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Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor
Open accessAbstract
Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.
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“Indole-3-propionate has been shown to affect host intestinal inflammation and to be reduced in patients with active colitis (Alexeev et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Alexeev et al., 2018
In the citing paper
“healthy ageing correlates with an increased presence of certain indoles, which are gut bacterial degradation products of tryptophan that mediate immune homeostasis upon binding to aryl hydrocarbon receptors and IL-10 receptors15–17”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [17]
In the citing paper
“indolepropionic acid, a microbial metabolite of tryptophan, maintains intestinal homeostasis and protects from experimental colitis (43).”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [43]
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“Indole-3-propionic acid, an indole derivative, has been found to protect neurons by attenuating (Hwang et al. 2009; Alexeev et al. 2018; Li et al. 2021).”
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“The AhR can be activated by many indole derivatives, such as indole-3-aldehyde, indole-3-acid-acetic acid, indole-3-propionic acid, ILA, and IAAD[46,47], which are partly responsible for the induction of tumor cell apoptosis[48].”
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“IPApromotesintestinalhomeostasisthroughanAHR-mediated regulationoftheintestinalepithelialcellIL-10R1 110 .”
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“59 Alternatively, increased secretion potential was predicted for trimethylamine N-oxide, serine, nicotinate, D-ribose, lactate, putrescine, and some bile acid metabolites (Supplementary Table S5 and Figure 1a-g).”
BackgroundSathyasaikumar, K. V., Ayala, T. B., Zheng, Y., Schwieler, L., Erhardt, S., Tufvesson‐Alm, M., Pöeggeler, B., & Schwarcz, R. M. (2024) · International Journal of Tryptophan Research · doi:10.1177/11786469241262876 · Cited by 18
“…IPrA facilitates regeneration and functional recovery of sensory axons through an immune-mediated mechanism, 69,70 promotes intestinal homeostasis, 71,72 boosts muscle tissue development and reduces muscle cell inflammation, 73 modulates mitochondrial function in cardiomyocytes, 74 mediates…”
BackgroundMa, C., Zheng, X., Zhang, Q., Renaud, S. J., Yu, H., Xu, Y., Chen, Y., Gong, J., Cai, Y., Hong, Y., et al. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.138931 · Cited by 18
Nieves, K., Flannigan, K. L., Hughes, E., Stephens, M., Thorne, A. J., Delanne-Cuménal, A., Strayer, K., Kola-Ilesanmi, D., Wickramasinghe, S., Mirzadzare, N., et al. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00256.2024 · Cited by 18
Microbial threads in the tapestry of rheumatoid arthritis
Li, J., & Kuhn, K. A. (2025) · Journal of Clinical Investigation · doi:10.1172/jci195374 · Cited by 21
“Metabolites such as short-chain fatty acids (SCFAs) (105), tryptophan catabolites (106, 107), and bile acids (108, 109) have been associated with RA.”
A Tryptophan Metabolite of the Microbiota Improves Neovascularization in Diabetic Limb Ischemia
Ma, X., Yang, J., Yang, G., Li, L., Hao, X., Wang, G., An, J., & Wang, F. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.910323 · Cited by 17
“The potential benefits provided by indole derivatives have been highlighted in animal models of colitis and experimental autoimmune encephalomyelitis (35, 36).”
BackgroundDvořák, Z., Li, H., & Mani, S. (2022) · Drug Metabolism and Disposition · doi:10.1124/dmd.122.000860 · Cited by 16
Zheng, L. (2022) · World Journal of Clinical Cases · doi:10.12998/wjcc.v10.i30.10823 · Cited by 17
Habibi, S., & Rashidi, A. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2229567 · Cited by 17
Lamichhane, S., Sen, P., Dickens, A. M., Kråkström, M., Ilonen, J., Lempainen, J., Hyöty, H., Lahesmaa, R., Veijola, R., Toppari, J., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1211015 · Cited by 17
Ma, W., Fu, Y., Zhu, S., Xia, D., Zhai, S., Xiao, D., Zhu, Y., Dione, M., Ben, L., Yang, L., et al. (2023) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/s40104-023-00912-6 · Cited by 17
“In addition, indole and its derivatives produced by the metabolism of tryptophan by intestinal microorganisms directly or indirectly activate host aromatic hydrocarbon receptors, upregulate the expression of interleukin-10 receptors, and alleviate intestinal inflammation [16].”
BackgroundThe Gut-Brain Axis in Alzheimer’s Disease: Exploring Microbial Influences and Therapeutic Strategies
Mustafa, M. A., Vadia, N., Varma, P., Al‐Shaker, H., Mohanty, B., Dhyani, A., Kaur, I., Chauhan, A. S., & Garg, G. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05474-4 · Cited by 18
“Tryptophan metabolism, in particular, generates metabolites via the kynurenine pathway, which regulates key functions such as neural transmission, immune responses, and inflammation [54, 55].”
Wu, F., Shi, Z., Lei, H., Chen, G., Yuan, P., Cao, Z., Chen, C., Zhu, X., Liu, C., Dong, M., et al. (2020) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c05921 · Cited by 16
Ismael, S., Rodrigues, C., Santos, G. M., Castela, I., Barreiros-Mota, I., Almeida, M. J., Calhau, C., Faria, A., & Araújo, J. R. (2023) · Nutrition Research and Practice · doi:10.4162/nrp.2023.17.4.616 · Cited by 17
“The results showed that the concentrations of IPA typically found in the intestinal lumen (1–500 μM) [7,14], did not induce Caco-2 cells cytotoxicity after treatment periods of 2, 24, and 72 h (Fig.”
BackgroundMethodInfluentialDiether, N. E., Hulshof, T. G., Willing, B. P., & Kempen, T. A. T. G. V. (2023) · PLoS ONE · doi:10.1371/journal.pone.0289214 · Cited by 16
Postbiotics in oncology: science or science fiction?
Kudra, A., Kaźmierczak-Siedlecka, K., Sobocki, B. K., Muszyński, D., Połom, J., Carbone, L., Marano, L., Roviello, F., Kalinowski, L., & Stachowska, E. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1182547 · Cited by 16
“It was also proven that indolic compounds may promote pro-inflammatory and antiinflammatory effects since they can act as AhR ligands (Alexeev et al., 2018).”
BackgroundWalter, K., Großkopf, H., Karkossa, I., von Bergen�, M., & Schubert, K. A. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph181910336 · Cited by 18
“Furthermore, indole metabolites up‐regulate the interleukin‐10 receptor expression on intestinal epithelial cells, reducing inflammatory processes and fostering intestinal homeostasis in mice and humans [18].”
BackgroundMaternal elevated salt consumption and the development of autism spectrum disorder in the offspring
Afroz, K. F., & Alviña, K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1666-2 · Cited by 16
Pomegranate Extract Improves Colitis in IL‐10 Knockout Mice Fed a High Fat High Sucrose Diet
Yang, J., Germano, P. M., Oh, S., Wang, S., Wang, J., Lee, R., Paige, H., Yang, S., Henning, S. M., Zhong, J., et al. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100730 · Cited by 16
Chen, Y., Wang, Z., Chen, X., Chao, G., & Zhang, S. (2023) · Journal of Applied Microbiology · doi:10.1093/jambio/lxad032 · Cited by 16
Calzadilla, N., Qazi, A., Sharma, A., Mongan, K., Comiskey, S., Manne, J., Youkhana, A. G., Khanna, S., Saksena, S., Dudeja, P. K., et al. (2023) · Metabolites · doi:10.3390/metabo13070873 · Cited by 15
“For example, decreases in indole metabolites such as indoleacetate, indolepropionate (IPA), and indole-3-carboxylate have been shown in the serum of subjects with ulcerative colitis with IPA serving as a marker for disease remission [51].”
BackgroundBiotics (Pre-, Pro-, Post-) and Uremic Toxicity: Implications, Mechanisms, and Possible Therapies
Mitrea, L., Medeleanu, M. L., Pop, C. R., Rotar, A. M., & Vodnar, D. C. (2023) · Toxins · doi:10.3390/toxins15090548 · Cited by 16
“More and more interest is paid to the prevention and reduction of metabolic and nutrition-associated affections, as the microbial community within the intestine has a fundamental role in the well-functioning of the entire human body [1].”
Hurtado‐Lorenzo, A., Honig, G., & Heller, C. A. (2020) · Crohn s & Colitis 360 · doi:10.1093/crocol/otaa087 · Cited by 15
Fritsch, D. A., Jackson, M. I., Wernimont, S. M., Feld, G. K., MacLeay, J. M., Brejda, J. J., Cochrane, C., & Gross, K. L. (2022) · BMC Veterinary Research · doi:10.1186/s12917-022-03315-3 · Cited by 16
“Likewise, circulating indolepropionate is also suppressed in both active human UC and mouse models of colitis [41].”
BackgroundSherchand, S. P., & Aiyar, A. A. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821652116 · Cited by 17
Wang, X.-N., Xia, W., Liu, J., Sun, F.-Y., Zhong, Z.-J., Liu, L., & Xin, G.-Z. (2021) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2021.114461 · Cited by 14
Méndez-López, L. F., de León, D. S., Lomelí, M. L.-C., González-Martínez, B. E., & Vázquez-Rodríguez, J. A. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.790440 · Cited by 15
“Hence, those factors shape the subset of T helper cells that are generated in the periphery (46, 51, 52).”
BackgroundZakerska‐Banaszak, O., Żuraszek-Szymańska, J., Eder, P., Ladziak, K., Słomski, R., & Skrzypczak-Zielińska, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179589 · Cited by 17
“Recent studies demonstrated that the commensal bacteria Peptostrep-tococcus russellii could reduce susceptibility to colitis by metabolizing tryptophan to IA (an AhR agonist), improving cell differentiation and reducing inflammatory signals [61].”
BackgroundKorean Traditional Medicine (Jakyakgamcho-tang) Ameliorates Colitis by Regulating Gut Microbiota
Seo, S.-H., Unno, T., Park, S., Kim, E., Lee, Y., Na, C.-S., & Son, H.-S. (2019) · Metabolites · doi:10.3390/metabo9100226 · Cited by 14
“[69] reported that tryptophan levels significantly increased in the colons of colitic mice.”
BackgroundGutiérrez‐Repiso, C., Moreno‐Indias, I., Martín‐Núñez, G. M., Ho‐Plagaro, A., Rodríguez‐Cañete, A., Gonzalo, M., García‐Fuentes, E., & Tinahones, F. J. (2020) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2020.04.008 · Cited by 16
Ralli, T., Neupane, Y. R., Saifi, Z., & Kohli, K. (2021) · Current Pharmaceutical Design · doi:10.2174/1389201022666210625141526 · Cited by 14
The Kynurenine Pathway Is Upregulated by Methyl‐deficient Diet and Changes Are Averted by Probiotics
Tillmann, S., Awwad, H. M., MacPherson, C. W., Happ, D. F., Treccani, G., Geisel, J., Tompkins, T. A., Ueland, P. M., Wegener, G., & Obeid, R. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100078 · Cited by 13
Metadata
- Authors
- Alexeev, E. E., Lanis, J. M., Kao, D. J., Campbell, E. L., Kelly, C. J., Battista, K. D., Gerich, M. E., Jenkins, B. R., Walk, S. T., Kominsky, D. J., & Colgan, S. P.
- Affiliations
- University of Colorado Anschutz (US)
- Queen's University Belfast (GB)
- Montana State University (US)
- Corresponding author
- Kominsky, Douglas J.
- Colgan, Sean P.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 188
- Issue
- 5
- Pages
- 1183-1194
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC5906738
- OpenAlex
- W2788222993
- Cited by
- 532
- References
- 55
- Citations by year
- 2026: 65 · 2025: 84 · 2024: 76 · 2023: 90 · 2022: 68 · 2021: 74 · 2020: 43 · 2019: 22 · 2018: 8
- FWCI
- 13.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (DK1047893, DK50189, DK095491, DK103639, DK103712)
- VA Merit (BX002182)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- gut microbiota, indole metabolites, indole-3-propionic acid, interleukin-10 receptor, IL-10 signaling, aryl hydrocarbon receptor, intestinal homeostasis, colitis, germ-free mice, Escherichia coli, intestinal epithelium, mucosal disease, anti-inflammatory therapy
- MeSH terms
- Animals, Cell Line, Colitis, Disease Models, Animal, Homeostasis, Humans, Indoles, Intestinal Mucosa, Dextran Sulfate, Mice, Receptors, Interleukin-10, Metabolomics, Microbiota
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