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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 microbiota–microglia axis in central nervous system disorders
Mossad, O., & Erny, D. (2020) · Brain Pathology · doi:10.1111/bpa.12908 · Cited by 98
“, derivatives of tryptophan) are produced by a few bacteria, such as peptostreptococcus russellii and Lactobacillus spp (99).”
BackgroundDargenio, V. N., Dargenio, C., Castellaneta, S., De Giacomo, A., Laguardia, M., Schettini, F., Francavilla, R., & Cristofori, F. (2023) · Nutrients · doi:10.3390/nu15071620 · Cited by 98
“Therefore, by controlling the amount of tryptophan, the microbiota can influence the brain’s amount of serotonin [86].”
BackgroundAmino Acids in Intestinal Physiology and Health
Beaumont, M., & Blachier, F. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-45328-2_1 · Cited by 101
Dietary and Microbial Determinants in Food Allergy
Victor, E. S., Crestani, E., & Chatila, T. A. (2020) · Immunity · doi:10.1016/j.immuni.2020.07.025 · Cited by 101
“Three major pathways are operative in the gut to degrade tryptophan to either serotonin, kynurenine or indole (Agus et al., 2018).”
BackgroundZou, J., Liu, C., Jiang, S., Qian, D., & Duan, J. (2021) · Infection and Immunity · doi:10.1128/iai.00014-21 · Cited by 101
“direct metabolism of tryptophan, the kynurenine pathway, and the serotonin pathway (171).”
BackgroundLeclercq, S., Schwarz, M., Delzenne, N. M., Stärkel, P., & de Timary, P. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01610-5 · Cited by 102
Gut and Vaginal Microbiomes in PCOS: Implications for Women’s Health
Gu, Y., Zhou, G., Zhou, F., Li, Y. O., Wu, Q., He, H., Zhang, Y., Ma, C., Ding, J., & Hua, K. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.808508 · Cited by 106
“In addition, hyperinsulinemia derived by insulin resistance could increase the level of testosterone by reducing sex hormone binding globulin (55).”
BackgroundSolomou, S., Logue, J., Reilly, S., & Algorta, G. P. (2022) · Health Education Research · doi:10.1093/her/cyac035 · Cited by 123
“Other candidate biological mechanisms include oxidative stress [105], maintenance of beneficial gut microbes [106], adult hippocampal neurogenesis [107], modulation of the tryptophan-kynurenine metabolism [108], maintenance of mitochondrial biogenesis [109] and regulation of epigenetic processes [110, 111].”
BackgroundXie, L., Cai, S., Lu, H.-Y., Tang, F., Zhu, R., Tian, Y., & Li, M. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2347722 · Cited by 112
“15,16 Trp metabolism in the gut primarily occurs through three major pathways: the indole pathway mediated by the gut microbiota, and the kynurenine and serotonin pathways mediated by the host.”
BackgroundOverview of the Potential Role of Malassezia in Gut Health and Disease
Spatz, M., & Richard, M. L. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00201 · Cited by 99
“In the IBD context, mycobiota in the feces and associated with the mucosa have been studied in various cohort patients, showing a clear modification of the fungal community during intestinal inflammation.”
BackgroundInfluentialOlvera-Rosales, L. B., Cruz-Guerrero, A. E., Ramírez‐Moreno, E., Lira, A. Q., Contreras‐López, E., Ordaz, J. J., Ovando, A. C., Añorve‐Morga, J., Calderón‐Ramos, Z. G., Arias‐Rico, J., et al. (2021) · Foods · doi:10.3390/foods10061261 · Cited by 108
Role of prebiotics in enhancing the function of next-generation probiotics in gut microbiota
Fei, Y., Chen, Z., Han, S., Zhang, S., Zhang, T., Lu, Y., Berglund, B., Xiao, H., Li, L., & Yao, M. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1958744 · Cited by 105
“…benefits related to prebiotics include 1) gut microbiota modulation along with beneficial microbial metabolites release as SCFAs and tryptophan (Agus, Planchais, and Sokol 2018); 2) directly contributing to the growth and fermentation of probiotics (Blaser 2016; Pranckut_e et al. 2016); 3)…”
BackgroundKynurenine Pathway in Diabetes Mellitus—Novel Pharmacological Target?
Kozieł, K., & Urbańska, E. M. (2023) · Cells · doi:10.3390/cells12030460 · Cited by 104
Li, S., Cai, Y., Guan, T., Zhang, Y., Huang, K., Zhang, Z., Cao, W., & Guan, X. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2374608 · Cited by 105
“43 In this study, we found that most of the differential metabolites of tryptophan metabolism belonged to the indole pathway and the kynurenine pathway (Figure 4e).”
BackgroundRole of Probiotics in Non-alcoholic Fatty Liver Disease: Does Gut Microbiota Matter?
Xie, C., & Halegoua-DeMarzio, D. L. (2019) · Nutrients · doi:10.3390/nu11112837 · Cited by 99
“These compounds maintain intestinal integrity, reduce bacterial translocation, prevent the release of microbiota-derived components, and limit inflammatory cascades [59,60].”
BackgroundWong, C. B., Tanaka, A., Kuhara, T., & Xiao, J. (2020) · Microorganisms · doi:10.3390/microorganisms8030398 · Cited by 96
“Studies have shown that indole derivatives produced by gut commensal bacteria from dietary tryptophan could act as vital signaling molecules in intestinal homeostasis, and may be involved in gut–brain communication [2,8,9].”
BackgroundLiu, D., Zhang, S., Li, S., Zhang, Q., Cai, Y., Li, P., Li, H., Shen, B., Liao, Q., Hong, Y., et al. (2023) · BMC Biology · doi:10.1186/s12915-023-01578-2 · Cited by 97
“distasonis activated the AhR signaling pathway in vivo According to the literature report [20], indoleacrylic acid is an endogenous AhR ligand.”
BackgroundTargeted modification of gut microbiota and related metabolites via dietary fiber
Nie, Q., Sun, Y., Li, M., Zuo, S., Chen, C., Lin, Q., & Nie, S. (2023) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2023.120986 · Cited by 99
Modulation of immunity by tryptophan microbial metabolites
Li, S. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1209613 · Cited by 104
“Metabolites can affect immune cells and intestinal barrier integrity by activating human receptors such as PXR or AhR, both highlighted in subsequent sections (9, 65).”
BackgroundMethodInfluentialShi, J., Du, P., Xie, Q., Wang, N., Li, H., Smith, E. E., Li, C., Liu, F., Huo, G., & Li, B. (2020) · Food & Function · doi:10.1039/d0fo02622k · Cited by 94
Engineered Living Materials for Advanced Diseases Therapy
Xue, D. Q., Wu, W. H., Pan, P., & Zhang, X. (2023) · Advanced Materials · doi:10.1002/adma.202304963 · Cited by 95
Wang, D., Li, D., Zhang, Y., Chen, J., Zhang, Y., Liao, C., Qin, S., Tian, Y., Zhang, Z., & Xu, F. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.07.017 · Cited by 94
Ghiboub, M., Verburgt, C. M., Sovran, B., Benninga, M. A., de Jonge, W. J., & Limbergen, J. V. (2020) · Nutrients · doi:10.3390/nu12092846 · Cited by 97
“For instance, (a) short-chain fatty acids (SCFAs), bacterial fermentation end products of dietary fibers, (b) bile acids, produced and recycled in the liver and (c) Tryptophan (Trp)-derivatives, are the most studied categories of metabolites implicated in host-microbiota cross talk [4,7].”
BackgroundInfluentialGut and obesity/metabolic disease: Focus on microbiota metabolites
Lin, K., Zhu, L., & Li, Y. (2022) · MedComm · doi:10.1002/mco2.171 · Cited by 99
Targeting the gut microbiota to influence brain development and function in early life
Wang, S., Harvey, L., Martı́n, R., van der Beek, E. M., Knol, J., Cryan, J. F., & Renes, I. B. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.09.002 · Cited by 97
Li, S., Hua, D., Wang, Q., Yang, L., Wang, X., Luo, A., & Yang, C. (2019) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyz061 · Cited by 94
“Three major pathways for tryptophan metabolism in the gastrointestinal tract exist: (1) several molecules metabolized from microbiota, including ligands for the aryl hydrocarbon receptor (AhR); (2) the kynurenine (Kyn) pathway via indoleamine 2,3-dioxygenase (IDO); and (3) 5-hydroxytryptamine (5-HT) synthesis via IDO…”
BackgroundLodovico, L. D., Mondot, S., Dore, J. M., Mack, I., Hanachi, M., & Gorwood, P. A. P. M. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110114 · Cited by 99
Hauser, J., Pisa, E., Vásquez, A. A., Tomasi, F., Traversa, A., Chiodi, V., Martin, F., Sprenger, N., Lukjančenko, O., Zollinger, A., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01054-9 · Cited by 101
Busnelli, M., Manzini, S., & Chiesa, G. (2019) · Nutrients · doi:10.3390/nu12010079 · Cited by 92
“Even though some bacterial species—such as Escherichia coli—are known to synthesize tryptophan, there is no evidence that the bacterial community makes a significant contribution toward its production in humans [58].”
BackgroundHeinken, A., Hertel, J., & Thiele, I. (2021) · npj Systems Biology and Applications · doi:10.1038/s41540-021-00178-6 · Cited by 93
Meynier, M., Baudu, E., Rolhion, N., Defaye, M., Straube, M., Daugey, V., Modoux, M., Wawrzyniak, I., Delbac, F., Villéger, R., et al. (2022) · Gut Microbes · doi:10.1080/19490976.2021.2022997 · Cited by 90
“Trp metabolism follows three pathways: the serotonin pathway in enterochromaffin cells, the kynurenine pathway in epithelial and immune cells, and the indole pathway in the gut microbiota.(10) A wide range of bacterial species are able to produce indole including Lactobacillus, Clostridium, and Bacteroides spp.”
BackgroundSelf-citationHong, Y., Li, B., Zheng, N., Wu, G., Ma, J., Tao, X., Chen, L., Zhong, J., Sheng, L., & Li, H. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00833 · Cited by 89
Role of gut microbiota-derived signals in the regulation of gastrointestinal motility
Zheng, Z., Tang, J., Hu, Y., & Zhang, W. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.961703 · Cited by 94
The Gut–Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production
Ju, S., Shin, Y., Han, S., Kwon, J., Choi, T. G., Kang, I., & Kim, S. S. (2023) · Nutrients · doi:10.3390/nu15204391 · Cited by 97
“Of these precursors, tryptophan is predominantly absorbed by the intestine and metabolized by the gut microbiota through three downstream pathways: the 5-hydroxytryptamine pathway, the kynurenine pathway, and the indole pathway [187].”
BackgroundThe microbiota-gut-brain axis: Focus on the fundamental communication pathways
Bistoletti, M., Bosi, A., Banfi, D., Giaroni, C., & Baj, A. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.08.012 · Cited by 91
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Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases
Bruneau, A., Hundertmark, J., Guillot, A., & Tacke, F. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.725390 · Cited by 93
“Discovery of a perturbed tryptophan metabolism in patients suffering from IBD or colitis suggests common mechanisms for patients suffering of liver diseases associated with intestinal dysbiosis (88).”
BackgroundFournier, E., Ratel, J., Denis, S., Leveque, M., Ruiz, P., Mazal, C., Amiard, F., Edely, M., Bézirard, V., Gaultier, E., et al. (2022) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2022.130383 · Cited by 100
Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation
Chen, Y., Wang, Y., Fu, Y., Yin, Y., & Xu, K. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01046-y · Cited by 92
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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