Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism

Abstract

The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.

Keywords: Trp metabolism; aryl hydrocarbon receptor; gut microbiota; intestinal immunity; intestinal inflammation.

Figure 1

Microbiota-associated tryptophan metabolism in the gut. (A) Trp is decarboxylated to tryptamine by the common gut Firmicutes Clostridium sporogenes and Ruminococcus gnavus. (B) Derivatization of indole pyruvic acid from Trp is catalyzed by tryptophanase, and then indole pyruvic acid is decarboxylated to indole acetaldehyde, which is the precursor of tryptophol and indole acetic acid. Indole acetic acid can be converted to skatole by Lactobacillus, Clostridium, Bacteroides, and others. (C) Indole pyruvic acid can be catalyzed to indole by tryptophanase; after absorption, indole is oxidized to indoxyl, conjugated with sulfate and excreted as urinary indican. (D) Indole pyruvic acid can also be converted to indole lactate, to indole acrylic acid, and to indole propionic acid by intestinal microorganisms. Indole propionic acid can be further converted to indole acrylic acid in the liver or kidney and combined with glycine to produce indolyl acryloyl glycine.

Figure 2

Summary of endogenous and bacterial tryptophan metabolites as AhR ligands. AhR nuclear translocator protein (ARNT), AhR activation and transcription of target genes interleukin-6 (IL-6), interleukin-22 (IL-22), prostaglandin G/H synthase 2 (PTGS2), vascular endothelial growth factor A (VEGFA), cytochrome P450 1A1 (CYP1A1).

Figure 3

A schematic representation of the effects of interaction among the intestinal microbiota, intestinal immunity and factors associated with Trp absorption and metabolism.

Figure 4

Representation of the effects of interaction between the intestinal microbiota and Trp metabolism in diseases associated with intestinal immunity.