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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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“Indoles (including indole-3-propionate (IPA)), which are produced from dietary tryptophan by some specific gut microbes (such as Clostridium sporogenes in case of IPA [58]), fortify the intestinal barrier decreasing the gut wall permeability and circulating inflammatory cytokines [59-63].”
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“Indole 3propionic acid (IPA) is a tryptophan deamination product derived from Lactobacillus reuteri, Akkermansia and Clostiridum genus, which mediate intracellular signaling activity (Dodd et al., 2017; Alexeev et al., 2018; Konopelski and Mogilnicka, 2022).”
BackgroundNguyen, H. D., Aljamaei, H. M., & Stadnyk, A. W. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.07.005 · Cited by 96
Hyland, N. P., Cavanaugh, C. R., & Hornby, P. J. (2022) · Amino Acids · doi:10.1007/s00726-022-03123-x · Cited by 92
“Circulating IPA levels are reduced in patients suffering from Inflammatory Bowel Disease and increased levels are associated with remission (Alexeev et al. 2018).”
BackgroundPotdar, A. A., Dube, S., Naito, T., Li, K., Botwin, G. J., Haritunians, T., Li, D., Casero, D., Yang, S., Bilsborough, J., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.10.041 · Cited by 88
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
“Indole metabolites enhance intestinal homeostasis through AHR-mediated regulation of the IEC IL-10R1 [110].”
BackgroundYang, J., Liang, J., Hu, N., He, N., Liu, B., Liu, G., & Qin, Y. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70091 · Cited by 109
“Additionally, microbiota-derived metabolic products like taurocholic acid, histamine, indole, and spermine influence downstream neuro-peptides, regulating NLRP6 inflammasomes, IL-10, and IL-18 secretion, which correlate with inflammatory factor levels and Alzheimer's severity [14, 121].”
BackgroundMicrobiota-derived tryptophan metabolism: Impacts on health, aging, and disease
Gupta, S. K., Vyavahare, S. S., Blanes, I. L. D., Berger, F. G., Isales, C. M., & Fulzele, S. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112319 · Cited by 96
“Recently, several groups confirmed the decreased production of IPA in the serum of patients suffering from UC compared to average healthy persons (Alexeev et al., 2018).”
BackgroundMolecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases
Hyun, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179139 · Cited by 87
Liu, Y., Pei, Z., Pan, T., Wang, H., Chen, W., & Lu, W. (2023) · Microbiological Research · doi:10.1016/j.micres.2023.127392 · Cited by 88
Limosilactobacillus reuteri in immunomodulation: molecular mechanisms and potential applications
Luo, Z., Chen, A., Xie, A., Liu, X., Jiang, S., & Yu, R. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1228754 · Cited by 86
Gut microbiota in pathophysiology, diagnosis, and therapeutics of inflammatory bowel disease
Pandey, H., Jain, D., Tang, D. W. T., Wong, S. H., & Lal, D. (2023) · Intestinal Research · doi:10.5217/ir.2023.00080 · Cited by 95
Gut health: The results of microbial and mucosal immune interactions in pigs
Peng, J., Tang, Y., & Huang, Y. (2021) · Animal nutrition · doi:10.1016/j.aninu.2021.01.001 · Cited by 86
Iyer, N. R., & Corr, S. C. (2021) · Nutrients · doi:10.3390/nu13124259 · Cited by 83
“GPR35 (predicted), Aryl hydrocarbon receptor (AHR), Pregnane X receptor (PXR) [106,111] - Indole derivatives promote expression of anti-microbials [108] - Indoles regulate epithelial repair and differentiation [109,112] - Indoles promote IL-10 signalling to increase goblet cell differentiation and strengthen mucus bar…”
BackgroundXie, Y., Zou, X., Han, J., Zhang, Z., Feng, Z., Ouyang, Q., Hua, S., Liu, Z., Li, C., Cai, Y., et al. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114081 · Cited by 80
Cao, C., Wang, L., Ai, C., Gong, G., Wang, Z., Huang, L., Song, S., & Zhu, B. (2022) · Food & Function · doi:10.1039/d2fo01283a · Cited by 81
Gut-microbiota derived bioactive metabolites and their functions in host physiology
Debnath, N., Kumar, R., Kumar, A., Mehta, P. K., & Yadav, A. K. (2021) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.2021.1989847 · Cited by 77
“This signalling system actively participates in epithelial cell renewal, intensify the integrity of epithelial barrier, and activates several immune cell types, such as intraepithelial lymphocytes, T helper 17 (Th17) cells, innate lymphoid cells, macrophages, DCs, and neutrophils (Alexeev et al., 2018).”
BackgroundLefèvre, A., Mavel, S., Nadal‐Desbarats, L., Galineau, L., Attucci, S., Dufour, D. F., Sokol, H., & Emond, P. (2018) · Talanta · doi:10.1016/j.talanta.2018.11.094 · Cited by 74
“the immune response, although their functions are not fully understood [6,7].”
BackgroundA dysbiotic microbiome promotes head and neck squamous cell carcinoma
Frank, D. N., Qiu, Y., Cao, Y. Q., Zhang, S., Lu, L., Kofonow, J. M., Robertson, C. E., Liu, Y., Wang, H., Levens, C. L., et al. (2022) · Oncogene · doi:10.1038/s41388-021-02137-1 · Cited by 81
Mar, J. S., Ota, N., Pokorzynski, N. D., Peng, Y., Jaochico, A., Sangaraju, D., Skippington, E., Lekkerkerker, A., Rothenberg, M. E., Tan, M., et al. (2023) · Microbiome · doi:10.1186/s40168-023-01486-1 · Cited by 78
“These observations are in line with prior studies describing depleted indole concentration, increased L-Kyn levels, and reduced AhR activity accompanying microbial dysbiosis in the stool of IBD patients [13, 23, 28].”
ResultClostridium sporogenes -derived metabolites protect mice against colonic inflammation
Krause, F. F., Mangold, K., Ruppert, A.-L., Leister, H., Hellhund, A., Krol, A. L., Pesek, J., Watzer, B., Winterberg, S., Raifer, H., et al. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2412669 · Cited by 79
“60 By colonizing mice with C. sporogenes we were able to restore IPA levels, promoting survival and alleviation of colitis.”
BackgroundIn vitro models and ex vivo systems used in inflammatory bowel disease
Joshi, A., Soni, A., & Acharya, S. R. (2022) · In vitro models · doi:10.1007/s44164-022-00017-w · Cited by 75
Sehgal, R., de Mello, V. D., Männistö, V., Lindström, J., Tuomilehto, J. O., Pihlajamäki, J., & Uusitupa, M. I. J. (2022) · Nutrients · doi:10.3390/nu14214695 · Cited by 75
“IPA is a biomarker of active ulcerative colitis and for disease, remission based on a study in human patients with intestinal bowel disorder [35].”
BackgroundMicrobiota and IBD: Current knowledge and future perspectives
Foppa, C., Rizkala, T., Repici, A., Hassan, C., & Spinelli, A. (2023) · Digestive and Liver Disease · doi:10.1016/j.dld.2023.11.015 · Cited by 86
Old Friends, immunoregulation, and stress resilience
Langgartner, D., Lowry, C. A., & Reber, S. O. (2018) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2228-7 · Cited by 76
Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity
Brown, J., Robusto, B. A., & Morel, L. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01741 · Cited by 68
Molecular interactions between the intestinal microbiota and the host
Hertli, S., & Zimmermann, P. (2022) · Molecular Microbiology · doi:10.1111/mmi.14905 · Cited by 82
“Wrzosek, L., Miquel, S., Noordine, M.- L., Bouet, S., Chevalier- Curt, M.J., Robert, V. et al. (2013) Bacteroides thetaiotaomicron and Faecalibacterium prausnitziiinfluence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent.”
BackgroundInfluentialLangan, D., Perkins, D. J., Vogel, S. N., & Moudgil, K. D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042017 · Cited by 71
“This observation contrasts with other reports where in vitro effects of IAld are described at 10 to 100 times higher concentration [24].”
BackgroundResultLi, N., Ma, P.-G., Li, Y., Shang, X., Nan, X., Shi, L., Han, X., Liu, J., Hong, Y., Li, Q., et al. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2290315 · Cited by 76
Beyond the Gut: The intratumoral microbiome's influence on tumorigenesis and treatment response
Zhang, H., Fu, L., Leiliang, X., Qu, C., Wu, W., Wen, R., Huang, N., He, Q., Cheng, Q., Liu, G., et al. (2024) · 癌症：英文版 · doi:10.1002/cac2.12597 · Cited by 74
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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