood pressure, and exerts anti-atherosclerotic effects.	Simko and Paulis⁸¹
Immunomodulation	Modulates both innate and adaptive immune responses.	Carrillo-Vico et al⁸²
Anti-inflammatory	Inhibits pro-inflammatory cytokine production and modulates immune cell activity.	Maarman and Reiter⁸³
Anti-tumoral	Exerts anti-tumor effects through inhibition of cell proliferation, induction of apoptosis, and suppression of angiogenesis.	Hill et al⁸⁴
Gastrointestinal tract activity	Protects the intestinal mucosa, regulates motility, and interacts with the gut microbiota.	Bubenik⁸⁵
Reproductive functions	Supports ovarian metabolism and oocyte quality (its role during pregnancy is discussed below).	Reiter and Sharma⁸⁶

Specific physiological conditions can modulate the action of these different tryptophan-derived metabolites especially during pregnancy: we will now explore how tryptophan metabolism is regulated throughout the 9 months of gestation.

Tryptophan Pathways Throughout Pregnancy

The placenta is the central organ of pregnancy, continuously developing throughout the 9 months of gestation. It is a highly specialized and multifunctional organ, which plays essential roles: maternal-fetal exchanges, immunoregulation, and endocrine system. Through selective uptake from maternal circulation, the placenta helps regulate the fetal environment by producing, metabolizing, or facilitating the transfer of essential elements to the fetal compartment. Additionally, pregnancy induces profound changes in maternal physiology. Within all these processes, tryptophan and its metabolites play a pivotal role.

Tryptophan

Tryptophan and Pregnancy Immunity

Pregnancy presents an immunological paradox: since the fetus expresses both paternal and maternal antigens, the maternal immune system would be expected to reject it. However, the embryo can develop for 9 months within the maternal body. Several hypotheses have been proposed to explain this phenomenon, notably the local inhibition of maternal immunity at the maternal-fetal interface.⁸⁷

It has been reported that circulating tryptophan levels decrease during pregnancy, and further decrease with gestational age.^88,89 Abnormal tryptophan level has been associated with an increased risk of fetal rejection.⁹⁰ Munn et al have shown that tryptophan metabolism is involved in T cell proliferation. Fetal rejection, normally triggered by paternal antigen expression, is mediated by maternal T cells that recognize trophoblast cells as potentially harmful. During pregnancy, the decrease in tryptophan, mediated by upregulation of IDO1, promotes immune tolerance by inhibiting T cell proliferation shortly after fecundation.^90,91 Other studies further explored the role of tryptophan in T cell regulation, showing that its availability – largely controlled by IDO1 – regulates T cell proliferation.^92-94 In parallel, the kynurenine/tryptophan ratio increases during pregnancy, suggesting that the decrease of tryptophan is essentially due to its catabolism via the kynurenine pathway.^95,96 Thus, the kynurenine/tryptophan ratio appears to be a more reliable biomarker for identifying pregnancies with immune-related complications than tryptophan. Other pregnancy complications such as preeclampsia or perinatal depression may also influence maternal tryptophan levels, making it a potential biomarker for those pathologies as well.⁹⁷

Impact of Altered Tryptophan Levels during Pregnancy, Role of LAT

The fetal uptake of essential amino acids during pregnancy is critical for protein synthesis, as well as for neurotransmitters and nucleotides synthesis. Tryptophan crosses the placenta via the active L-type amino acid transporter (LAT),⁹⁸ a sodium-independent system composed notably of 2 exchangers, LAT1 and LAT2.⁹⁹ LAT1 and LAT2 are both expressed in human placenta on the syncytiotrophoblast,^6,100 while only LAT2 is present on the fetal endothelial cells.¹⁰¹

Some studies suggest that LAT expression levels may correlate with pregnancy parameters such as fetal weight, and with pregnancy outcomes such as intrauterine growth restriction (IUGR, associated with decreased LAT expression) or fetal overgrowth (associated with increased LAT expression).¹⁰² Indeed, dysregulation of LAT expression affects the transport of essential amino acid such as tryptophan. Amino acids are essential for protein synthesis during fetal development.^103-105 Amino acid deficiency has been associated with IUGR, and a supplementation can be prescribed to pregnant women. Conversely, LAT1 overexpression and excess amino acids have been linked to fetal overgrowth, as well as abnormal development of structures such as the heart and the blood-brain barrier.^106-109

Nonetheless, the causal relationship between LAT expression and pregnancy complications remains unclear, and it is not yet established whether changes in LAT expression are a cause or a consequence of these outcomes.

The impact of dietary tryptophan has also been studied in different models. A high-tryptophan diet before conception was associated with increased body weight, brain weight, and blood pressure. Alterations in embryonic hormonal balance, increased protein synthesis, and a decreased number of serotonergic neurons were also reported.^110,111 A tryptophan-free diet before conception was associated with hypoandrogenism, hypoprolactinemia, and cardiorespiratory alterations.^112-114 Finally, elevated systemic tryptophan levels were associated with a lower risk of preeclampsia and pregestational diabetes mellitus.¹¹⁵ These effects may be explained by the role of tryptophan in protein synthesis, but are also likely largely driven by its downstream effects on serotonin, indole, and kynurenine synthesis.

Kynurenine

Kynurenine Levels during Pregnancy

As previously mentioned, plasma tryptophan levels decrease during pregnancy. According to Munn et al , this decline is attributed to the overexpression in placenta of IDO, which suggests a concurrent increase in circulating kynurenine.⁹⁰ However, studies have shown that kynurenine levels in maternal blood remain stable throughout non-complicated pregnancy,¹¹⁶ and consequently, the kynurenine/tryptophan ratio increases.¹¹⁷ There is a lack of comprehensive studies on plasma kynurenine levels during gestation. One hypothesis is that kynurenine produced during pregnancy is rapidly metabolized or utilized.

The placenta produces and metabolizes kynurenine, expressing both key enzymes IDO1 and IDO2, with IDO1 being the predominant isoform. The precise localization of IDO1 within placental tissues remains debated. Studies reported IDO1 expression in syncytiotrophoblast and extravillous cytotrophoblasts, with a marked increase expression at term.^96,118-120 However, 1 group challenged these observations, suggesting that IDO1 detected in trophoblast cells may originate from fetal endothelial cells. The authors suggested the existence of an IDO1 expression gradient within the maternal-fetal vascular system.¹²¹ IDO1 expression increases significantly as pregnancy progresses.^122,123 The second enzyme involved in kynurenine synthesis, TDO, is also present in the human placenta notably in villi’s cells,¹²⁴ though at low and stable levels throughout gestation.^125,126 Altogether, these findings demonstrate the placenta’s capacity to synthesize kynurenine itself.

Kynurenine Metabolites during Pregnancy

The kynurenine can cross the placenta to reach the fetal circulation. Oral administration of kynurenine has been shown to markedly increase its concentration in maternal plasma, placenta, fetal plasma and fetal brain tissues.¹²⁷ However, not all kynurenine metabolites are equally transferred. For instance, kynurenic acid is taken up by the placenta but is not transported to the fetal side, suggesting that the embryo may synthesize kynurenine metabolites.¹²⁷

Several enzymes of the kynurenine pathway – such as kynurenine monooxygenase (KMO), kynurenine aminotransferases (KYAT), kynureninase (KYNU), and quinolinate phosphoribosyltransferase (QPRT) – have also been identified in the placenta. Their expression decreases during the third trimester.¹²² The authors suggest that placental kynurenine is mainly used for the production of metabolites such as kynurenic acid, useful for its neuroprotective properties^25,128, 3-HAA and 3-HK for their immunosuppressive effects, and quinolinic acid for NAD⁺ synthesis – essential for placental metabolism, including mitochondrial function and DNA repair.^129,130

Impact of Altered Kynurenine Metabolite Levels during Pregnancy

Proper regulation of kynurenine-derived compounds is crucial for fetal development. Indeed, abnormal levels of kynurenine metabolites in placenta or fetal tissues have been associated with adverse pregnancy outcomes, such as abnormal birth weight or impaired central nervous system development.^131,132

Several studies reported that elevated levels of kynurenic acid, hydroxykynurenine, and kynurenine are associated with preeclampsia and gestational diabetes mellitus.^115,133 Overactivation of the kynurenine pathway may be related to the inflammatory environment observed for instance in preeclampsia. Lipopolysaccharide injection, an inflammatory stimulus, has been shown to overactivate the kynurenine pathway and increase the production of its metabolites. Excess levels of certain metabolites can lead to fetal alterations; for example, quinolinic acid has neurotoxic effects when overproduced.^134-136 Upregulation of this pathway may also alter NAD⁺ production, contributing to cellular dysfunction.

The kynurenine pathway has also been linked to hormonal regulation. Estrogens can decrease kynurenic and picolinic acids, whereas progesterone increases kynurenic and quinolinic acid levels.^137,138 It is well established that the large decrease in progesterone and estrogen levels after delivery contributes to the normalization of the kynurenine pathway postpartum. Endocrine alterations may contribute to kynurenine dysregulation and increased inflammatory responses.¹³⁹

Finally, in a uninephrectomized mouse model with an impaired adaptive increase of kynurenine, this failure to increase kynurenine led to preeclampsia-like symptoms, including impaired placentation.¹⁴⁰ This finding is consistent with reports linking abnormal kynurenine levels to fetal growth restriction, a common consequence of preeclampsia.¹⁴¹ These effects may be explained by the role of the kynurenine pathway in trophoblast migration and invasion, which are critical steps in placental development; their impairment can contribute to fetal rejection. Most mechanistic studies have been conducted in placental cell lines and in vivo data remain limited. Nevertheless, current evidence suggests that disruption of the kynurenine pathway may contribute to abnormal placental development.¹⁴²

Indole Pathway

Little is known about the potential roles of indoles on placenta and pregnancy. However, it has been reported that during pregnancy, levels of indole-3-lactic acid (ILA) increase in both maternal plasma and the umbilical vein.¹⁴³ ILA may act as a protective molecule against preeclampsia through its anti-inflammatory properties and its ability to regulate Th17 differentiation.¹⁴⁴ ILA has also been shown to regulate trophoblast migration and invasion by interacting with the AhR receptor.^145-147 Targeting the AhR receptor through tryptophan supplementation or ILA treatment is a promising approach for diseases involving AhR, such as chronic kidney disease or irritable bowel syndrome. ILA, via the AhR receptor, influences cell proliferation and tumorigenesis.^148,149 Interestingly, in the context of renal injury, indole-3-aldehyde can stimulate the expression of proteins involved in cell junctions, notably zonula occludens-1 (ZO-1).¹⁵⁰ ZO-1 plays a critical role in placental development, particularly in the fusion of trophoblast cells. Investigating the indole pathway in placental diseases associated with impaired trophoblast fusion could represent a promising area of research.

Serotonin (5-HT)

Serotonin Levels During Pregnancy

The regulation of plasma serotonin levels during pregnancy remains poorly understood. Very few studies have investigated plasma serotonin under various physiological and pathological conditions. In 2011, Brand and Anderson conducted a comprehensive review of studies measuring plasma serotonin levels and highlighted the considerable heterogeneity of the results. This variability was attributed to differences in measurement techniques and the physiological storage of serotonin in platelets, which may, or not, release serotonin into plasma prior to sampling.^151,152

Source of Serotonin in the Placenta

While it is generally accepted that the placenta synthesizes serotonin, whether placental synthesis alone can provide sufficient levels of serotonin during pregnancy remains a subject of debate. In 2011, Bonnin et al proposed that the placenta produces serotonin during gestation, influencing embryonic development.¹⁵³ However, subsequent studies, including Kliman et al,¹⁵⁴ suggested that most of the serotonin needed during gestation comes from maternal blood, and is transported by platelets. Evidence supports the idea that maternal serotonin is crucial for embryo development,⁵⁸ and that the placenta is equipped to uptake maternal serotonin.^122,155 Thus, placental serotonin likely originates from both maternal and placental sources, with maternal serotonin playing a crucial role, especially in early pregnancy.

Expression of Components of the Serotonergic System in the Placenta

It is well established that the placenta expresses components of the serotonergic system.¹⁵⁶ Studies have demonstrated the expression of Tph in the placenta. Both isoforms (Tph1 and Tph2) are expressed in villous and extravillous cytotrophoblasts.^157,158

The placenta, via the serotonin transporter (SERT) expressed on the syncytiotrophoblast layer, takes up serotonin from the maternal blood. This endocrine layer is enriched in monoamine oxidase (MAO), which degrades serotonin and thus regulates placental serotonin levels before it reaches the cytotrophoblast. Then, serotonin crosses into the fetal compartment through the organic cation transporter 3 (OCT3), which, although less specific than SERT, is efficient for serotonin transport.^154,159,160

Expression of serotonergic components in the placenta varies with gestational age. Tph gene expression declines, while MAO expression increases during pregnancy. However, Tph enzymatic activity remains unchanged, in contrast to MAO activity, which rises over time. This suggests that the influence of serotonin on the placenta decreases toward the end of gestation.¹²² MAO regulation is particularly important to control placental serotonin levels and avoid vasoconstriction caused by elevated serotonin.^157,161,162 However, serotonin transporter expression increases toward term,^122,155,163 likely reflecting the growing serotonergic needs of the developing fetus.

Impact of Altered Serotonin Levels during Pregnancy

Given the well-established function of serotonin in the central nervous system, several studies have investigated its role in neurodevelopment.

For instance, altered serotonin levels have been observed in children with neurodevelopmental disorders such as autism, suggesting a potential role for serotonin in neurodevelopment.^164-167

Dysregulation of the serotonergic system during gestation has been associated with long-term consequences, including behavioral disorders such as hyperactivity, depression, and anxiety.^165,168

A study using a Tph2 KO mouse model has highlighted abnormalities in neuroplasticity mechanisms.¹⁶⁹

Impaired fetal brain development has been reported in pregnancy with dysregulations in placental serotonergic components, notably increased serotonin synthesis and transport, and reduced degradation.¹⁷⁰ These last findings suggest that placental serotonin signaling, rather than total serotonin levels, may play a key role in early fetal brain development.

Regarding peripheral serotonin, analysis of the Tph1 KO mouse model (deficient in peripheral serotonin) has revealed developmental delays in embryos,⁵⁸ particularly affecting the cardiac system.⁴⁴

Several hypotheses have been proposed to explain this developmental delay. Key reproductive tissues contain serotonin and components of the serotoninergic system, including the uterus and the oocyte microenvironment (cumulus cells, oocytes and granulosa cells).^171,172 Serotonin receptors expressed in reproductive tissue can activate the cyclic adenosine monophosphate (cAMP) signaling pathway, which is critical for hormonal synthesis, particularly steroidogenesis.¹⁷³ Dysregulation of serotonin levels may lead to abnormal steroidogenesis which has been associated with IUGR or impaired implantation.^174,175

Moreover, serotonin-mediated activation of the cAMP pathway is involved in cell proliferation, a process essential for normal embryonic development.¹⁷⁶

In addition, serotonin is known to be present in stem cells, where it contributes to stem cell survival. Reduced serotonin levels can increase stem cell apoptosis via the protein kinase B (AKT)-Forkhead box O1 (Foxo1) signaling pathway.^177,178

Another hypothesis that could explain developmental delay involves alterations at the maternal-fetal interface. Serotonin also plays a crucial role in placental development. Inhibition of SERT expression, which likely affects local serotonin availability, leads to abnormal placental structures in rat models.¹⁵⁹ It has been suggested that serotonin contributes to placentation through its effects on hormone secretion, such as estrogen, and on cell proliferation via activation of the 5-HT₂A receptor.^179-181

Finally, peripheral serotonin is essential for embryonic cardiovascular development and function, as demonstrated by cardiac hypertrophy, altered hemodynamics, and heart failure in Tph1 KO mice model.⁴⁴

SSRI Exposure during Pregnancy

In clinical settings, serotonin reuptake inhibitors (SSRIs), which block SERT, are commonly prescribed for anxiety or depression. Some studies report a small risk of developmental abnormalities associated with SSRI exposure during pregnancy, such as congenital heart defects.^182,183 These effects may be related to elevated serotonin levels induced by SERT inhibition.¹⁸⁴

Furthermore, it has been shown that SSRI treatment on BeWo cells and placental explants affects endocrine function, cell proliferation and differentiation.^181,185

The evidence argues that the use and dosage of SSRIs during pregnancy should be carefully evaluated and adjusted according to the severity of maternal depression.¹⁸⁶

Melatonin

Melatonin Levels during Pregnancy

Placental serotonin is metabolized into melatonin. The placenta expresses both enzymes involved in melatonin synthesis (AANAT, HIOMT) and the receptors involved in its signaling (MT1A and MT1B (MT2).^187-189 Melatonin present in the maternal circulation – coming from either pineal or extra-pineal sources – can cross the placenta and enter the fetal circulation.¹⁹⁰ During pregnancy, maternal plasma melatonin levels increase with a pic at term and rapidly return to baseline immediately after placental delivery.^191,192

Impact of Altered Melatonin Levels during Pregnancy

While global melatonin homeostasis during pregnancy remains insufficiently characterized, several studies have highlighted the crucial role of placental melatonin. First, melatonin seems to contribute to placentation and trophoblast fusion. In vitro studies using the BeWo trophoblast cell line have shown that melatonin treatment negatively modulates forskolin-induced β-hCG secretion, suggesting an influence on trophoblast differentiation.⁷⁷ The authors proposed that this effect is mediated through activation of melatonin receptors MT1A and MT1B.

A negative correlation has been observed between MT1A receptor expression and adverse pregnancy outcomes such as placental insufficiency and intrauterine growth restriction.¹⁸⁷ The main hypothesis is that melatonin exerts antioxidant effects via its receptors, which may counteract the excess inflammation caused by trophoblast cell apoptosis. Insufficient melatonin receptor expression could lead to increased inflammation and abnormalities in fetal development.^193-195

Beyond its role in placentation, melatonin exerts protective effects in the primary human trophoblast cells by modulating autophagy under hypoxic conditions, improving cellular respiration and mitochondrial activity as well as potent anti-inflammatory and antioxidant.^188,190,196 It has notably cytoprotective effects in pregnancies complicated by placental dysfunction, such as those associated with maternal obesity.^197,198 Melatonin is also thought to play a role in immune regulation during gestation. It promotes maternal immunotolerance by modulating lymphocyte differentiation, particularly toward Th17 phenotype.¹⁹⁹ Current evidence is, however, still limited.

Melatonin appears particularly critical during the early stages of embryonic development. Indeed, melatonin has been proposed to improve outcomes in in vitro fertilization²⁰⁰ and is implicated in the regulation of early cell divisions. Moreover, MT1 receptors are particularly expressed in the blastocyst, suggesting an important role of melatonin in early stages of gestation.^201-203 Collectively, these properties support a key role for melatonin in promoting a healthy pregnancy and preventing developmental abnormalities.

Finally, melatonin also plays a role in gametogenesis. Variations in melatonin levels have been correlated with sperm quality (particularly chromatin condensation and sperm motility), which influence fertilization rates and embryo quality.^86,204,205

In the female organism, melatonin modulates granulosa cell function by reducing oxidative stress and protecting cells from apoptosis through decreased p53 expression.^206,207 Similar signaling pathways have been described in oocytes.²⁰⁸

Altogether, the effects of melatonin on reproductive tissues lead to improved embryo quality and fertilization rates.

Conclusion

Tryptophan metabolism plays a crucial role in pregnancy, acting through multiple downstream pathways that contribute to fetal development, placental development and function, and maternal adaptation. Among its metabolites, serotonin and melatonin stand out as key modulators of embryonic and placental development. Several studies have highlighted the importance of peripheral serotonin, particularly during early gestation, in various processes such as placental structure, hormone secretion, immune tolerance, and oxidative stress responses. The placenta is both a regulator and a potential source of serotonin and melatonin, reflecting the complexity of tryptophan-derived signaling in pregnancy.

However, the current body of evidence is subject to several limitations. Many findings are derived from animal models, which may not fully recapitulate human pregnancy, and human studies are often observational, limiting causal inference. In addition, methodological heterogeneity in the assessment of tryptophan metabolites, differences in gestational timing, and limited longitudinal data complicate direct comparisons across studies. Furthermore, the interactions between the serotonin, melatonin, and kynurenine pathways remain incompletely understood.

Altogether, these findings still underscore the significance of maintaining balanced tryptophan metabolism during gestation. Disruptions in its pathways – whether due to genetic, environmental, or pharmacological factors – may contribute to pregnancy complications or long-term developmental outcomes.

Future research should focus on longitudinal and integrative approaches to better characterize the dynamic regulation of tryptophan metabolism throughout pregnancy and to evaluate its potential as a therapeutic target to support maternal and fetal health.

Footnotes

Abbreviations

3-HAO: kynurenine 3-monooxygénase

5-HIAA: acide 5-hydroxyindoleacétique

5-HT: 5-hydroxytryptophan = serotonin

5-HTR: 5-HT receptor

AAD: aromatic amino acid decarboxylase

AhR: aryl hydrocarbon receptor

AMPA receptor: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AANAT: Serotonin N-acetyltransferase

ASMT: Acetylserotonin O-methyltransferase

IDO: indoleamine 2,3 dioxygenase

KAT: kynurenine-amino transferase

KMO: Kynurenine 3-monooxygenase

KO: knock-out

LAT: L-type amino acid transporters

NAD+: nicotinamide adenine dinucleotide

NAT: serotonin-N-acetyltransferase

NMDA receptor: N-methyl-D-aspartate receptor

MAO: monoamine oxidase

MT1 and MT2: melatonin receptors

PD-1: programed cell death protein 1

SERT: serotonin transporter

SSRI: selective serotonin reuptake inhibitors

TDO: tryptophan 2,3-dioxygenase

Tph: tryptophan hydroxylase

Tregs: regulatory T cells

VMAT: vesicular monoamine transporter

WT: wild type

ORCID iDs

Benoît Gendrot

Cathy Vaillancourt

Guillemette Fouquet

Author Contributions

In loving memory of Francine Côté.

Conception and design: BG, GF

Manuscript writing and editing: BG, CV, GF

Reviewing: BG, GF

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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