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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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“Allison et al. also found that Trp metabolism is associated with host intestinal in fl ammation, epithelial barrier, and energy homeostasis in IBD (80), and is closely related to the intestinal fl ora.”
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The Impact of Nutrition and Intestinal Microbiome on Elderly Depression—A Systematic Review
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“Tryptophan is known to have a direct effect on the dietary composition of microflora [51,52].”
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“Microbes can also modulate the metabolism of tryptophan, which performs a critical role in the correct functioning of the immune system and the brain– gut axis (Agus et al., 2018).”
BackgroundThe role of virome in the gastrointestinal tract and beyond
Tiamani, K., Luo, S., Schulz, S., Xue, J., Costa, R., Mirzaei, M. K., & Deng, L. (2022) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuac027 · Cited by 58
Interactions between Gut Microbiota and Polyphenols: New Insights into the Treatment of Fatigue
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“Tryptophan is metabolized mainly through three different pathways, namely the kynurenine pathway, 5-HT pathway, and microbial metabolic pathway [44].”
BackgroundMelatonin–Microbiome Two-Sided Interaction in Dysbiosis-Associated Conditions
Ieșanu, M. I., Zahiu, C. D. M., Dogaru, I.-A., Chiţimuș, D. M., Pîrcălăbioru, G. G., Voiculescu, S. E., Isac, S., Galoş, F., Pavel, B., O’Mahony, S. M., et al. (2022) · Antioxidants · doi:10.3390/antiox11112244 · Cited by 63
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Essential Amino Acid Metabolites as Chemical Mediators of Host-Microbe Interaction in the Gut
McCann, J. R., & Rawls, J. F. (2023) · Annual Review of Microbiology · doi:10.1146/annurev-micro-032421-111819 · Cited by 64
Wang, S., van Schooten, F., Jin, H., Jonkers, D. M. A. E., & Godschalk, R. (2023) · Nutrients · doi:10.3390/nu15132886 · Cited by 58
“TRP metabolism follows three main pathways in the GI tract [6,7] (see Figure 1).”
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“The serotonin production pathway is the most important pathway of tryptophan metabolism, which is closely related to gut microbiota and intestinal inflammation [53].”
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Lu, Y.-P., Zhang, Z., Wu, H., Fang, L.-J., Hu, B., Tang, C., Zhang, Y., Yin, L., Tang, D., Zheng, Z., et al. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03629-8 · Cited by 58
“‘a’, the serotonin metabolism pathway; ‘b’, the indole pathway; ‘c’, the kynurenine pathway; ‘d’, NAD+ de novo synthesis pathway; ‘e’, the salvage synthesis pathway of NAD+; ‘f ’, purine degradation pathway; ‘g’, ATP‑degradation mediated purine nucleotide conversion bypass; ‘h’, pyrimidine de novo synthesis pathway Cl…”
BackgroundInfluentialYan, M., Guo, X., Ji, G., Huang, R., Huang, D., Li, Z., Zhang, D., Chen, S., Cao, R., Yang, X., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1097853 · Cited by 57
“It has been reported from experimental studies that the gut microbiota can directly utilize tryptophan and produce bacteria-derived indole (86, 87).”
BackgroundSu, J., Lin, X., Li, D., Yang, C.-M., Lv, S., Chen, X., Yang, X., Pan, B., Xu, R. P., Ren, L., et al. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2347757 · Cited by 59
“51 There have been several paradox reports concerning the relationship between Prevotella and Trp.”
BackgroundRepairing gut barrier by traditional Chinese medicine: roles of gut microbiota
Zhou, Y., Zhang, D., Cheng, H., Wu, J., Liu, J., Feng, W., & Peng, C. Y. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1389925 · Cited by 66
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“In general, the metabolism of tryptophan by intestinal bacteria is decreased in patients with IBD, leading to disruption of the intestinal microenvironment [ 85 ].”
Gut Microbiota-Derived Metabolites in the Development of Diseases
Shen, G., Wu, J., Ye, B., & Qi, N. (2021) · Canadian Journal of Infectious Diseases and Medical Microbiology · doi:10.1155/2021/6658674 · Cited by 58
“AhR affects T cell differentiation and)17 development and upregulates the IL-22 level to maintain the immune homeostasis in the intestinal tract [51, 55].”
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“Lastly, gut metabolism of the essential amino acid tryptophan has attracted significant attention for its role in mediating intestinal homeostasis and for its dysregulation during intestinal inflammation, with subsequent extra-intestinal consequences [132].”
BackgroundStudies of xenobiotic-induced gut microbiota dysbiosis: from correlation to mechanisms
Chi, L., Tu, P., Ru, H., & Lü, K. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1921912 · Cited by 60
Pu-erh Tea Restored Circadian Rhythm Disruption by Regulating Tryptophan Metabolism
Hu, S., Luo, L., Bian, X., Liu, R. H., Zhao, S., Chen, Y., Sun, K., Jiang, J., Liu, Z., & Zeng, L. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c01883 · Cited by 57
Stem Cell-Based Therapies for Inflammatory Bowel Disease
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“Initially, smoking was an environmental risk factor associated with IBD [14].”
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Metabolomic Insights into Human Arboviral Infections: Dengue, Chikungunya, and Zika Viruses
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“Though 95% of tryptophan is converted to NAD+ via the kynurenine pathway, it can also be converted to serotonin or catabolized to pyruvate and acetyl-CoA to enter the TCA cycle [101,110,111].”
BackgroundEditorial: Aromatic Amino Acid Metabolism
Han, Q., Phillips, R. S., & Li, J. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00022 · Cited by 56
“Among the array of metabolites at the interface between these microorganisms and the host is the essential aromatic amino acid tryptophan (Agus et al., 2018).”
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Anti-obesity natural products and gut microbiota
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Sleep and the gut microbiota in preschool-aged children
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“org 11 mood, anxiety, stress response, and social behaviors (Agus et al., 2018).”
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Interactions Between Antidepressants and Intestinal Microbiota
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“In addition, specific intestinal microbiota can directly transfer Trp to Kyn and its derivatives, as they encode enzymes homologous to those of the eukaryotic kynurenine pathway [112, 113].”
Background
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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