1H-Indole, 2,3-Benzopyrrole, Indol
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Indole, or 2,3-Benzopyrrole, is an aromatic compound made of a benzene ring and a pyrrole ring with eight carbon atoms and one nitrogen atom. Bacteria and plants produce indole from tryptophan and use it for signaling and defending against intruders. In humans, the precursor of indole is tryptophan, which is taken up with animal and plant proteins from food. From these, the gut microbiota produces several tryptophan derivatives, including indole, tryptamine, and serotonin.
In bacteria, indole is an important signaling compound controlling bacterial physiology and pathogenesis. Plants use indole as a growth factor and for defense. In the human body, indole and indole derivatives affect several metabolic pathways, gut health, the oxidative stress response, and the immune response. As a natural compound of coal tar, jasmine oil, and orange blossom oil, and due to its unique smell, indole is used in the perfume and tobacco industry.
Indole and the gut microbiome
Indole is a degradation product of the essential amino acid tryptophan, which we take up with the diet. The gut microbiome produces indole, which is why the indole concentration in the gastrointestinal tract depends both on diet and the composition of the gut microbiome1.
More than 85 commensal gut bacterial species are known to make indole as well as several substituted indole compounds; among them Escherichia coli, Bacteroides ovatus, Clostridium limosum, and Enterococcus faecalis. Indole and indole derivatives are absorbed, distributed via blood circulation, and transported to the liver, affecting liver metabolism and the immune response.
In bacteria, indole functions as a signaling molecule modifying gene expression. Beneficial gut bacteria are attracted to indole, while it repels foreign and pathogenic bacteria. Indole and its derivatives control interbacterial communication, drug resistance, plasmid stability, biofilm formation, and the production of virulence factors.
Indole and health and disease
As byproducts of tryptophan metabolism, indole and indole compounds are important markers for the immune system, health, and diseases. Indole supports immune homeostasis in the gastrointestinal tract by activating intestinal immune cells, strengthening the gut barrier, and promoting the growth of beneficial gut bacteria.
However, research has shown that patients with gastrointestinal diseases or metabolic disorders contain a disturbed gut microbiome. This results in a shift in tryptophan metabolism and altered composition of indole derivatives. A healthy diet together with indole supplementation was shown to improve symptoms in patients with inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and liver inflammation, as well as metabolic complications such as diabetes, obesity, and insulin resistance2.
When degrading tryptophan, the gut microbiome produces a few toxic indole compounds, such as indoxyl sulfate and indoleacetic acid. In healthy people, these uremic toxins are eliminated by the kidneys. Yet, in patients with chronic kidney disease, the kidney is injured or damaged and thus unable to eliminate the uremic toxins. At the same time, the gut microbiome is altered and produces these toxins in high concentrations, leading to their accumulation in the body, where they can become dangerous and affect almost all systems in the body3.
Indole and therapy
Indole and substituted indoles have broad pharmacological activities due to their anti-fungal, anti-platelet, anti-cancer, anti-plasmodial, anti-insecticidal, and anti-oxidant effects. As indole occurs naturally, substituted indoles are some of the most important compounds for pharmaceutical development.
Several indole compounds have extensive anti-tumor effects and target different pathways in cancer cells4. Patients with colon cancer were shown to have an altered tryptophan metabolism. Hence, the impact of an indole- and tryptophan-rich diet, containing cabbage, broccoli, kale, collards, turnip greens, mustard, radish, rapeseed, kohl rabi, and Brussel sprouts, are widely studied in cancer prevention, including colon cancer.
Due to their antibacterial effects, indole derivatives are currently investigated as therapeutics against multi-drug resistant bacteria5. Similarly, several substituted indoles are active against Plasmodium, and might thus be potent drugs for patients with malaria6.
- Li X, Zhang B, Hu Y, et al. New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases. Front Pharmacol 2021;12:769501.
- Su X, Gao Y, Yang R. Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis. Cells 2022;11(15):2296.
- Cigarran Guldris S, González Parra E, and Cases Amenós A. Gut microbiota in chronic kidney disease. Nefrologia 2017;37(1):9-19.
- Luo ML, Huang W, Zhu HP, et al. Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy. Biomed Pharmacother 2022;149:112827.
- Meng T, Hou Y, Shang C, et al. Recent advances in indole dimers and hybrids with antibacterial activity against methicillin-resistant Staphylococcus aureus. Arch Pharm (Weinheim) 2021;354(2):e2000266.
- Surur AS, Huluka SA, Mitku ML, et al. Indole: The After Next Scaffold of Antiplasmodial Agents? Drug Des Devel Ther 2020;14:4855-4867.