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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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“Indeed, a dysregulation of Trp metabolism has been associated with the occurrence of diverse pathological conditions and the therapeutic efficacy of balancing among the distinct fates of Trp metabolism is increasingly being recognized [4].”
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“This may reflect the expansion of bacteria in TC gut that canmetabolize kynurenine into hydroxyanthranilic acid (Agus et al., 2018).”
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“2,18 We focus our discussion on Trp derivatives that are higher in patients with low Trp relative to healthy individuals since they are more likely to convey information about the fate of Trp under extreme catabolism rather than diet-speci fi c information.”
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“Similarly, another product of tryptophan metabolism, indole-3-acetic acid, is recognized as a defense mechanism againstvariousformsofstress 23,24 .”
Gut Biofactory—Neurocompetent Metabolites within the Gastrointestinal Tract. A Scoping Review
Skonieczna‐Żydecka, K., Jakubczyk, K., Maciejewska, D., Janda, K., Kaźmierczak-Siedlecka, K., Kaczmarczyk, M., Łoniewski, I., & Marlicz, W. M. (2020) · Nutrients · doi:10.3390/nu12113369 · Cited by 52
“Instead, Trp and 5- HT could pass the BBB, as precursors for the production of 5-HT [165].”
BackgroundTryptophan metabolites get the gut moving
Benech, N., Rolhion, N., & Sokol, H. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.01.009 · Cited by 49
Self-citationHeiss, B. E., Ehrlich, A. M., Maldonado-Gómez, M. X., Taft, D. H., Larke, J. A., Goodson, M. L., Slupsky, C. M., Tancredi, D. J., Raybould, H. E., & Mills, D. A. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1986666 · Cited by 51
“produce agonists that activate the aryl hydrocarbon receptor (AhR) pathway shown to be involved in intestinal homeostasis.(30) Specifically, Bifidobacterium produce indole metabolites such as indole-3-lactate which is an agonist for the AhR and interacts with the serotonin reuptake transporter, Slc6a4.”
BackgroundInflammatory bowel disease: A potential pathogenic factor of Alzheimer's disease
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“The diminished level of amino acids mainly reflected a decline in tryptophan with age (Table S7), potentially related to the ability of the gut microbiota to metabolize tryptophan to produce indole and p-cresol (Agus et al., 2018; Figure S3).”
BackgroundA cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases
Losol, P., Wolska, M., Wypych, T. P., Yao, L., O’Mahony, L., & Sokołowska, M. (2024) · Clinical and Translational Allergy · doi:10.1002/clt2.12339 · Cited by 54
The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut
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Tang, X., Huang, Y., Zhu, Y., & Xu, Y. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1610435 · Cited by 56
“Trp, an essential amino acid, is metabolized by gut microbiota into various bioactive compounds—such as indole and its derivatives (e.g., indole propionic acid, indole acetic acid), 5-hydroxytryptamine (5-HT), and kynurenine—following dietary intake (Agus et al., 2018).”
The gut microbiota–brain axis: Role of the gut microbial metabolites of dietary food in obesity
Song, X., Wang, L., Liu, Y., Zhang, X., Weng, P., Liu, L., Zhang, R., & Wu, Z. (2022) · Food Research International · doi:10.1016/j.foodres.2022.110971 · Cited by 57
Pathophysiologic Role of Neurotransmitters in Digestive Diseases
Yang, X., Lou, J., Shan, W., Ding, J., Jin, Z., Hu, Y., Du, Q., Liao, Q., Xie, R., & Xu, J. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.567650 · Cited by 48
Amino Acids in Microbial Metabolism and Function
Dai, Z., Wu, Z., Zhu, W., & Wu, G. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-85686-1_7 · Cited by 50
TrpNet: Understanding Tryptophan Metabolism across Gut Microbiome
Lu, Y. P., Chong, J., Shen, S., Chammas, J.-B., Chalifour, L. E., & Xia, J. (2021) · Metabolites · doi:10.3390/metabo12010010 · Cited by 46
“For instance, serotonin was termed as a host-limited metabolite [26], yet our investigation showed that several species such as Lactococcus lactis, Lactobacillus plantarum, and Klebsiella pneumoniae produced serotonin in a similar way to their mammalian host via aromatic amino-acid decarboxylase (AAAD) [27–29].”
BackgroundShi, Z., Zhang, C., Lei, H., Chen, C., Cao, Z., Song, Y., Chen, G., Wu, F., Zhou, J., Lu, Y., et al. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c06212 · Cited by 51
Total parenteral nutrition impairs glucose metabolism by modifying the gut microbiome
Wang, P., Sun, H., Maitiabula, G., Zhang, L., Yang, J., Zhang, Y., Gao, X., Li, J., Xue, B., Li, C., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00744-8 · Cited by 50
Wei, J., Yang, Z., Li, J., Zhang, Y., Zhang, W., Doherty, M., Yang, T., Yang, Y., Li, H., Wang, Y., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104892 · Cited by 52
“30,36,37 Previous studies have shown that the gut microbiota plays a crucial role in the modulation of tryptophan metabolism by directly transforming the tryptophan into several molecules or indirectly affecting the balance among different tryptophan metabolism pathways.”
Hsu, C., Yu, H., Lin, I.-C., Tiao, M., Huang, L., Hou, C., Chang‐Chien, G., Lin, S., & Tain, Y. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109090 · Cited by 48
Truyens, M., Lobatón, T., Ferrante, M., Bossuyt, P., Vermeire, S., Pouillon, L., Dewint, P., Cremer, A., Peeters, H., Lambrecht, G., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.07.052 · Cited by 48
Communication between the gut microbiota and peripheral nervous system in health and chronic disease
Cook, T. M., & Mansuy‐Aubert, V. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2068365 · Cited by 47
“For instance, dietary fibers like inulin are fermented by our gut bacteria and can provide therapeutic benefits to people who are overweight,119 diabetic,120 or suffering from IBS.121 Probiotics and postbiotics are viable or dead cultures of bacteria, respectively.”
BackgroundInfluentialMicrobial sensing in the intestine
Wan, T., Wang, Y., He, K., & Zhu, S. (2023) · Protein & Cell · doi:10.1093/procel/pwad028 · Cited by 50
Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy
Wang, X., Wen, X., Yuan, S., & Zhang, J. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106499 · Cited by 47
“Research indicates that disturbances in tryptophan metabolism, mediated by gut dysbiosis, can interfere with serotoninergic neurotransmission and contribute to the occurrence of gastrointestinal and neuropsychiatric disorders (Agus et al., 2018; Roth et al., 2021).”
Host–microbe serotonin metabolism
Nunzi, E., Pariano, M., Costantini, C., Garaci, E., Puccetti, P., & Romani, L. R. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.07.014 · Cited by 49
“The importance of tryptophan metabolism in human health L-Tryptophan (Trp) is an essential amino acid whose availability is largely dependent on dietary intake [1].”
BackgroundPi, Y., Fang, M., Li, Y., Cai, L., Han, R., Sun, W., Jiang, X., Chen, L., Du, J., Zhu, Z., et al. (2024) · Nutrients · doi:10.3390/nu16172838 · Cited by 55
“Recent studies have shown that depending on the diversity of the gut microbiota, tryptophan microbial metabolites are closely associated with various metabolic diseases [113,114].”
BackgroundLi, H., Du, Y., Cheng, K., Chen, Y., Wei, L., Pei, Y., Wang, X., Wang, L., Zhang, Y., Hu, X., et al. (2024) · Cell Discovery · doi:10.1038/s41421-024-00709-5 · Cited by 48
“A total of 97 subjects in the discovery cohort and 73 in an independent cohort were recruited after a rigorous diagnostic and exclusion process.”
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“Recently, Trp emerged as the hub of host–microbiota crosstalk considering that Trp metabolism pathways leading to serotonin, kynurenine (Kyn), and indole derivatives are under the direct or indirect control of the microbiota [24].”
BackgroundDehhaghi, M., Panahi, H. K. S., Kavyani, B., Heng, B., Tan, V. X., Braidy, N., & Guillemin, G. J. (2022) · Aging and Disease · doi:10.14336/ad.2021.0824 · Cited by 48
“[113] Agus A, Planchais J, Sokol H (2018).”
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The gut-brain axis in ischemic stroke: its relevance in pathology and as a therapeutic target
Benakis, C., & Liesz, A. (2022) · Neurological Research and Practice · doi:10.1186/s42466-022-00222-8 · Cited by 52
“Tryptophan metabolites Tryptophan is an essential amino acid sourced from the diet that can be metabolized via three different pathways: the kynurenine pathway, mainly by immune cells and epithelial cells, the serotonin pathway by enterochromaffin cells and the indole pathway by the gut microbiota [67].”
BackgroundYang, Y., Wang, N., Xu, L., Liu, Y., Huang, L., Gu, M., Wu, Y., Guo, W., & Sun, H. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05616-3 · Cited by 49
“Notably, tryptophan is an important source of AhR agonists that can be metabolized into AhR ligands mainly via indole and kynurenine pathways, but not the serotonin pathway [22].”
BackgroundXu, J., Yang, Y., Li, X., Ding, S., Zheng, L., Xiong, C., & Yang, Y. (2023) · iMeta · doi:10.1002/imt2.124 · Cited by 47
“The gut microbiota plays a role in the biosynthesis of various bioactive compounds, including bile acids [23], short ‐ chain fatty acids [24], amino acids [25], and trimethylamine/trimethylamine N ‐ oxide (TMAO) [26] (Figure 1).”
BackgroundGuo, J., Li, L., Cai, Y., & Kang, Y. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01611-z · Cited by 46
“Agus et al. [40] found that the reduced of certain intestinal flora inhibited the conversion of tryptophan to indole and its derivatives, and AhR as a receptor of indole and its derivatives, its activation will reduced, thereby inhibiting the intestinal TJP and AhR-Nrf2 pathway, leading to the…”
BackgroundGao, Y., Tan, Y.-J., & Fang, J. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01026-w · Cited by 50
“These metabolites act as ligands of the aryl hydrocarbon receptor (AhR) and have roles in regulating intestinal barrier integrity, immune homeostasis and antitumour immunity 108,109 .”
Therapeutic potential of natural products against atherosclerosis: Targeting on gut microbiota
Zhao, X., Oduro, P. K., Tong, W., Wang, Y., Gao, X., & Wang, Q. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105362 · Cited by 47
Role of gut microbes in acute lung injury/acute respiratory distress syndrome
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Neuro-Signals from Gut Microbiota: Perspectives for Brain Glioma
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“…Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. the microbes or derived from the transformation of environmental or host molecules (Agus et al. 2018).”
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Gut microbiota determines the fate of dietary fiber-targeted interventions in host health
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“120 Parabacteroides treat-ment affects tryptophan metabolism in the mouse hippocampus as evidenced by elevated 5-HT concentration and elevated 5-HT/Trp ratio.”
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Gut microbiota and epigenetic inheritance: implications for the development of IBD
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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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