Microbial tryptophan catabolites in health and disease

Henrik M Roager, Tine R Licht, Henrik M Roager, Tine R Licht

Abstract

Accumulating evidence implicates metabolites produced by gut microbes as crucial mediators of diet-induced host-microbial cross-talk. Here, we review emerging data suggesting that microbial tryptophan catabolites resulting from proteolysis are influencing host health. These metabolites are suggested to activate the immune system through binding to the aryl hydrocarbon receptor (AHR), enhance the intestinal epithelial barrier, stimulate gastrointestinal motility, as well as secretion of gut hormones, exert anti-inflammatory, anti-oxidative or toxic effects in systemic circulation, and putatively modulate gut microbial composition. Tryptophan catabolites thus affect various physiological processes and may contribute to intestinal and systemic homeostasis in health and disease.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Mechanisms of action of microbial tryptophan catabolites on host physiology. Degradation of dietary proteins leads to the release of tryptophan, which is converted into various catabolites by the gut microbiota. The tryptophan catabolites include indole, tryptamine, indoleethanol (IE), indolepropionic acid (IPA), indolelactic acid (ILA), indoleacetic acid (IAA), skatole, indolealdehyde (IAld) and indoleacrylic acid (IA) and may affect host physiology in numerous ways. Indole, IPA and IA affect mucosal homeostasis by decreased intestinal permeability possibly mediated by the pregnane X receptor (PXR). Indole induces the release of glucagon-like peptide 1 (GLP-1) in enteroendocrine L-cells. GLP-1 is known to suppress appetite, insulin secretion and to slow gastric emptying. Several tryptophan catabolites act on the aryl hydrocarbon receptor (AHR) found in intestinal immune cells and thereby alter innate and adaptive immune responses in a ligand-specific fashion (e.g. IAld induces increased production of interleukin-22 (IL-22) via AHR activation). Tryptamine induces the release of 5-hydroxytryptamine (5-HT, serotonin) by enterochromaffin cells. 5-HT stimulates gastrointestinal motility by acting on enteric nervous system neurons. Tryptophan catabolites are absorbed through the intestinal epithelium and enter the bloodstream where some (e.g. IPA, IE, IA) have anti-oxidative and anti-inflammatory effects, whereas indoxyl-sulfate (IS), which is produced in the liver from indole by the actions of CYP2E1 and sulfotransferases (SULT), has cytotoxic effects in high concentrations
Fig. 2
Fig. 2
Microbial generation of tryptophan catabolites in the human gut. Overview of the different ways microbes degrade tryptophan in the human gut. The metabolites that are most often found in the human gut are colored in green. Dashed lines represent pathways where no enzymes have been identified
Fig. 3
Fig. 3
Proposed strategy to identify tryptophan-catabolite-producing microbes and to investigate their role in human health and disease. Although a number of tryptophan-catabolite producing microbes have currently been identified (Table 1), no studies have until now taken their starting point from human data, meaning that we do not know the main bacterial producers of tryptophan catabolites in the human gut. Therefore, we suggest to start from human studies and combine metagenomics and metabolomics data in order to pinpoint the most relevant and potential tryptophan-catabolite producing microbes. Based on these associations, selected target species should be cultured in the laboratory and their in vitro production of tryptophan catabolites should be assessed by growth experiments and metabolic profiling. Combined with knowledge about their genomes, this will allow the identification of genes responsible for generation of tryptophan catabolites. Knocking out identified genes of interest will subsequently allow for confirmation of the function of the gene and for testing the importance of the particular gene in relevant animal models as recently exemplified. Colonizing mice with a given mutant strain and the wild-type counterpart will furthermore allow the investigation of modes of action of the tryptophan catabolites on e.g., intestinal immune cells, intestinal barrier function, intestinal hormone secretion, the inherent gut microbiota, as well as on the immune cells in systemic circulation. Together, this will provide new insights about the role of tryptophan catabolites, and lead to a better understanding of the gut microbiota in human health and disease

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