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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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“The KYN arm of TRP metabolism has important physiologic functions both in the periphery and in the CNS, via downstream by-products such as kynurenic acid (KynA) and quinolinic acid (QA) and, as more recently demonstrated, picolinic acid (PA) [266,267,282].”
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“Trp metabolism follows three major pathways in the gastrointestinal tract, of which the serotonin [5-hydroxytryptamine (5-HT)] production pathway is a crucial one (Agus et al., 2018).”
BackgroundInfluentialTian, T., Mao, Q., Xie, J., Wang, Y., Shao, W., Zhong, Q., & Chen, J. (2021) · Journal of Advanced Research · doi:10.1016/j.jare.2021.10.002 · Cited by 151
“About 90% of 5-HT is produced in the gut, and the metabolic pathway leading to 5-HT from Tryptophan is under the control of gut microbiota [52].”
BackgroundKim, C.-S., Jung, S., Hwang, G., & Shin, D. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.04.001 · Cited by 152
A potential role for the gut microbiome in substance use disorders
Meckel, K. R., & Kiraly, D. D. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05232-0 · Cited by 146
“Tryptophan is an essential amino acid that is primarily derived from dietary protein (O’Mahony et al. 2015; Agus et al. 2018; Roager and Licht 2018).”
InfluentialModoux, M., Rolhion, N., Lefèvre, J. H., Oeuvray, C., Nádvorník, P., Illéš, P., Emond, P., Parc, Y. R., Mani, S., Dvořák, Z., et al. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2105637 · Cited by 147
Self-citationPotential Causes and Consequences of Gastrointestinal Disorders during a SARS-CoV-2 Infection
Trottein, F., & Sokol, H. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107915 · Cited by 141
“thus reduces the production of nicotinamide and (potentially) other tryptophan-derived metabolites with a critical role in intestinal homeostasis (Hashimoto et al., 2012; Agus et al., 2018).”
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The Immunopathogenesis of Alzheimer’s Disease Is Related to the Composition of Gut Microbiota
Leblhuber, F., Ehrlich, D., Steiner, K., Geisler, S., Fuchs, D., Lanser, L., & Kurz, K. (2021) · Nutrients · doi:10.3390/nu13020361 · Cited by 149
Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite
Renga, G., Nunzi, E., Pariano, M., Puccetti, M., Bellet, M. M., Pieraccini, G., D’Onofrio, F., Santarelli, I., Stincardini, C., Aversa, F., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003725 · Cited by 147
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“Tryptophan can also be metabolized by the gut microbiota into indole and its derivatives (34).”
BackgroundDelzenne, N. M., Knudsen, C., Beaumont, M., Rodriguez, J., Neyrinck, A. M., & Bindels, L. B. (2019) · Proceedings of The Nutrition Society · doi:10.1017/s0029665118002756 · Cited by 146
The Gut and Parkinson's Disease—A Bidirectional Pathway
Santos, S. F., de Oliveira, H. L., Yamada, E. S., Neves, B. C., & Pereira, A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00574 · Cited by 148
“In the gut, there are three major metabolic pathways leading from the essential amino acid tryptophan (Trp) to 5-HT, kynurenine (Kyn), and indole derivatives, which are under the direct or indirect control of the microbiota (105).”
BackgroundThe Role of Diet and Gut Microbiota in Regulating Gastrointestinal and Inflammatory Disease
Gill, P. A., Inniss, S., Kumagai, T., Rahman, F. Z., & Smith, A. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.866059 · Cited by 164
Molecules Produced by Probiotics and Intestinal Microorganisms with Immunomodulatory Activity
Delgado, S., Sánchez, B., Margollés, A., Ruas‐Madiedo, P., & Ruíz, L. (2020) · Nutrients · doi:10.3390/nu12020391 · Cited by 139
“Also, it has been suggested that some amino acid derivatives, such as indole, display lower fecal concentration levels in patients suffering from ulcerative colitis [4].”
BackgroundMicrobiota-derived tryptophan metabolites in vascular inflammation and cardiovascular disease
Paeslack, N., Mimmler, M., Becker, S., Gao, Z., Khuu, M. P., Mann, A., Malinarich, F., Regen, T., & Reinhardt, C. (2022) · Amino Acids · doi:10.1007/s00726-022-03161-5 · Cited by 150
Araújo-Rodrigues, H., Sousa, A. S., Relvas, J. B., Tavaria, F. K., & Pintado, M. (2024) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2024.121978 · Cited by 147
Zhou, Y., Chen, Y., He, H., Peng, M., Zeng, M., & Sun, H. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109690 · Cited by 147
Tryptophan‐derived serotonin‐kynurenine balance in immune activation and intestinal inflammation
Haq, S., Grondin, J. A., & Khan, W. I. (2021) · The FASEB Journal · doi:10.1096/fj.202100702r · Cited by 144
Hidradenitis Suppurativa: Where We Are and Where We Are Going
Scala, E., Cacciapuoti, S., Garzorz-Stark, N., Megna, M., Marasca, C., Seiringer, P., Volz, T., Eyerich, K., & Fabbrocini, G. (2021) · Cells · doi:10.3390/cells10082094 · Cited by 135
“In addition, a dysregulation of tryptophan catabolism (with overactivation of the kynurenine pathway and consequent stimulation of cytokines by inflammatory cell infiltrates) and of an aryl hydrocarbon receptor (AHR) (with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-produ…”
BackgroundLi, K., Hao, Z., Du, J., Gao, Y., Yang, S., & Zhou, Y. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107183 · Cited by 134
Ortega, M. A., Álvarez-Mon, M. Á., Montero, C. G., Fraile‐Μartinez, O., Monserrat, J., Martinez-Rozas, L., Rodríguez–Jiménez, R., Álvarez‐Mon, M., & Lahera, G. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-01964-w · Cited by 137
“Although tryptophan can cross the BBB, serotonin produced in the gut cannot [211].”
BackgroundTryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders
Li, D., Yu, S., Long, Y., Shi, A., Deng, J., Ma, Y., Wen, J., Li, X., Liu, S., Zhang, Y., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.985378 · Cited by 129
“Including tryptamine, indoleacetic-3-acid (IAA), indolepropionic-3-acid (IPA), indolelactic acid (ILA), indole3-aldehyde (IAld), indoleacrylic acid (IA), indole-3acetaldehyde (IAAld), etc (35).”
Gut Microbiome Alterations in COVID-19
Zuo, T., Wu, X., Wen, W., & Lan, P. (2021) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2021.09.004 · Cited by 134
“Incidentally, the amount of tryptamine, a tryptophan metabolite of microbiota known to accelerate bowel transit [64,65], was also increased in the feces of SARS-CoV-2-infected macaques [28].”
Kynurenine emerges from the shadows – Current knowledge on its fate and function
Marszałek‐Grabska, M., Walczak, K., Gaweł, K., Wicha-Komsta, K., Wnorowska, S., Wnorowski, A., & Turski, W. A. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107845 · Cited by 128
The Gut-Microglia Connection: Implications for Central Nervous System Diseases
Wang, Y., Wang, Z., Wang, Y., Li, F., Jia, J., Song, X., Qin, S., Wang, R., Jin, F., Kitazato, K., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02325 · Cited by 130
“However, AhR ligands are solely produced by a few bacteria, such as Peptostreptococcus russellii and Lactobacillus spp (126).”
BackgroundLeung, M. H. Y., Tong, X., Bastien, P., Guinot, F., Tenenhaus, A., Appenzeller, B. M. R., Betts, R. J., Mezzache, S., Li, J., Bourokba, N., et al. (2020) · Microbiome · doi:10.1186/s40168-020-00874-1 · Cited by 127
Gut microbiota‐stem cell niche crosstalk: A new territory for maintaining intestinal homeostasis
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“Indoles and indole derivatives, such as indole ‐ 3 ‐ aldehyde, indole ‐ 3 ‐ acid ‐ acetic, indole ‐ 3 ‐ propionic acid, indole ‐ 3 ‐ acetaldehyde, and indoleacrylic acid are important signaling molecules [116].”
BackgroundImpaired Autonomic Nervous System-Microbiome Circuit in Hypertension
Zubcevic, J. A., Richards, E. M., Yang, T., Kim, S., Sumners, C., Pepine, C. J., & Raizada, M. K. (2019) · Circulation Research · doi:10.1161/circresaha.119.313965 · Cited by 126
“Increased kynurenine has been suggested to predict a decrease in serotonin synthesis in the hypertensive gut because of a shift towards synthesis of kynurenine from tryptophan, at the expense of serotonin.(147) Serotonin synthesis may be further compromised in hypertension because tryptophanase A, the gene for the bac…”
BackgroundLi, X., Zhang, Z., Zabed, H. M., Yun, J., Zhang, G., & Qi, X. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000461 · Cited by 129
Role of the Intestinal Epithelium and Its Interaction With the Microbiota in Food Allergy
Ali, A., HuiYing, T., & Kaiko, G. E. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.604054 · Cited by 131
Altomare, A., Rosa, C. D., Imperia, E., Emerenziani, S., Cicala, M., & Guarino, M. P. L. (2021) · Nutrients · doi:10.3390/nu13051506 · Cited by 140
“There might be connections with physiopathology of IBS-D and impaired Trp metabolism [81] as 5-HT colon contents are increased in IBS-D [82].”
BackgroundGut‐liver axis‐mediated mechanism of liver cancer: A special focus on the role of gut microbiota
Ohtani, N., & Hara, E. (2021) · Cancer Science · doi:10.1111/cas.15142 · Cited by 128
Ortega, M. A., Álvarez-Mon, M. Á., Montero, C. G., Fraile‐Μartinez, O., Guijarro, L. G., Lahera, G., Monserrat, J., Valls, P., Mora, F., Rodríguez–Jiménez, R., et al. (2022) · Metabolites · doi:10.3390/metabo12010050 · Cited by 131
“Conversely, the gut microbiota is critical for Trp metabolism, determining the benefits or harms [109].”
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“Serotonin is a bioamine converted from tryptophan, and the conversion is mainly proceeded by the enterochromaffin cells of gut [11].”
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“Considering that IA and IPA are downstream metabolites of ILA, these changes in microbial ecosystem structure may be a response to the elevated ILA levels.”
InfluentialZhou, Y., Wang, Y., Quan, M., Zhao, H., & Jia, J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201497 · Cited by 125
“…may be related to the production of these NPS. Gut microbiota can produce various metabolites and neuroactivesubstancessuchasGABA,5-HT,andcat-echolamines, influencing brain function and behavior and may be involved in neuropsychiatric disorders, including anxiety, depression, autism, etc. [68–71].”
Sexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome
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Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses
Merlo, L. M. F., DuHadaway, J. B., Montgomery, J. D., Peng, W., Murray, P. J., Prendergast, G. C., Caton, A. J., Muller, A. J., & Mandik‐Nayak, L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01861 · Cited by 124
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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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