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Cited by 519Tryptophan and brain disordersGut microbiota and healthAmino Acid Enzymes and Metabolism

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Tryptophan Metabolism and Gut-Brain Homeostasis

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Roth, William, Zadeh, Kimia, Vekariya, Rushi, Ge, Yong, Mohamadzadeh, Mansour·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22062973PMC PMC8000752
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Abstract

Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.

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Crossref · 10.3390/ijms22062973

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Figure 1 Tryptophan Metabolic Pathways. Tryptophan metabolism in hosts occurs via the kynurenine pathway or the serotonin pathway to produce bioactive metabolites. (A) 90% of kynurenine pathway degradation occurs in the liver via TDO conversion of TPH to kynurenine. The remaining kynurenine degradation occurs by IDO in the brain, GI tract and liver. Kynurenine is metabolized to kynurenic acid by KAT enzymes. It can also be metabolized to quinolinic acid, which is then converted to NAD+. Alternatively, kynurenine is converted to 3-HK and subsequently to XA. (B) In the serotonin pathway, TPH is converted to 5-HTP by TPH1 in enterochromaffin cells, or TPH2 in enteric or central neurons. 5-HTP is decarboxylated to form serotonin. Serotonin can be further metabolized to form melatonin, or degraded by MAO to 5-HIAA, which is excreted in the urine. (C) In gut microbes, tryptophan is metabolized into indole and indole derivatives. Microbes express different enzymes that utilize TPH. Conversion of TPH to IPA occurs initially through aromatic amino acid decarboxylase to IPYA, which is then converted to ILA and IA prior to conversion to IPA. Through other tryptophan-degrading enzymes, microbes can create metabolic end-products IAld and IAAld. IAAld, which is formed from tryptamine, can also be converted to IAA and subsequently to IAld. Microbes may also convert TPH directly to indole. AAAD = aromatic amino acid decarboxylase, ArAT = aromatic amino acid aminotransferase, 3-HAA = 3-hydroxyanthranilic acid, 5-HIAA = 5-hydroxyindoleacetic acid, 3-HK = 3-hydroxykynurenine, 5-HT = 5-hydroxytryptamine, 5-HTP = 5-hydroxytryptophan, IA = anholocyclic acid, IAA = indole-3-acetic acid, IAAld = indole-3-acetaldehyde, IAld = indole-3-aldehyde, IAM = indole-3-acetamide, IDO = indoleamine 2,3-dioxygenase, ILA = indole-3-lactic acid, IPA = indole-3-propionic acid, IPYA = indole-3-pyurvic acid, KAT = kynurenine aminotransferase, MAO = monoamine oxidase, NAD = Nicotinamide adenine dinucleotide, TDO = tryptophan 2,3-dioxygenase, XA = xanthurenic acid.
Figure 1 Tryptophan Metabolic Pathways. Tryptophan metabolism in hosts occurs via the kynurenine pathway or the serotonin pathway to produce bioactive metabolites. (A) 90% of kynurenine pathway degradation occurs in the liver via TDO conversion of TPH to kynurenine. The remaining kynurenine degradation occurs by IDO in the brain, GI tract and liver. Kynurenine is metabolized to kynurenic acid by KAT enzymes. It can also be metabolized to quinolinic acid, which is then converted to NAD+. Alternatively, kynurenine is converted to 3-HK and subsequently to XA. (B) In the serotonin pathway, TPH is converted to 5-HTP by TPH1 in enterochromaffin cells, or TPH2 in enteric or central neurons. 5-HTP is decarboxylated to form serotonin. Serotonin can be further metabolized to form melatonin, or degraded by MAO to 5-HIAA, which is excreted in the urine. (C) In gut microbes, tryptophan is metabolized into indole and indole derivatives. Microbes express different enzymes that utilize TPH. Conversion of TPH to IPA occurs initially through aromatic amino acid decarboxylase to IPYA, which is then converted to ILA and IA prior to conversion to IPA. Through other tryptophan-degrading enzymes, microbes can create metabolic end-products IAld and IAAld. IAAld, which is formed from tryptamine, can also be converted to IAA and subsequently to IAld. Microbes may also convert TPH directly to indole. AAAD = aromatic amino acid decarboxylase, ArAT = aromatic amino acid aminotransferase, 3-HAA = 3-hydroxyanthranilic acid, 5-HIAA = 5-hydroxyindoleacetic acid, 3-HK = 3-hydroxykynurenine, 5-HT = 5-hydroxytryptamine, 5-HTP = 5-hydroxytryptophan, IA = anholocyclic acid, IAA = indole-3-acetic acid, IAAld = indole-3-acetaldehyde, IAld = indole-3-aldehyde, IAM = indole-3-acetamide, IDO = indoleamine 2,3-dioxygenase, ILA = indole-3-lactic acid, IPA = indole-3-propionic acid, IPYA = indole-3-pyurvic acid, KAT = kynurenine aminotransferase, MAO = monoamine oxidase, NAD = Nicotinamide adenine dinucleotide, TDO = tryptophan 2,3-dioxygenase, XA = xanthurenic acid.CC BY · PubMed Central
Figure 2 Tryptophan Metabolism and Transport. Dietary and microbial tryptophan (TPH) is absorbed in small intestinal epithelium. In enterochromaffin cells (ECs), TPH is released unaltered into the peripheral circulation, where it is degraded in the liver and other peripheral tissues to kynurenine and its metabolites. Or, it is converted to serotonin in ECs via tryptophan hydroxylase 1 (TPH1). TPH is transported across the blood-brain barrier (BBB) into astrocytes via Lat-1 large neutral amino acid transporter. In neurons and glia, it is converted to serotonin via TPH2, or catabolized by the kynurenine degradation pathway to kynurenic acid. Most of the brain quinolinic acid derives from TPH catabolism in microglia.
Figure 2 Tryptophan Metabolism and Transport. Dietary and microbial tryptophan (TPH) is absorbed in small intestinal epithelium. In enterochromaffin cells (ECs), TPH is released unaltered into the peripheral circulation, where it is degraded in the liver and other peripheral tissues to kynurenine and its metabolites. Or, it is converted to serotonin in ECs via tryptophan hydroxylase 1 (TPH1). TPH is transported across the blood-brain barrier (BBB) into astrocytes via Lat-1 large neutral amino acid transporter. In neurons and glia, it is converted to serotonin via TPH2, or catabolized by the kynurenine degradation pathway to kynurenic acid. Most of the brain quinolinic acid derives from TPH catabolism in microglia.CC BY · PubMed Central

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Metadata

Authors
Roth, W., Zadeh, K., Vekariya, R., Ge, Y., & Mohamadzadeh, M.
Affiliations
University of Florida (US)
Corresponding author
  • Roth, William
  • Mohamadzadeh, Mansour
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-03-15
Volume
22
Issue
6
Pages
2973
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22062973
PMC
PMC8000752
OpenAlex
W3137164735
Cited by
519
References
194
Citations by year
2026: 102 · 2025: 150 · 2024: 139 · 2023: 72 · 2022: 46 · 2021: 10
FWCI
6.30
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (DK109560C, R01AI154630-01)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
tryptophan metabolism, gut-brain axis, gut microbiota, serotonin, kynurenine pathway, tryptophan catabolites, neuroinflammation, enteric nervous system, neurological disorders, mental illness, microbiota-targeted therapy
MeSH terms
Gastrointestinal Microbiome, Brain, Colon, Homeostasis, Humans, Hunger, Kynurenine, Pain, Serotonin, Sleep, Tryptophan, Enteric Nervous System

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