Dual Role of Indoles Derived From Intestinal Microbiota on Human Health

Abstract

Endogenous indole and its derivatives (indoles), considered as promising N-substituted heterocyclic compounds, are tryptophan metabolites derived from intestinal microbiota and exhibit a range of biological activities. Recent studies indicate that indoles contribute to maintaining the biological barrier of the human intestine, which exert the anti-inflammatory activities mainly through activating AhR and PXR receptors to affect the immune system's function, significantly improving intestinal health (inflammatory bowel disease, hemorrhagic colitis, colorectal cancer) and further promote human health (diabetes mellitus, central system inflammation, and vascular regulation). However, the revealed toxic influences cannot be ignored. Indoxyl sulfate, an indole derivative, performs nephrotoxicity and cardiovascular toxicity. We addressed the interaction between indoles and intestinal microbiota and the indoles' effects on human health as double-edged swords. This review provides scientific bases for the correlation of indoles with diseases moreover highlights several directions for subsequent indoles-related studies.

Keywords: dual role; indole; indoxyl sulfate; inflammation; intestinal flora.

Figure 1

Metabolic pathways of tryptophan in the intestine. TPH, tryptophan hydroxylase; TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenases; IAM, indole-3-acetamine; IAAld, indole-3-acetaldehyde; IPyA, indole-3-pyruvate; IEA, indole-3-ethanol; IAA, indole-3-acetate; ILA, indole-3-lactate; IAld, indole-3-aldehyde; IA, indole-3-acrylate; IPA, indole-3-propionate.

Figure 2

Effects of indoles on three barriers. Indoles affect the biological barrier by increasing beneficial bacteria, inhibiting pathogenic bacteria and regulating virulence gene expression of intestinal pathogens. Indoles enhance intestinal epithelial cell function by regulating several genes involved in mechanical barrier formation. Indoles increase mucin and goblet cell secretion products, which strengthen the mucus barrier. AJs, adherens junctions; DC, dendritic cell; E. coli, Escherichia coli; EHEC, enterohemorrhagic escherichia coli; IA, indoleacrylic acid; IECs, intestinal epithelial cells; IgA, immunoglobulin A; IL-10, interleukin-10; IPA, indole 3-propionic acid; MUC, mucin; M cell, membranous cell; P. aeruginosa, Pseudomonas aeruginosa; TJs, Tight junctions.

Figure 3

Schematic diagram of indoles signal pathway. Indole, Skatole, IA, Trytamine, IAA, IAld, ILA are AhR ligands. Indoles activates AhR to promote mucosal immunity, and AhR is present on intestinal epithelial cells and immune cells such as ILC3, DC. Indole, IA, IPA are the ligands of PXR and they activate PXR to affect tight junctions. In the absence of ligand, AhR/PXR exists in cytoplasm as an inactive complex. After indoles binding, AhR/PXR enters the nucleus, forms a dimer with ARNT/RXR, and then induces the expression of immune-related genes. IAA, indole-3-acetate; ILA, indole-3-lactate; IAld, indole-3-aldehyde; IA, indole-3-acrylate; IPA, indole-3-propionate; AhR, aryl hydrocarbon receptor; PXR, pregnane X receptor; TJ, tight junctions; IL, interleukin; DC, dendritic cells; DPIELs, double-positive intraepithelial T lymphocytes; ILC3, Group 3 innate lymphoid cells; HSP90, heat shock protein 90; P23, HSP90 co-chaperone p23; XAP2, X-associated protein 2; ARNT, AhR nuclear translocator.

Figure 4

Benefits and toxic effects of indoles. The benefits of indoles use the green line. The toxicities of indoles use the red line. IPA, indole 3-propionic acid; PXR, pregnane X receptor; IFN, type I interferon; AhR, aryl hydrocarbon receptor; CNS, central nervous system; CRC, colorectal cancer; MUC, mucin; TNF-α, tumor necrosis factor-α; IL, interleukin; IDO1, indoleamine 2,3-dioxygenase; EHEC, enterohemorrhagic Escherichia coli; IBD, inflammatory bowel disease; IECs, intestinal epithelial cells.