Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis

Abstract

Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4⁺CD8αα⁺ regulatory cells, IL-10⁺ and/or IL-35⁺B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.

Keywords: Trp metabolites; anti-inflammatory macrophages; gut microbiota; regulatory B cells; regulatory T cells.

Figure 1

Production and regulation of Trp metabolites in the gut microbiota. Trp is an essential amino acid, which can be naturally provided by dietary proteins. Trp metabolism in the gut microbiota follows two major pathways: (1) Direct transformation. Trp is converted into various catabolites by the gut microbiota, such as indole, IAA, IPA, IA, IAld, tryptamine, IE, IAAld and Skatole. (2) Kynurenine pathway. Trp is catalyzed to produce Kyn and downstream metabolites such as 3-HAA and 3H-Kyn. There are some factors, including natural substances and chemical drugs inside the circle (red dotted line), which can regulate tryptophan metabolism in the gut microbiota. Words in red are a key enzyme. Background, gut microbiota.

Figure 2

Effects of Trp metabolites derived from the gut microbiota on the immune cells and immune-associated diseases. Trp metabolites promote the differentiation and/or function of immunosuppressive cells such as anti-inflammatory macrophages, myeloid-derived suppressor cells, Tr1, Treg, CD4⁺CD8αα⁺, PD-1^highCD8⁺, ILC3, IL-22-producing CD4, CD21^highCD24^highIL-10⁺Breg and IgM⁺IgD⁺IL-10⁺IL35⁺Breg, whereas the differentiation and/or function of some immune cells such as dendritic cells, TH1, TH17 and NK cells are inhibited. Trp metabolites derived from the gut microbiota can affect the occurrence and development of some diseases through regulating immune cells, such as inflammatory bowel diseases, vascular inflammation and cardiovascular diseases, hepatic fibrosis, diseases in the nervous system, obesity and metabolic syndrome, tumors and infectious diseases.