Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders

Abstract

The trillions of commensal microorganisms comprising the gut microbiota have received growing attention owing to their impact on host physiology. Recent advances in our understandings of the host-microbiota crosstalk support a pivotal role of microbiota-derived metabolites in various physiological processes, as they serve as messengers in the complex dialogue between commensals and host immune and endocrine cells. In this review, we highlight the importance of tryptophan-derived metabolites in host physiology, and summarize the recent findings on the role of tryptophan catabolites in preserving intestinal homeostasis and fine-tuning immune and metabolic responses. Furthermore, we discuss the latest evidence on the effects of microbial tryptophan catabolites, describe their mechanisms of action, and discuss how perturbations of microbial tryptophan metabolism may affect the course of intestinal and extraintestinal disorders, including inflammatory bowel diseases, metabolic disorders, chronic kidney diseases, and cardiovascular diseases.

Keywords: cardiovascular diseases (CVD); chronic kidney diseases (CKD); inflammation; metabolic syndrome; microbiota; tryptophan.

Figure 1

Myriad commensal bacteria can metabolize dietary and host-derived carbohydrates or proteins generating short-chain fatty acids (e.g., butyrate, acetate, propionate, and lactate) and diverse amino acids’ catabolites (through diverse bacterial pathways degrading aromatic, sulfur-containing, branched-chain, and other amino acids), respectively.

Figure 2

Simplified illustration of the eukaryotic and bacterial pathways of tryptophan degradation in the gastrointestinal tract: Eukaryotic enzymes: IDO (indoleamine 2,3-dioxygemase), TDO (tryptophan 2,3-dioxygemase), TPH (tryptophan hydroxylase), CYP2E1 (cytochrome P450 2E1), SULT (sulfotransferase). Bacterial enzymes: TMO (tryptophan 2-monooxygenase), TrD (tryptophan decarboxylase), ArAT (aromatic amino acid aminotransferase), TNA (tryptophanase), IDO homologs.

Figure 3

Microbiota-derived tryptophan metabolites modulate various host physiological processes. From left to right: indole signals to enteroendocrine L cells to induce the secretion of GLP-1, which stimulates insulin secretion by pancreatic beta cells. Many of the bacterial tryptophan catabolites—such as indole acetic acid (IAA), indole-3-acetaldehyde, indole-3-aldehyde (IAld), indole-3-lactic acid (ILA), indole-3-propionic acid (IPA), tryptamine, and skatole—activate the aryl hydrocarbon receptor (AhR) in intestinal immune cells; AhR activation in dendritic cells (DC) and type 3 innate lymphoid cells (ILC3) promotes production of IL-22—a central cytokine for intestinal homeostasis—and favors the expansion of anti-inflammatory T cells. After absorption into the bloodstream, indoles reach the liver, where they exhibit protective effects against lipid accumulation and inflammation; however, hepatic enzymes can convert indole into the uremic toxin indoxyl sulfate (IS), which is harmful to kidney epithelial cells as well as endothelial cells. IS levels are correlated with kidney dysfunction in chronic kidney diseases (CKDs) and increased risk of cardiovascular disease (CVD). Microbial tryptamine can incite enterochromaffin cells (EChr) to release 5-hydroxytryptamine (5-HT), which stimulates gastrointestinal mobility. Lastly, indoles regulate intestinal homeostasis and barrier function by activating AhR and the pregnane X receptor (PXR) within intestinal epithelial cells (IECs).