The tryptophan metabolic pathway of the microbiome and host cells in health and disease

Abstract

The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cellular and bacteria processes, producing bioactive compounds such as 5-hydroxytryptamine (5-HT) and kynurenine derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting the role of the aryl hydrocarbon receptor in inflammation modulation. Dysregulation of this pathway is implicated in various diseases, such as Alzheimer's and Parkinson's diseases, mood disorders, neuronal diseases, autoimmune diseases such as multiple sclerosis (MS), and cancer. In this article, we describe the impact of the 5-HT, Trp, indole, and Trp metabolites on health and disease. Furthermore, we review the impact of microbiome-derived Trp metabolites that affect immune responses and contribute to maintaining homeostasis, especially in an experimental autoimmune encephalitis model of MS.

Keywords: GPR35; brain disease; immune cell; kynurenic acid.

Graphical Abstract

Figure 1.

Overview of tryptophan metabolism via the kynurenine, 5-HT, indole, and I3P pathway.

Figure 2.

Tryptophan metabolites derived from the host cells and gut microbiota and the blood–brain barrier.

Figure 3.

The role of the Kyn pathway in immune regulation. (A) In DSS-induced colitis, kynurenine via the intestinal epithelial AHR leads to an increase in IL-10 receptor-1 (IL-10R1) expression. This consequently exerts an anti-inflammatory effect through IL-10 signaling. (B) The IDO1-AHR axis in the induction of infection resistance upregulates TGF-β and induces Tregs. (C) The collaborative interaction between TGF-β and AHR plays a pivotal role in the transdifferentiation process of Th17 cells, leading to the generation of IL-10-producing Tr1 cells and Foxp3⁺ Treg cells.

Figure 4.

The 5-HIAA-GPR35 axis is implicated in the recruitment of immune cells (A) platelet- and mast cell-derived, a metabolite of serotonin, 5-HIAA serves as a ligand for the chemoattractant receptor GPR35, facilitating GPR35⁺ neutrophil transendothelial migration and their recruitment to inflammatory tissue during Listeria monocytogenes infections. (B) When Cryptococcus neoformans infects the lungs, it produces 5-HIAA derived from platelets and mast cells through macrophage-mediated inflammation. This process promotes the recruitment of GPR35⁺ eosinophils to the infected lung, leading to the exacerbation of the disease. (C) Mast cells located in the subepithelial dome produce 5-HIAA to recruit GPR35⁺ cDC2s. This consecutive series of events results in an increased synthesis of immunoglobulin A (IgA) by plasma-cells.

Figure 5.

Indole derivatives derived from bacteria serve as facilitators for augmenting the efficacy of chemotherapy and ICI in cancer. (A) Trp metabolites originating from the gut microbiome accelerate the chemotherapy response in pancreatic cancer. Intestinal bacteria generate IAA from absorbed dietary Trp. IAA is transported to PDAC through the bloodstream, where it may undergo oxidation to produce toxic molecules (IAAp) facilitated by myeloperoxidase (MPO) and cytotoxic anticancer drugs such as 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) within intratumoural neutrophils. Subsequently, IAAp and FOLFIRINOX jointly contribute to the downregulation of GPX3/7, enzymes responsible for degrading ROS, leading to the accumulation of ROS within cancer cells. Ultimately, elevated ROS levels inhibit the autophagy pathway, a crucial process in cancer cell proliferation. (B) L. reuteri translocates to, colonizes, and persists within melanoma, where, through the release of its dietary tryptophan catabolite I3A, it locally enhances the generation of IFN-γ-producing CD8⁺ T cells, thereby augmenting the efficacy of ICI. Furthermore, I3A was found to be both necessary and sufficient to stimulate antitumour immunity, and the loss of AHR signaling within CD8⁺  T cells abolished antitumour effects.

Figure 6.

Indole derivatives originating from the gut microbiota exert anti-inflammatory effects through the AHR. Indole derivatives, generated by the microbial conversion of dietary Trp, can activate AHR in Group 3 innate lymphoid cells (ILC3s), thereby promoting IL-22-mediated tissue protection. Indole derivatives can activate AHR in T cells, leading to the generation of Tregs and subsequent reduction in inflammation, resulting in improved disease outcomes in EAE. Additionally, AHR in microglia contributes to the suppression of inflammation in EAE.

Figure 7.

The gut microbiota-induced KYNA recruits GPR35⁺ macrophages to promote experimental encephalitis. (Left) Inflammation was initiated in the small intestine prior to the manifestation of the phenotype in the EAE model of MS. Inflammation elevated antimicrobial peptides and modified the microbiome. The intestinal epithelium cells (IECs) and microbiome collaborated in the production of KYNA. GPR35⁺ CX3CR1⁺ Ly6C⁺ cells utilizing KYNA as a chemokine ligand were recruited to the small intestine. GPR35⁺ CX3CR1⁺ Ly6C⁺ cells exhibit high levels of IL-6 expression and an expanded population of pathogenic myelin-responsive Th17 cells. Pathogenic myelin-responsive Th17 cells migrated to the SC, triggering inflammation. (Right) The administration of CB led to the suppression of inflammation in the small intestine. CB altered the microbiome and gene expression in the IECs, leading to the inactivation of the Kyn pathway. The diminished KYNA levels resulted in a reduced recruitment of GPR35⁺ CX3CR1⁺ Ly6C⁺ cells. The number of pathogenic myelin-responsive Th17 cells induced by GPR35⁺ CX3CR1⁺ Ly6C⁺ cells was decreased. Inflammation was attenuated due to a decrease in the number of pathogenic myelin-responsive Th17 cells migrating to the SC. The potential preventive effect of CB on MS was suggested.