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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 the citing paper
“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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“87 IDO is the rate-limiting enzyme in the degradation of tryptophan to Kyn.”
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Schjødt, M. S., Gürdeniz, G., & Chawes, B. (2020) · Metabolites · doi:10.3390/metabo10120511 · Cited by 44
“Although the role of tryptophan metabolism in asthma pathogenesis is still not fully understood, intermediates of tryptophan metabolism, produced via the kynurenine pathway and microbial catabolism, are important mediators of immune responses [47].”
BackgroundSchaafsma, A., Mallee, L., van den Belt, M., Floris, E., Kortman, G. A. M., Veldman, J., van den Ende, D., & Kardinaal, A. F. M. (2021) · Nutrients · doi:10.3390/nu13072204 · Cited by 43
“, GABA) are produced or intestinal production of serotonin and melatonin is stimulated in a sufficient way [10,11,20,53].”
BackgroundSelective Isotope Labeling and LC-Photo-CIDNP Enable NMR Spectroscopy at Low-Nanomolar Concentration
Yang, H., Li, S., Mickles, C. A., Guzmán‐Luna, V., Sugisaki, K., Thompson, C. M., Dang, H. H., & Cavagnero, S. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c01809 · Cited by 40
Role of the Gut Microbiome in Skeletal Muscle Physiology and Pathophysiology
Lefevre, C., & Bindels, L. B. (2022) · Current Osteoporosis Reports · doi:10.1007/s11914-022-00752-9 · Cited by 41
Zhang, S., Jin, M., Ren, J., Sun, X., Zhang, Z., Luo, Y., & Sun, X. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114559 · Cited by 40
Wang, T., Song, Y., Ai, Z., Liu, Y., Li, H., Xu, W., Chen, L., Zhu, G., Yang, M., & Su, D. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154852 · Cited by 41
Wang, H., He, Y., Dang, D., Zhao, Y., Zhao, J., & Lu, W. (2024) · Foods · doi:10.3390/foods13091336 · Cited by 41
Coretti, L., Buommino, E., & Lembo, F. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1433747 · Cited by 42
Influence of the gut microbiota on immune cell interactions and cancer treatment
Liu, C., Fu, L., Wang, Y., & Yang, W. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05709-3 · Cited by 47
“Gut microbiota dysbiosis can impact energy metabolism, immune homeostasis, gut defence mechanisms, organic compounds, vitamin production, and abnormal hormone regulation [109, 110].”
BackgroundSalt-Responsive Gut Microbiota Induces Sex-Specific Blood Pressure Changes
Bardhan, P., Mei, X., Lai, N. T., Mell, B., Tummala, R., Aryal, S., Manandhar, I., Hwang, H., Jhuma, T. A., Atluri, R., et al. (2024) · Circulation Research · doi:10.1161/circresaha.124.325056 · Cited by 39
“8 Holle et al 9 reported increased gut microbiota–derived tryptophan metabolites in patients with chronic kidney disease and inflammatory bowel disease, both of which are independent risk factors for hypertension.”
Cui, J., Xiao, S., Cao, Y., Zhang, Y., Yang, J., Zheng, L., Zhao, F., Liu, X., Liu, D., Zhou, Z., et al. (2024) · Environmental Science & Technology · doi:10.1021/acs.est.4c07427 · Cited by 43
Gut Microbiota Modulation through Akkermansia spp . Supplementation Increases CAR T-cell Potency
Marcos-Kovandzic, L., Avagliano, M., Khelil, M. B., Srikanthan, J., Abdallah, R., Petrocelli, V., Rengassamy, J., Alfaro, A., Bied, M., Fidelle, M., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1230 · Cited by 42
“In summary, AhR engagement on CAR T cells is required for their phenotypic shift and improved tumor control upon Akkermansia spp. administration, but a compendium of in-doles or other AhR-engaging metabolites in addition to IPA are likely required to potentiate the effect of CAR T cells.”
InfluentialSelf-citationZhang, Y., Wang, N., Zhang, L., Zhuang, Y., Xin, Q., Gu, X., Jiang, C., & Wu, J. (2025) · MedComm · doi:10.1002/mco2.70383 · Cited by 46
Harnessing the microbiota for therapeutic purposes
Liwinski, T., & Elinav, E. (2019) · American Journal of Transplantation · doi:10.1111/ajt.15753 · Cited by 39
Onyszkiewicz, M., Jaworska, K., & Ufnal, M. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370219900898 · Cited by 39
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Targeting the gut microbial metabolic pathway with small molecules decreases uremic toxin production
Wang, Y., Li, J., Chen, C., Lu, J., Yu, J., Xu, X., Peng, Y., Zhang, S., Jiang, S., Guo, J., et al. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1823800 · Cited by 41
“Following nutrient ingestion, indole can be formed from dietary tryptophan by intestinal bacteria tryptophanases (TnaA).(21) Following absorption into the portal vein, indole is metabolized to indoxyl and then sulfated to IS in the host liver.”
BackgroundInfluentialAspergillus fumigatus tryptophan metabolic route differently affects host immunity
Zelante, T., Choera, T., Beauvais, A., Fallarino, F., Paolicelli, G., Pieraccini, G., Pieroni, M., Galosi, C., Beato, C., LUCA, A. D., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108673 · Cited by 39
“Because we found that the DidoA/B/C mutant can release indole derivatives via the indolepyruvate route (Figure 2E), and knowing also that indoles coming from the microbiota are effective AhR ligands (Agus et al., 2018), we also measured the main AhR downstream target gene Cyp1a1 at 7 dpi (Figure 4E).”
BackgroundGut Microbial Dysbiosis and Cognitive Impairment in Bipolar Disorder: Current Evidence
Dai, W., Liu, J., Yan, Q., Teng, Z., Li, S., Yuan, H., Huang, J., Xiang, H., Tang, H., Wang, B., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.893567 · Cited by 42
Mills, D. A., German, J. B., Lebrilla, C. B., & Underwood, M. A. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2192458 · Cited by 39
Hong, D., Zhang, C., Wu, W., Lu, X., & Zhang, L. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1133546 · Cited by 38
Pan, S., Guo, Y., Hong, F., Xu, P., & Zhai, Y. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166281 · Cited by 37
Interplay between Phytochemicals and the Colonic Microbiota
Kwon, C., Ediriweera, M. K., & Cho, S. K. (2023) · Nutrients · doi:10.3390/nu15081989 · Cited by 46
Liu, W., Wang, L., Yuan, Q., Hao, W., Wang, Y., Wu, D., Chen, X., & Wang, S. (2023) · Food & Function · doi:10.1039/d3fo04430k · Cited by 38
Yu, J., Ren, J. F., Ren, Y., Wu, Y., Zeng, Y., Zhang, Q., & Xiao, X. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105008 · Cited by 44
“46,47 Trp metabolism can affect the function of islet β -cells, IR, intestinal barrier and angiogenesis in diabetes mellitus.”
BackgroundPlasma and milk metabolomics profiles in dairy cows with subclinical and clinical ketosis
Huang, Y., Zhang, B., Mauck, J., Loor, J. J., Wei, B., Shen, B., Wang, Y., Zhao, C., Zhu, X., & Wang, J. (2024) · Journal of Dairy Science · doi:10.3168/jds.2023-24496 · Cited by 43
“There are 3 main routes of tryptophan catabolism, i.e., (i) indole/AhR (aryl hydrocarbon receptor), (ii) kynurenine (Kyn), and (iii) serotonin (5-hydroxytryptamine [5-HT]) pathways (Agus et al., 2018).”
BackgroundLi, L., Xu, Z., Ni, H., Meng, Y., Xu, Y., Xu, H., Zheng, Y., Zhang, Y., Xue, G., & Shang, Y. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.08.009 · Cited by 39
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Zuo, X., Zhang, T., Dong, X., Liu, J., & Liu, Y. (2025) · Food Research International · doi:10.1016/j.foodres.2025.115766 · Cited by 39
Microbial modulation of tryptophan metabolism links gut microbiota to disease and its treatment
Zhao, P., Chen, Y., Zhou, S., & Li, F. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107896 · Cited by 40
Gut Microbiota-Derived Metabolites in Atherosclerosis: Pathways, Biomarkers, and Targets
Tonch-Cerbu, A.-K., Boicean, A., Stoia, O., & Teodoru, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178488 · Cited by 46
“Without longitudinal and functional studies, cross-sectional measurements risk misinterpretation [124].”
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“Indole, which was also one of the OFM metabolites, has been found in higher concentration in fecal samples in children with ASD and other neurodevelopmental conditions [17], consistent with the results of this study, and is an important metabolite for tryptophan metabolism [42].”
ResultCord blood metabolic signatures predictive of childhood overweight and rapid growth
Handakas, E., Keski‐Rahkonen, P., Chatzi, L., Alfano, R., Roumeliotaki, T., Plusquin, M., Maître, L., Richiardi, L., Brescianini, S., Scalbert, A., et al. (2021) · International Journal of Obesity · doi:10.1038/s41366-021-00888-1 · Cited by 38
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Luo, X., Zhang, B., Pan, Y., Gu, J., Tan, R., & Gong, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.893561 · Cited by 40
“Over 90% of peripheral 5-HT is produced in the gut (Agus et al., 2018).”
BackgroundLiu, L., Tian, F., Li, G.-Y., Xu, W., & Xia, R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.1012087 · Cited by 40
Diet-microbiome interactions in cancer
Abdeen, S. K., Mastandrea, I., Stinchcombe, N., Puschhof, J., & Elinav, E. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.03.013 · Cited by 36
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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