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Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease
Open accessAbstract
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.
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“In addition to the metabolic pathways leading to the production of 5-HT and kynurenine, microbial-derived indole derivatives of tryptophan are increasingly recognized as vital in the crosstalk between microbiota and host (Agus et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Agus et al., 2018
In the citing paper
“Thus, via influencing the amount of serotonin precursortryptophan, microbiota influence the amount of serotonin in the brain [32].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [32]
In the citing paper
“Tryptophan metabolism across the serotonin, kynurenine and indole pathways, which are under control of the microbiota (Agus et al., 2018), has a strong influence on mucosal immunity and numerous systemic effects.”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Agus et al., 2018
In the citing paper
“In the gut, it may be further metabolized under direct or indirect control by the GM, giving rise to several compounds, such as serotonin, kynurenines, tryptamine, and indolic compounds, which participate in MGB communication (197, 198).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [197]
In the citing paper
“Its synthesis by microbes has been well described (197).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [197]
In the citing paper
“Indoles are precursor molecules to many compounds that are critical for brain health and function and have been detected in the GI tract, brain, and the systemic circulation [32].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [32]
In the citing paper
“Of extreme relevance, the altered microbiota of patients could transfer the disease from a human host to a mouse host (113, 116–120).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [119]
In the citing paper
“The gut microbiota metabolizes dietary tryptophan into AhR agonists (119).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [119]
In the citing paper
“Tryptophan metabolism, specifically the main pathways leading to the production of 5-HT, kynurenine, and indole derivatives, appears to be closely regulated by the gut microbiota (378, 387).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [387]
In the citing paper
“Finally, the gut microbiota may influence 5-HT production by regulating tryptophan metabolism in the gut [ 69 ]. For example, the gut microbiota may upregulate the production of indole and kynurenine from tryptophan, thereby reducing the substrate for the production of 5-HT and consequently leading to FC.”
From Role of gut microbiota in functional constipation (2021) · cites this paper as [69]
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Citations
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InfluentialTryptophan metabolites and gut microbiota play an important role in pediatric migraine diagnosis
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“For example, tryptophan metabolism was reported to regulate lipogenesis, low-grade chronic inflammation and energy expenditure contributing to metabolic improvement [62, 63].”
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“Disease duration, d 31 (11-397) 27 (14-76) .”
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Therapeutic applications of gut microbes in cardiometabolic diseases: current state and perspectives
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“Allison et al. also summarized the main ways that tryptophan, a metabolite of intestinal flora, affects diseases, especially the 5-HT, Kyn, and AhR pathways, which are affected differently in diseases, but are still closely connected (Agus et al. 2018).”
Shao, J., Qu, L., Liu, Y., Zhang, J., Liu, Y., Deng, J., Ma, X., & Fan, D. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c07599 · Cited by 27
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“In prior studies, indole derivatives have been reported to exert beneficial effects on colitis, cancer, atopic dermatitis, and immune homeostasis (Agus, Planchais, and Sokol 2018).”
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“Neuro-transmitters such as γ -aminobutyric acid (GABA), norepinephrine (NE), serotonin (5-HT), dopamine (DA), short-chain fatty acids (SCFAs) [17], glutamate (Glu), tryptophan (Trp) [18], histamine (His) [19], and secondary bile acids [20] produced by gut bacteria reach the CNS.”
BackgroundCai, X., Cai, X., Xie, Q., Xiao, X., Li, T., Zhou, T., & Sun, H. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00917 · Cited by 27
“Under normal physiological conditions, 5-HT cannot cross the BBB, whereas tryptophan and indoles are able to do so (Agus et al., 2018).”
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Microbiota-derived metabolites in inflammatory bowel disease
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“…indole-3-acetic acid, acetic acid, tryptophan, kynurenine, kynurenate/kynurenic, xanthurenate/ xanthurenic, serotonin, tryptamine, indole-3-ethanol, indole-3-pyru-vate three main biological routes: the kynurenine pathway, the serotonin pathway, and into various indolic compounds [72].”
How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells
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“[3]) that modulate the pathogenesis of EAE [133].”
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“Under normal physiological conditions, peripheral 5-HT is unable to cross the blood–brain barrier (BBB) [34], suggesting that central and peripheral 5-HT have different pools.”
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Microbial metabolites and their influence on the tumor microenvironment
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“…by the host for protein synthesis and metabolized via its intrinsic kynurenine pathway but also undergoes substantial breakdown and transformation by the gut microbiota through a unique set of enzymatic systems, generating a diverse array of metabolites with distinct structures and functions (101).”
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“18 Metabolites from the indole pathway, including indole and its derivatives such as indole-3-propionic acid (IPA), indole-3-acrylic acid, and indole-3-lactic acid, 19 are ligands for the aryl hydrocarbon receptor (AHR).”
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Gut microbiota-brain interaction: An emerging immunotherapy for traumatic brain injury
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Alarcan, H., Chaumond, R., Emond, P., Bretagne, I. B., Lefèvre, A., Bakkouche, S. E., Veyrat‐Durebex, C., Vourc’h, P., Andres, C. R., Corcia, P., et al. (2021) · Biomolecules · doi:10.3390/biom11050691 · Cited by 27
“Apart from KP and serotonin, TRP is also catabolized by another metabolic pathway: Direct metabolism into indole and derivates by the gut microbiota [31].”
BackgroundOsteoarthritis and gut microbiome
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“On the one hand, some tryptophan metabolites may have a pro-inflammatory role, in particular through the activation of the IDO (indolamine 2,3 dioxygenase) pathway and the excessive kynurenin production [12].”
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Chronic Jet Lag Exacerbates Jejunal and Colonic Microenvironment in Mice
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“However, as both Kyn and ILA are aryl hydrocarbon receptor (AhR, a ligand-activated transcription factor) ligands [8, 9, 39, 44], their actions might be mediated via the AhR signaling pathway [40, 44].”
BackgroundEffect of microbiota metabolites on the progression of chronic hepatitis B virus infection
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“The signal plays a key role in the intestinal mucosal immune barrier and is essential for intestinal mucosal homeostasis [44].”
BackgroundInfluentialNuclear receptors: a bridge linking the gut microbiome and the host
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“Trp in the intestine could be changed to AHR ligand (including indole) by the microbiome metabolism and then can regulate multiple pathways, including IL22 signaling, AHR-xenobiotics metabolism, GLP-1 secretions, and gut-brain (CNS) axis (Agus et al. 2018).”
BackgroundIntestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis
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Metadata
- Authors
- Agus, A., Planchais, J., & Sokol, H.
- Affiliations
- AgroParisTech (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Sokol, Harry
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 23
- Issue
- 6
- Pages
- 716-724
- ISSN
- 1931-3128 (ISSN-L)
- OpenAlex
- W2807728333
- Cited by
- 3,180
- References
- 60
- Citations by year
- 2026: 628 · 2025: 609 · 2024: 527 · 2023: 400 · 2022: 393 · 2021: 294 · 2020: 225 · 2019: 84 · 2018: 18
- FWCI
- 15.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Horizon 2020 Framework Programme (ANR-15-HDIM-0001-1, ERC-2016-StG-71577)
- European Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- gut microbiota, tryptophan metabolism, serotonin, kynurenine pathway, indole derivatives, microbial metabolites, aromatic amino acids, pathogenesis, therapeutic target
- MeSH terms
- Gastrointestinal Microbiome, Autistic Disorder, Colitis, Communicable Diseases, Crohn Disease, Humans, Indoles, Kynurenine, Obesity, Serotonin, Short Bowel Syndrome, Tryptophan, Inflammatory Bowel Diseases, Metabolic Syndrome, Gastrointestinal Tract
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