Abstract
Tryptophan (Trp) is an essential amino acid primarily derived from the diet for use by the host for protein synthesis. The intestinal tract is lined with cells, both host and microbial, that uptake and metabolize Trp to also generate important signaling molecules. Serotonin (5-HT), kynurenine and its downstream metabolites, and to a lesser extent other neurotransmitters are generated by the host to signal onto host receptors and elicit physiological effects. 5-HT production by neurons in the CNS regulates sleep, mood, and appetite; 5-HT production in the intestinal tract by enterochromaffin cells regulates gastric motility and inflammation in the periphery. Kynurenine can signal onto the aryl hydrocarbon receptor (AHR) to elicit pleiotropic responses from several cell types including epithelial and immune cells, or can be further metabolized into bioactive molecules to influence neurodegenerative disease. There is a remarkable amount of cross-talk with the microbiome with regard to tryptophan metabolites as well. The gut microbiome can regulate the production of host tryptophan metabolites and can use dietary or recycled trp to generate bioactive metabolites themselves. Trp derivatives like indole are able to signal onto xenobiotic receptors, including AHR, to elicit tolerogenic effects. Here, we review studies that demonstrate that tryptophan represents a key intra-kingdom signaling molecule.
Highlights
The intestinal mucosa provides crucial metabolic functions and forms a barrier that protects host tissue from foreign luminal content and pathogens
Though it might seem that the mucosa defends against an army of outsiders, mucosal defense depends upon “peacekeeping” molecules derived from the diet or commensal microbes
On the right side are other pathways involving Intestinal epithelial cells (IECs) and immune cell functions that are influenced by Trp metabolite signaling: TJ formation, antimicrobial peptide (AMP) and mucus secretion, IFN-g signaling, and the differentiation of immune cell subsets that regulate inflammatory responses (e.g. Th17, Treg and ILC22 cells)
Summary
The intestinal mucosa provides crucial metabolic functions and forms a barrier that protects host tissue from foreign luminal content and pathogens. Though it might seem that the mucosa defends against an army of outsiders, mucosal defense depends upon “peacekeeping” molecules derived from the diet or commensal microbes. It is well-supported that the gut microbiome and diet each influence host metabolism, homeostatic processes, and inflammatory responses, and many of these functions are modulated to a large extent by small molecule metabolites [1,2,3,4]. Some Trp metabolites, both host- and microbe-derived, modulate intestinal mucosal function as well as extra-intestinal tissue physiology through direct binding to the host transcription factor aryl hydrocarbon receptor (AHR) [7,8,9]. We review Trp uptake and metabolism by host and microbiome and its role in maintaining mucosal tissue homeostasis and modulation of host inflammatory responses, as well as the role of these metabolites in the modulation of extra-intestinal tissue function
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