New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

Abstract

The interaction between host and microorganism widely affects the immune and metabolic status. Indole and its derivatives are metabolites produced by the metabolism of tryptophan catalyzed by intestinal microorganisms. By activating nuclear receptors, regulating intestinal hormones, and affecting the biological effects of bacteria as signaling molecules, indole and its derivatives maintain intestinal homeostasis and impact liver metabolism and the immune response, which shows good therapeutic prospects. We reviewed recent studies on indole and its derivatives, including related metabolism, the influence of diets and intestinal commensal bacteria, and the targets and mechanisms in pathological conditions, especially progress in therapeutic strategies. New research insights into indoles will facilitate a better understanding of their druggability and application in intestinal and liver diseases.

Keywords: indole; indole derivates; intestinal inflammation; liver diseases; tryptophan metabolites.

FIGURE 1

Pathways of intestinal Trp metabolism. Indole and its derivatives are derived from the metabolism of Trp by gut microorganisms. There are three main pathways in intestinal microorganism–derivated Trp metabolism: the Trp-Indole pathway, Trp-IPyA-ILA-IA-IPA pathway, and Trp-IAA-Skatole or IAld pathway. Abbreviations: IPyA, indole-3-pyruvate; ILA, indole-3-lactate; IA, indole-3-acrylate; IPA, indole-3-propionate; IAAld, indole-3-acetaldehyde; IAA, indole-3-acetate; IAld, indole-3-aldehyde; IAM, indole-3-acetamine; IEA, indole-3-ethanol; TnaA gene, encode Tryptophanase; iaaM gene, encode Tryptophan 2-monooxygenase; iaaH gene, encode indole-3-acetamide hydrolase; TrpD gene: encode Tryptophan decarboxylase enzyme; ArAT gene, encode aromatic amino acid aminotransferase; fldH gene, encode phenyllactate dehydrogenase; fldBC gene, encode (R)-phenyllactyl-CoA dehydratase alfa and beta subunits; acdA gene, encode acyl-CoA dehydrogenase; ipdC gene, encode Indole-3-pyruvate decarboxylase.

FIGURE 2

Pathways of indole and indole derivate metabolism in the liver. (A) indole; (B) indole-3-acetate (IAA); (C) indole-3-propionate (IPA). The absorption of indole and its derivatives through the intestinal epithelium and their further metabolism by liver CYP450 and sulfotransferase enzymes and conjugation with some other amino acids like glutamine and glycine and, finally, excretion by the kidney.

FIGURE 3

Effects of indole and its derivatives on the intestine and liver. The microbiota converts Trp into indole and its derivatives as signaling molecules to regulate epithelial integrity, immune response, and gastrointestinal motility through intestinal receptors and enter the liver through the circulation to regulate liver inflammation and glucose and lipid metabolism. Abbreviations: IPA, indole-3-propionate; IAA, indole-3-acetate; ILA, indole-3-lactate; IAld, indole-3-aldehyde; AhR, aromatic hydrocarbon receptor; PXR, pregnane X receptor; 5-HT₄R, 5-HT4 receptors; GLP-1, glucagon-like peptide 1; TLR4, toll-like receptor 4.