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.

Highlights

  • The gut microbiota and microbial metabolites are important for maintaining healthy bowels

  • We provide a brief outline of studies that support an influence of dietary Trp on intestinal inflammation and other peripheral inflammation, outline the connection between Trp metabolism and the gut microbiota, and discuss which Trp metabolites intersect with the immune system

  • 95% of the Trp ingested is degraded to kynurenine, kynurenic acid (KA), quinolinic acid, picolinic acid, and nicotinamide adenine dinucleotide (NAD) through kynurenine pathway (KP), which is regulated by two rate-limited enzymes: tryptophan 2,3-dioxygenase (TDO) in the liver and indoleamine 2,3-dioxygenase (IDO) in extrahepatic tissues (Peters, 1991)

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Summary

INTRODUCTION

The gut microbiota and microbial metabolites are important for maintaining healthy bowels. We discuss studies that increase our understanding of how Trp metabolism interacts with the gut microbiota, how Trp functions in host–microbiota interactions and how Trp influences gut immune homeostasis. We provide a brief outline of studies that support an influence of dietary Trp on intestinal inflammation and other peripheral inflammation, outline the connection between Trp metabolism and the gut microbiota, and discuss which Trp metabolites intersect with the immune system. Understanding these interactions may provide novel targets for the treatment of various intestinal disorders that are associated with the microbiota and Trp metabolism

GUT MICROBIOTA AND HOST IMMUNITY
Endogenous Trp Metabolism
Bacterial Trp Metabolism
Interplay between Endogenous and Bacterial Trp Metabolism
Host Trp Metabolism
Bacterial Trp Metabolites
SUMMARY AND PERSPECTIVE
Findings
AUTHOR CONTRIBUTIONS
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