Research ArticleDietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice☆
Introduction
Ulcerative colitis (UC) is the typical progression of chronic inflammatory bowel disease (IBD) [1]. IBD is a fatal and relapsing inflammatory disorder of the gastrointestinal (GI) tract that is characterized by chronic, uncontrolled inflammation in the intestinal mucosa, and IBD affects millions of people worldwide and incurs a substantial economic cost [2]. The severity and pathogenesis of UC are considered to be influenced by multiple genetic factors, immune responses, intestinal flora and oxidative stress [3], and the conventional UC treatments used to date have demonstrated variable efficacy, adverse side effects and potential long-term toxicity [4], [5]. Therefore, it is critical to develop alternative beneficial strategies for UC treatment.
Tryptophan is an essential amino acid for mammals that is readily obtained through the diet and is regarded as a key regulator of metabolic pathways, and recent findings have demonstrated that tryptophan plays a role in protecting health [1], [6], [7], [8]. In the GI tract, tryptophan can enter several metabolic pathways, most notably protein synthesis, serotonin, and kynurenine pathways and microbiota-mediated degradation [9], [10]. Tryptophan metabolites such as indole-3-aldehyde, kynurenine, indole-3-acetic acid and tryptamine can act as ligands for aryl hydrocarbon receptor (Ahr) [10], [11], [12], [13], which is a ligand-activated transcription factor and a member of the basic helix–loop–helix/Per–Arnt–Sim homology superfamily [14]. Ahr functions as a cytosolic sensor of xenobiotics such as polycyclic aromatic compounds, including 2,3,7,8-tetrachlorodibenzo-p-dioxin [15]. Upon ligand binding, Ahr translocates from the cytoplasm into the nucleus, where it heterodimerizes with Ahr nuclear translocator (Arnt) and then activates the transcription of several genes involved in xenobiotic metabolism, including members of the cytochrome P450 superfamily [14], [15], [16]. Ahr mediates several toxic effects, including endocrine disruption, tumor development, cell differentiation, thymic atrophy and immune suppression, and as compared to wild-type (WT) mice, Ahr-deficient (knockout; KO) mice are more susceptible to toxicological effects, including advancement of cardiac hypertrophy, impairment of embryonic development, skin lesions and abnormal liver development [17], [24]. Ahr regulation by its natural ligands has been shown to lead to an abolishment carcinogenesis in the mouse intestine, where Ahr functions as a critical player in mucosal barrier defense, most notably because of its role in interleukin (Il)-22 production by innate lymphoid cells (ILCs) [15], [18]. Il-22 also serves as a strong activator of the pleiotropic transcription factor Stat3 (signal transducer and activator of transcription 3) [19]. Moreover, Ahr controls the regulatory T cells (Tregs) that express the forkhead transcription factor Foxp3, which play a critical role in immune tolerance [20], [21].
Ahr has been reported to play a key role in attenuating UC induced by dextran sodium sulfate (DSS) [22]. DSS carries a highly negative charge that is contributed by sulfate groups, and DSS is toxic to colonic epithelia and induces erosions; this ultimately results in an abnormal influx of microbes and the activation of inflammatory cells and enhancement of inflammatory mediators, leading to severe colitis. DSS-induced colitis exhibits several characteristics resembling those of human UC [23]. A few previous studies have described a role of tryptophan supplementation in protection against UC [1], [10], but the precise molecular mechanisms involved remain incompletely understood. Here, we investigated the functional involvement of Ahr in intestinal inflammation by providing a tryptophan-containing diet to mice and then examined the regulatory contribution of Il-22/Stat3. Our main objective in this study was to elucidate the potential mechanisms by which dietary tryptophan supplementation protects against DSS-induced colitis through Ahr.
Section snippets
Materials
We purchased DSS salt (MW>40 kD) from Sigma-Aldrich (St. Louis, MO, USA), tryptophan from Wako Pure Chemicals (Tokyo, Japan), and myeloperoxidase (MPO) from Biovision (Milpitas, CA, USA). The amounts of tumor necrosis factor α (Tnfα) and Il-6 in mouse serum were determined using commercially available mouse enzyme-linked immunosorbent assay (ELISA) kits from Diaclone SAS (Besancon Cedex, France) and R&D Inc. (Minneapolis, MN, USA), respectively.
Animals
Female C57BL/6 WT and KO mice (10–12 weeks old)
General observation of colitis
Average food and tryptophan intake and DSS-containing water consumption did not differ in a statistically significant manner among the groups (Supplementary Fig. 1). In mice exposed to DSS, colitis symptoms, for example, body weight lowering and bloody stools, increased markedly after Day 4 and reached maximal severity at Day 8 in all groups except the WT group that received the tryptophan diet. As a result, food and water consumption was affected in all groups except the WT group receiving
Discussion
We have demonstrated a mechanism by which l-tryptophan protects against DSS-induced colitis in mice. Tryptophan supplementation reduced body weight loss, disease activity indices and local inflammatory-cytokine expression and improved epithelial structural integrity in WT but not Ahr KO mice. This is because tryptophan metabolites, not tryptophan itself, act as ligands for Ahr [41] and their binding causes Ahr to regulate intestinal immunity [10], [11], [25]. Generally, only a small fraction of
Acknowledgment
This work was partially supported by a grant from the research project on the development of agricultural products and foods with health promoting benefits (National Agriculture and Food Research Organization), Japan. The authors declare that they have no conflict of interests.
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Funding sources/conflict of interest: The authors declare no conflicts of interest.