Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation

Abstract

The gut microbiota has a crucial effect on regulating the intestinal mucosal immunity and maintaining intestinal homeostasis both in health and in disease state. Many effects are mediated by gut microbiota-derived metabolites and tryptophan, an essential aromatic amino acid, is considered important among many metabolites in the crosstalk between gut microbiota and the host. Kynurenine, serotonin, and indole derivatives are derived from the three major tryptophan metabolism pathways modulated by gut microbiota directly or indirectly. Aryl hydrocarbon receptor (AHR) is a cytoplasmic ligand-activated transcription factor involved in multiple cellular processes. Tryptophan metabolites as ligands can activate AHR signaling in various diseases such as inflammation, oxidative stress injury, cancer, aging-related diseases, cardiovascular diseases (CVD), and chronic kidney diseases (CKD). Accumulated uremic toxins in the body fluids of CKD patients activate AHR and affect disease progression. In this review, we will elucidate the relationship between gut microbiota-derived uremic toxins by tryptophan metabolism and AHR activation in CKD and its complications. This review will provide therapeutic avenues for targeting CKD and concurrently present challenges and opportunities for designing new therapeutic strategies against renal fibrosis.

Keywords: Chronic kidney disease; Intestinal flora; Natural products; Tryptophan metabolites.

Fig. 1

The AHR signaling pathway. Inactive AHR is complexed with HSP90, XAP2, and p23 to maintain stability and keep it in a high-affinity state for its ligands. When the ligands bind to AHR, the complex translocates to the nucleus where it combines ARNT through HSP90 displacement. The AHR-ARNT heterodimer binds to XREs to induce the transcription of downstream target genes, such as CYP1A1, CYP1B1, AHRR, etc. AhRR is also a negative regulator of AHR that can bind to ARNT but does not induce transcription. Besides, the ligands–AHR complex also interacts with other regulator proteins, such as NF-κB, etc

Fig. 2

Mechanisms of action of microbial tryptophan catabolites on host physiology and disease. Tryptophan in the colonic lumen is converted into various catabolites by the gut microbiota. Indole and indole-3-propionate (IPA) may mediate the pregnane X receptor (PXR) to decrease intestinal permeability and affect mucosal homeostasis. Indole is metabolized to indoxyl sulfate by CYP2E1 and sulfotransferases in the liver leading to the accumulation of IS, which is toxic and associated with renal dysfunction. Indole also induces the release of glucagon-like peptide 1 (GLP-1) in enteroendocrine L-cells, suppressing appetite and insulin secretion and slowing gastric emptying. Several tryptophan catabolites activate AHR in intestinal immune cells to alter innate and adaptive immune responses maintaining mucosal reactivity. In enterochromaffin cells, tryptamine induces the release of 5-HT stimulating gastrointestinal motility by acting on enteric nervous system neurons

Fig. 3

AHR ligands from tryptophan metabolism. Tryptophan in cruciferous vegetables produce glucosinolate via hydrolysis reaction, yielding indolo[3,2,-b]carbazole. 95% tryptophan can be metabolized to kynurenine, which is mediated by IDO and TDO. In the gastrointestinal tract, metabolites such as tryptamine, indole-3-acetaldehyde, indole-3-acetic acid, and indole-3-aldehyde are from the microbial metabolic process. Besides, tryptophan can be metabolized to 6-formylindolo-(3,2-b)-carbazole from ultraviolet radiation. Asterisks indicate metabolites with AHR agonistic activity