Mediators of Inflammation

Mediators of Inflammation / 2020 / Article
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The Impact of Nutrients, Dietary Components and Derivatives on the Gut Microbiota and Inflammation-Related Diseases, from Molecular Basis to Therapy

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Review Article | Open Access

Volume 2020 |Article ID 9706140 | https://doi.org/10.1155/2020/9706140

Xueyan Ding, Peng Bin, Wenwen Wu, Yajie Chang, Guoqiang Zhu, "Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review", Mediators of Inflammation, vol. 2020, Article ID 9706140, 10 pages, 2020. https://doi.org/10.1155/2020/9706140

Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review

Academic Editor: Xiaolu Jin
Received08 Apr 2020
Accepted26 May 2020
Published12 Jun 2020

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from the homeostasis imbalance of intestinal microenvironment, immune dysfunction, environmental and genetic factors, and so on. This disease is associated with multiple immune cells including regulatory T cells (Tregs). Tregs are a subset of T cells regulating the function of various immune cells to induce immune tolerance and maintain intestinal immune homeostasis. Tregs are correlated with the initiation and progression of IBD; therefore, strategies that affect the differentiation and function of Tregs may be promising for the prevention of IBD-associated pathology. It is worth noting that tryptophan (Trp) metabolism is effective in inducing the differentiation of Tregs through microbiota-mediated degradation and kynurenine pathway (KP), which is important for maintaining the function of Tregs. Interestingly, patients with IBD show Trp metabolism disorder in the pathological process, including changes in the concentrations of Trp and its metabolites and alteration in the activities of related catalytic enzymes. Thus, manipulation of Treg differentiation through Trp metabolism may provide a potential target for prevention of IBD. The purpose of this review is to highlight the relationship between Trp metabolism and Treg differentiation and the role of this interaction in the pathogenesis of IBD.

1. Introduction

Inflammatory bowel disease (IBD) is an autoimmune disease with high incidence and unclear etiology, mainly including ulcerative colitis (UC), Crohn’s disease (CD), and indeterminate colitis (IC) [1]. UC is an ulcerative bowel disease that only occurs in the colon with a slow and occult onset, and usually, it has a tendency to recur. CD is a chronic, proliferative, and transmural inflammatory disease that can invade any part of the gastrointestinal tract in a discontinuous manner [2]. IBD can seriously lower the quality of lives of patients and significantly increase the risk to colon cancer that result from the proneoplastic effects of chronic intestinal inflammation [3]. A variety of factors, such as genetic, environmental, and microbial factors, are all known to be responsible for the occurrence of IBD [4, 5]. In addition, multiple immune cells like macrophages, dendritic cells (DCs), and lymphoid cells play important roles in the development of IBD, and the turbulence in the differentiation and function of certain T lymphocytes [e.g., regulatory T cells (Tregs)] could contribute to the pathogenesis of IBD [6, 7]. Hence, the thorough understanding of precise regulation of Tregs may be helpful to perceive IBD-related pathology.

Usually, the generation, differentiation, and function of Tregs are significantly affected by the availability of amino acids in the local microenvironment. Depletion of certain essential amino acids from the local milieu results in the generation of Tregs [810]. For example, low concentrations of Trp inhibit T cell growth but enhance Treg production through mTOR-dependent mechanisms [11]. In the gastrointestinal tract, Trp undergoes several different metabolic pathways, and Trp metabolism can influence the differentiation and function of Tregs. Trp catabolism is a tolerogenic effector system in Treg function, and its modulation is thought to function as a general mechanism of action of Tregs that express T-lymphocyte antigen-4 (CTLA-4) [12]. In addition, Trp starvation and Trp catabolites could induce the generation of a regulatory phenotype in naive CD4+ T cells, and previous studies indicated that there is a close relationship between indoleamine 2,3-dioxygenase (IDO) activity and the occurrence of Tregs [1214]. Notably, Trp metabolism disorder is also associated with the development and progression of IBD [1517]. For example, the decreased Trp concentration and increased kynurenine (Kyn) concentration are observed in the IBD patients, and the activity of IDO is also altered as well [1823]. Thus, regulation of Tregs through altering Trp metabolism may provide potential targets for prevention of IBD.

Herein, we provide an in-depth review highlighting the understanding of the regulatory roles of Trp metabolism in Treg differentiation and discuss the availability of manipulating Trp metabolism to Tregs, which further prevent or ameliorate IBD.

2. Tregs and IBD

2.1. The Mechanism of Action of Tregs in IBD

In normal intestinal mucosa, effector cells and Tregs are in a state of dynamic equilibrium. Tregs play an important role in maintaining intestinal homeostasis and can significantly suppress immune responses to maintain autoimmune tolerance and immune stability through multiple ways, such as cell-cell contact or cytokine-dependent mechanism [24].

2.1.1. Cell-Cell Contact Mechanism

CD4+CD25+ Tregs can constitutively express inhibitory regulatory molecules such as cytotoxic CTLA-4, transforming growth factor β (TGF-β) and glucocorticoid-induced TNF receptor (GITR), which can bind to the corresponding receptors and transmit inhibition signals to prevent excessive activation of target immune cells [25]. The binding is capable of inhibiting the expression of IL-2Rα chain and reduce the reactivity of target cells to IL-2, thereby inhibiting the proliferation of effector T cells (Teffs). A variety of ligand-receptors including costimulatory molecules such as CTLA-4, GITR, OX40 (CD134), and lymphocyte activation gene 3 (LAG-3) are involved in this process [2629]. Thus, costimulatory molecule receptors play a significant role in the activation process of Tregs. Studying the mechanisms of their abnormal expression and on how to regulate the signaling pathways may bring new light for a deeper understanding of the mechanism of action of Tregs. In addition, Tregs also express programmed death receptors and ligands, which stabilize the relationship between Tregs and antigen presenting cells (APCs) while promoting the differentiation of inducible regulatory T cells (iTregs) [30]. Moreover, Tregs can downregulate the expression levels of costimulatory molecules CD80 and CD86 on DCs and affect the function of DCs, thereby achieving immunosuppressive effects [31].

2.1.2. Cytokine-Dependent Mechanism

Tregs can achieve their functions by releasing inhibitory cytokines such as interleukin-10 (IL-10), TGF-β, and interleukin-35 (IL-35). High mRNA expression of IL-10 and TGF-β was found in the CD4+CD25+ Tregs in vitro, and CD4+CD25+ Tregs can directly secrete IL-10 and TGF-β under appropriate stimulation [32]. In the CD4+CD45RBhigh T-induced IBD model, TGF-β and IL-10 play an important role in the protective effect of Tregs on IBD. CD4+CD25+ Tregs isolated from TGF-β knockout mice or CD4+CD45RBlow T cells derived from IL-10 knockout mice lost their anti-IBD function [33, 34]. IL-35 is a heterodimeric cytokine comprising Epstein-Barr virus-induced gene 3 (Ebi3) and IL-12 alpha (IL-12α) chain, which was expressed in Foxp3+ Tregs, and Tregs lacking Ebi3 or IL-12α lost their inhibition in the T cell metastatic colitis model. Exogenous IL-35 inhibits T cell proliferation, and the vector encoding IL-35 achieves in vitro inhibitory activity by retroviral transduction into Teffs [35]. More potential mechanisms of action of Tregs in IBD have not been established. Nevertheless, strategies that induce the generation of a regulatory phenotype may be a treatment option in preventing or improving the pathological process of IBD.

2.2. Tregs Are Associated with the Development and Progression of IBD

Available evidence suggests that Tregs play an important role in the development and immune regulation of IBD (Figure 1). It has been demonstrated that Tregs maintain intestinal homeostasis and reduce tissue damage during the progression of IBD by inhibiting the responsiveness of immune cells [36, 37]. Changes in the number, phenotype, and inhibitory function of Tregs may contribute to the pathogenesis of IBD. For example, Tregs from mice deficient in cytotoxic CTLA-4, IL-35, IL-10, or LAG-3 are unable to effectively suppress T cell proliferation and fail to prevent chronic T cell-mediated colitis in vivo [28, 29, 35, 38]. In addition, Tregs in the inflamed mucosa or periphery blood of patients with IBD or animal models are considerably different [39, 40]. For example, Maul et al. found that CD4+CD25+ Tregs were reduced in peripheral blood during the active phase of IBD, while the frequency of Tregs at the mucosal level was higher than healthy controls [41]. Moreover, the frequency of Foxp3+ Tregs was found to be significantly lower in patients with active IBD [42]. In addition, Wang et al. [6] suggest that insufficient Tregs in peripheral blood may be associated with the recurrence of IBD. However, there are still reports that Tregs fail to exert the inhibition function in the context of IBD [43, 44], which might be explained by the individual differences of patients. Therefore, understanding Tregs in IBD can be helpful in monitoring the cellular immune status of IBD patients and opening up new immunotherapeutic approaches for the treatment of IBD.

Mechanistically, Tregs could be considered as therapeutic targets for controlling IBD (Figure 1). Fortunately, many cases of IBD have been successfully cured or alleviated by manipulating Tregs in animal models or patients [4556]. For example, Treg transfer is sufficient to alleviate experimental colitis including IBD, and tTregs and iTregs can work together [5760]. Tregs and IL-10 producing Tr1 cells have the potential to prevent or cure colitis, which is supported by a favourable safety profile in phase I clinical trials [61]. However, it should not be overlooked that Treg-based therapies may be attached by some adverse reactions. For example, excessive Treg activity may simultaneously weaken the protective immunity against pathogens and tumors, which could be reduced by controlling the antigen specificity of Tregs [62]. In addition, the phenotype of the original population and culture conditions are also critical for achieving maximum purity of therapeutic Tregs and ensuring phenotypic stability [63, 64]. Therefore, before developing new strategies to improve Treg function, it is very important to study the detailed mechanism of how Tregs function to limit potential negative side effects. It would be meaningful to explore whether it can be more effective when Treg-based therapy is combined with other therapies.

3. Trp Metabolism in the Differentiation and Function of Tregs

3.1. Trp Metabolism in the Gut

Trp is ubiquitous in many foods and has important physiological functions. Once in the gastrointestinal tract, Trp enters several different metabolic pathways by host or intestinal microbiota [65]. We mainly focus on microbial-mediated degradation, KP, and serotonin pathway. About 4-6% of Trp undergoes microbial degradation, by which intestinal microbes directly convert Trp into several molecules, including indoles and its derivatives [66]. Notably, KP is the major route for Trp catabolism which is mediated by the rate-limiting enzyme IDO1. KP can produce Kyn and its downstream products such as quinolinic acid (QA), niacin, nicotinamide adenine dinucleotide (NAD), and kynurenic acid (KA) [67, 68]. KP metabolites are associated with many biological processes involved in neurotransmission, inflammation, and immune responses. In addition to KP, approximately 1-2% of the dietary Trp is converted to serotonin mediated by tryptophan hydroxylase 1 (TpH1) [69]. There is evidence of the importance of serotonin in regulating gastrointestinal function [70, 71]. Collectively, Trp and its metabolites are essential for the development and maintenance of human and animal health, and all these metabolic pathways work together to maintain the homeostasis.

3.2. Trp Promotes Treg Differentiation through Microbiota-Mediated Degradation

Intestinal microorganisms can directly catabolize Trp into indoles and its derivatives, which play an important role in regulating intestinal immune tolerance [72]. Most indoles and its derivatives, such as indole-3-aldehyde (IAld), indole-3-acid-acetic (IAA), indole-3-propionic acid (IPA), indole-3-acetaldehyde (IAAld), and indoleacrylic acid (IA), are the ligands of aryl hydrocarbon receptor (AhR) (Figure 2).

AhR is a ligand-activated transcription factor that is widely found in immune cells and intestinal epithelial cells, and it is sensitive to certain environmental chemicals and plays an important role in the immune response. Previous work demonstrated the importance of AhR in the differentiation and function of Tregs and Teffs by controlling the production of IL-10 and IL-22 [7377]. Indole and its derivatives infiltrate into intestinal epithelial cells and deposit in the host circulatory system, which could be recognized by immune cells and then activated AhR signaling pathway. It has been well demonstrated that AhR signaling can induce the proliferation of CD4+CD25+Foxp3+ Tregs (Figure 2), which play an indispensable role in adaptive immune tolerance, such as inhibiting the immune function of activated T cells [7880]. Collectively and mechanistically indole and its derivatives derived from Trp regulate the differentiation of Tregs through AhR-ligand-Treg axis, thereby affecting the function of Tregs [8190].

3.3. Trp Promotes Treg Differentiation through KP

KP is the main pathway of Trp catabolism, through which Kyn and other metabolites are produced, such as KA, anthranilic acid (AA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and QA [9193]. Some KP metabolites bind to AhR to induce FoxP3 expression and promote the generation and differentiation of FoxP3+ Tregs [75, 9497] (Figure 2). In addition, 3-HK and the downstream product pyridine-2-3-dioxoic acid can trigger the activity of Tregs. This is consistent with the long-term synergistic effect of Trp deficiency, and high Kyn induced the transformation of naive CD4+ T cells into Tregs [12].

Since IDO is the main enzyme that catalyzes Trp to produce Kyn and other metabolites, the level of IDO expression is important for KP [98, 99]. IDO is expressed in APCs, and its immunoregulatory function is mainly achieved by DCs. IDO suppresses CD4+ T cell function by inhibiting cell proliferation, inducing apoptosis and promoting cell differentiation into Tregs. This is achieved by degrading Trp in the microenvironment where immune responses occur [100, 101]. Francesca et al. found that there was a positive regulatory loop by which Tregs expand their own population through the IDO mechanism. In contrast, the activity of IDO enzyme can be inhibited by 1-Methyl-tryptophan (1-MT) [102, 103]. Therefore, manipulating the activity of IDO or the application of synthetic Kyn could provide an idea for the therapeutic agents of IBD [104]. Later, it was discovered that the relationship between IDO and Tregs was bidirectional [96] (Figure 2). IDO can induce the production of Tregs, and the increase of Tregs can in turn induce the expression of IDO [105]. Given the complex relationship between IDO and Tregs, combining IDO blockade with other immunotherapies may be beneficial to overcome the shortcomings of immune counterregulation.

Likewise, serotonin has been reported to be involved in the pathogenesis of experimental colitis [106, 107]. Therefore, Trp metabolism in the gut is a target that can be considered, such as using either molecules targeting a specific pathway or exploiting bacteria affecting Trp metabolism as probiotics. However, the complicated interactions between microbes and hosts need to be elucidated to achieve better therapeutic effects. Moreover, the metabolic pathways influencing Treg differentiation and function are amenable for modulation in therapeutic settings, thus providing the clinician with potentially valuable tools in the fight against immune-mediated diseases. At the same time, the deviation between diseases and models requires further investigation to refine targets and therapeutic interventions.

4. Modulation of Trp Metabolism in Tregs for IBD

Because Trp metabolism has an important effect on Treg differentiation and function, measures that target Trp metabolism may reduce the severity of IBD, but the possibility deserves further exploration. However, most investigations about effects of Trp metabolism on Treg differentiation were conducted in vitro with mouse Tregs; it is not known if Trp metabolism has similar effects in human Treg differentiation in vitro or in vivo. Indeed, accumulating evidence suggests that Trp promotes intestinal integrity and function, and its metabolism has an important effect on spontaneous and induced IBD models [108111]. Trp and its metabolism show a high correlation with the etiology of IBD (Figure 3). Usually, Trp deficiency could contribute to the development of IBD or aggravate disease activity [17, 112]. Patients with IBD have lower levels of Trp in serum and feces than healthy subjects [18, 19, 113115]. Moreover, some Trp metabolites and metabolic enzymes are also found to be significantly different in patients and healthy volunteers [20, 116118]. Increased Kyn and Kyn/Trp ratios were observed in IBD patients indicating that Trp metabolism along the KP is increased in active IBD [20, 21]. In addition, consumption of Trp metabolites in the intestinal tract may affect the severity of IBD. For example, the concentration of the AhR agonist IAA in feces of IBD patients was significantly reduced [19]. Also, the content of IPA in circulating serum from patients with active colitis was selectively diminished compared to healthy subjects [119, 120]. However, IDO1 levels in the intestine are higher in patients with IBD, although the role of IDO1 in colitis is somewhat controversial [22, 23]. Besides, the content of serotonin in the intestine has changed dramatically in human IBD and animal models of colitis, which suggests that serotonin plays an important role in the occurrence and development of intestinal inflammation [107, 121, 122].

Conversely, dietary supplementation with Trp and Trp metabolites could alleviate symptoms such as weight loss, fecal hemorrhage, and colonic structural damage in experimental mouse colitis (Figure 3) [72, 106]. The protective effect of Trp administration on IBD may be achieved by reducing proinflammatory cytokines and activating apoptosis initiators, while another anticolitis mechanism may be antioxidative or nitration stress [106, 123]. For example, dietary supplementation of 0.5% Trp inhibited colonic inflammatory symptoms and proinflammatory cytokine secretion in mice by activating AhR [124]. Mice or piglets fed a Trp-supplemented diet had reduced inflammation and decreased severity of dextran sodium sulfate- (DSS-) induced colitis [112, 123, 125], whereas mice fed a low­Trp diet became susceptible to chemically induced inflammation. In addition, the administration of Trp metabolites, such as Kyn, indole, and IPA, were observed to ameliorate colonic inflammation in mice [119, 120, 126]. Simultaneously, manipulation of IDO1 activity has great potential as treatment for IBD [127]. Moreover, indirect manipulation of the gut microbiota affecting Trp metabolism could be considered to develop new therapeutic drugs that target IBD individuals. For example, the use of Lactobacillus (a kind of bacterium that degrades Trp into AhR agonists) lightened the severity of colitis in mice, and probiotics can serve as a supportive therapy for patients with intestinal disorders [125]. Collectively, Trp and its metabolites can be used as biomarkers and promising targets for the treatment of IBD, but further investigation is necessary to validate the effectiveness and feasibility [17, 128]. Therefore, the levels of Trp and its metabolites in patients with IBD need to be analyzed to assess their impact on the progression of IBD.

Collectively, patients with IBD have lower Trp levels, higher Kyn levels, and elevated IDO expression. This is positively correlated with reduced Tregs in IBD. Thus, manipulation of Treg differentiation through these metabolites may be a promising strategy for the treatment of IBD.

5. Conclusions and Future Perspectives

In summary, Tregs are associated with the development of IBD and strategies to manipulate Treg differentiation by Trp metabolism may lead to new therapeutic approaches for the treatment of IBD (Figure 4). Therefore, it is important for researchers to elucidate the exact regulatory mechanism of Trp metabolism in Tregs during the development of IBD. Fortunately, Trp and its metabolites are known to be beneficial for IBD patients and related animal models, although it is unclear whether they regulate the progression of IBD by precisely affecting the differentiation and function of Tregs. Considering that other metabolic pathways also regulate the proliferation and function of Tregs (such as the CD39-CD73-adenosine pathway), combining Trp metabolism with other metabolic pathways will be a better strategy for preventing IBD-related pathologies. At the same time, the manipulation of metabolic pathways in Tregs can be combined with traditional drugs that affect Treg function to achieve better preventive and therapeutic effects. But at present, very satisfactory results have not been achieved in the treatment of IBD. Therefore, an in-depth study of the role of immune cells and amino acid metabolism in IBD will provide a more meaningful basis for the early diagnosis, effective treatment, and progression evaluation of IBD, which will be a serious challenge in the medical field.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Xueyan Ding, Peng Bin, and Guoqiang Zhu conceptualized the idea. Xueyan Ding and Peng Bin performed literature search and wrote and revised the manuscript. Xueyan Ding, Peng Bin, Wenwen Wu, Yajie Chang, and Guoqiang Zhu revised the manuscript. All authors agreed to the final version of the manuscript. Xueyan Ding and Peng Bin contributed equally to this work.

Acknowledgments

This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (grant KYCX19_2116), the Programs from Ministry of Science and Technology of the People’s Republic of China (grants 2016YFD0500905 and 2017YFD0500203), and the Chinese National Science Foundation (grants 30771603, 31072136, 31270171, 31502075, and 31672579).

References

  1. M. Guindi and R. H. Riddell, “Indeterminate colitis,” Journal of Clinical Pathology, vol. 57, no. 12, pp. 1233–1244, 2004. View at: Publisher Site | Google Scholar
  2. R. Hodson, “Inflammatory bowel disease,” Nature, vol. 540, no. 7634, p. S97, 2016. View at: Publisher Site | Google Scholar
  3. R. W. Stidham and P. D. R. Higgins, “Colorectal cancer in inflammatory bowel disease,” Clinics in Colon and Rectal Surgery, vol. 31, no. 3, pp. 168–178, 2018. View at: Publisher Site | Google Scholar
  4. J. Wehkamp, M. Götz, K. Herrlinger, W. Steurer, and E. F. Stange, “Inflammatory bowel Disease: Crohn’s disease and ulcerative colitis,” Deutsches Aerzteblatt Online, vol. 113, no. 5, pp. 72–82, 2016. View at: Publisher Site | Google Scholar
  5. N. Goyal, A. Rana, A. Ahlawat, K. R. V. Bijjem, and P. Kumar, “Animal models of inflammatory bowel disease: a review,” Inflammopharmacology, vol. 22, no. 4, pp. 219–233, 2014. View at: Publisher Site | Google Scholar
  6. Y. Wang, X. P. Liu, Z. B. Zhao, J. H. Chen, and C. G. Yu, “Expression of CD4+ forkhead box P 3 (FOXP3)+ regulatory T cells in inflammatory bowel disease,” Journal of Digestive Diseases, vol. 12, no. 4, pp. 286–294, 2011. View at: Publisher Site | Google Scholar
  7. G. Muzes, B. Molnar, and F. Sipos, “Regulatory T cells in inflammatory bowel diseases and colorectal cancer,” World Journal of Gastroenterology, vol. 18, no. 40, pp. 5688–5694, 2012. View at: Publisher Site | Google Scholar
  8. H. Hörig, G. C. Spagnoli, L. Filgueira et al., “Exogenous glutamine requirement is confined to late events of T cell activation,” Journal of Cellular Biochemistry, vol. 53, no. 4, pp. 343–351, 1993. View at: Publisher Site | Google Scholar
  9. M. Munder, K. Eichmann, and M. Modolell, “Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype,” The Journal of Immunology, vol. 160, no. 11, pp. 5347–5354, 1998. View at: Google Scholar
  10. M. Munder, “Suppression of T-cell functions by human granulocyte arginase,” Blood, vol. 108, no. 5, pp. 1627–1634, 2006. View at: Publisher Site | Google Scholar
  11. R. Metz, S. Rust, J. B. DuHadaway et al., “IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan,” OncoImmunology, vol. 1, no. 9, pp. 1460–1468, 2014. View at: Publisher Site | Google Scholar
  12. F. Fallarino, U. Grohmann, S. You et al., “The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells,” Journal of Immunology, vol. 176, no. 11, pp. 6752–6761, 2006. View at: Publisher Site | Google Scholar
  13. A. Curti, S. Pandolfi, B. Valzasina et al., “Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells,” Blood, vol. 109, no. 7, pp. 2871–2877, 2006. View at: Publisher Site | Google Scholar
  14. F. Li, R. Zhang, S. Li, and J. Liu, “IDO1: an important immunotherapy target in cancer treatment,” International Immunopharmacology, vol. 47, pp. 70–77, 2017. View at: Publisher Site | Google Scholar
  15. W. W. Wang, S. Y. Qiao, and D. F. Li, “Amino acids and gut function,” Amino Acids, vol. 37, no. 1, pp. 105–110, 2009. View at: Publisher Site | Google Scholar
  16. S. Chen, M. Wang, L. Yin et al., “Effects of dietary tryptophan supplementation in the acetic acid-induced colitis mouse model,” Food & Function, vol. 9, no. 8, pp. 4143–4152, 2018. View at: Publisher Site | Google Scholar
  17. S. Nikolaus, B. Schulte, N. Al-Massad et al., “Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases,” Gastroenterology, vol. 153, no. 6, pp. 1504–1516.e2, 2017. View at: Publisher Site | Google Scholar
  18. T. Hisamatsu, S. Okamoto, M. Hashimoto et al., “Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease,” Plo S one, vol. 7, no. 1, p. e31131, 2012. View at: Publisher Site | Google Scholar
  19. B. Lamas, M. L. Richard, V. Leducq et al., “CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands,” Nature Medicine, vol. 22, no. 6, pp. 598–605, 2016. View at: Publisher Site | Google Scholar
  20. A. M. Wolf, D. Wolf, H. Rumpold et al., “Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease,” Clinical Immunology, vol. 113, no. 1, pp. 47–55, 2004. View at: Publisher Site | Google Scholar
  21. M. A. Sofia, M. A. Ciorba, K. Meckel et al., “Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis,” Inflammatory Bowel Diseases, vol. 24, no. 7, pp. 1471–1480, 2018. View at: Publisher Site | Google Scholar
  22. G. Matteoli, E. Mazzini, I. D. Iliev et al., “Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction,” Gut, vol. 59, no. 5, pp. 595–604, 2010. View at: Publisher Site | Google Scholar
  23. M. A. Ciorba, E. E. Bettonville, K. G. McDonald et al., “Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis,” Journal of Immunology, vol. 184, no. 7, pp. 3907–3916, 2010. View at: Publisher Site | Google Scholar
  24. P.-F. Hou, L.-J. Zhu, Y. Pan, X.-C. Sun, and J. Pu, “Relation entre les cellules T regulatrices et la radiotherapie,” Cancer/Radiothérapie, vol. 24, no. 1, pp. 81–84, 2020. View at: Publisher Site | Google Scholar
  25. B. Langhans, H. D. Nischalke, B. Krämer et al., “Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma,” Cancer Immunology, Immunotherapy, vol. 68, no. 12, pp. 2055–2066, 2019. View at: Publisher Site | Google Scholar
  26. F. Fallarino, U. Grohmann, K. W. Hwang et al., “Modulation of tryptophan catabolism by regulatory T cells,” Nature Immunology, vol. 4, no. 12, pp. 1206–1212, 2003. View at: Publisher Site | Google Scholar
  27. K. Uraushihara, T. Kanai, K. Ko et al., “Regulation of murine inflammatory bowel disease by CD25+ and CD25- CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells,” The Journal of Immunology, vol. 171, no. 2, pp. 708–716, 2014. View at: Publisher Site | Google Scholar
  28. S. Read, V. Malmstrom, and F. Powrie, “Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation,” The Journal of Experimental Medicine, vol. 192, no. 2, pp. 295–302, 2000. View at: Publisher Site | Google Scholar
  29. C. T. Huang, C. J. Workman, D. Flies et al., “Role of LAG-3 in regulatory T cells,” Immunity, vol. 21, no. 4, pp. 503–513, 2004. View at: Publisher Site | Google Scholar
  30. S. Dai, R. Jia, X. Zhang, Q. Fang, and L. Huang, “The PD-1/PD-Ls pathway and autoimmune diseases,” Cellular Immunology, vol. 290, no. 1, pp. 72–79, 2014. View at: Publisher Site | Google Scholar
  31. X. Chen, Y. Du, Q. Hu, and Z. M. Huang, “Tumor-derived CD4 + CD25 + regulatory T cells inhibit dendritic cells function by CTLA-4,” Pathology - Research and Practice, vol. 213, no. 3, pp. 245–249, 2017. View at: Publisher Site | Google Scholar
  32. M. C. E. Guedes, M. J. Arroz, C. Martins, M. Angelo-Dias, R. D. Proença, and L. M. Borrego, “Regulatory T cells and IL-17A levels in noninfectious uveitis,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 258, no. 6, pp. 1269–1278, 2020. View at: Publisher Site | Google Scholar
  33. M. M. Shull, I. Ormsby, A. B. Kier et al., “Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease,” Nature, vol. 359, no. 6397, pp. 693–699, 1992. View at: Publisher Site | Google Scholar
  34. C. Asseman, S. Mauze, M. W. Leach, R. L. Coffman, and F. Powrie, “An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation,” Journal of Experimental Medicine, vol. 190, no. 7, pp. 995–1004, 1999. View at: Publisher Site | Google Scholar
  35. L. W. Collison, C. J. Workman, T. T. Kuo et al., “The inhibitory cytokine IL-35 contributes to regulatory T-cell function,” Nature, vol. 450, no. 7169, pp. 566–569, 2007. View at: Publisher Site | Google Scholar
  36. M. . C. Fantini, A. Rizzo, D. Fina et al., “IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells,” European Journal of Immunology, vol. 37, no. 11, pp. 3155–3163, 2007. View at: Publisher Site | Google Scholar
  37. A. Yamada, R. Arakaki, M. Saito, T. Tsunematsu, Y. Kudo, and N. Ishimaru, “Role of regulatory T cell in the pathogenesis of inflammatory bowel disease,” World Journal of Gastroenterology, vol. 22, no. 7, pp. 2195–2205, 2016. View at: Publisher Site | Google Scholar
  38. E. G. Schmitt, D. Haribhai, J. B. Williams et al., “IL-10 produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-iTregs during immunotherapy,” The Journal of Immunology, vol. 189, no. 12, pp. 5638–5648, 2012. View at: Publisher Site | Google Scholar
  39. C. G. Mayne and C. B. Williams, “Induced and natural regulatory T cells in the development of inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 19, no. 8, pp. 1772–1788, 2013. View at: Publisher Site | Google Scholar
  40. M. C. Kullberg, V. Hay, A. . W. Cheever et al., “TGF-β1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation,” European Journal of Immunology, vol. 35, no. 10, pp. 2886–2895, 2005. View at: Publisher Site | Google Scholar
  41. J. Maul, C. Loddenkemper, P. Mundt et al., “Peripheral and Intestinal Regulatory CD4+CD25high.T Cells in Inflammatory Bowel Disease,” Gastroenterology, vol. 128, no. 7, pp. 1868–1878, 2005. View at: Publisher Site | Google Scholar
  42. M. Takahashi, K. Nakamura, K. Honda et al., “An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis,” Digestive Diseases and Sciences, vol. 51, no. 4, pp. 677–686, 2006. View at: Publisher Site | Google Scholar
  43. N. Holmén, A. Lundgren, S. Lundin et al., “Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity,” Inflammatory Bowel Diseases, vol. 12, no. 6, pp. 447–456, 2006. View at: Publisher Site | Google Scholar
  44. Q. T. Yu, M. Saruta, A. Avanesyan, P. R. Fleshner, A. H. Banham, and K. A. Papadakis, “Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis,” Inflammatory Bowel Diseases, vol. 13, no. 2, pp. 191–199, 2007. View at: Publisher Site | Google Scholar
  45. F. Powrie, M. W. Leach, S. Mauze, L. B. Caddie, and R. L. Coffman, “Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17scid mice,” International Immunology, vol. 5, no. 11, pp. 1461–1471, 1993. View at: Publisher Site | Google Scholar
  46. F. Powrie, R. Correa-Oliveira, S. Mauze, and R. L. Coffman, “Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity,” The Journal of Experimental Medicine, vol. 179, no. 2, pp. 589–600, 1994. View at: Publisher Site | Google Scholar
  47. C. Mottet, H. H. Uhlig, and F. Powrie, “Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells,” Journal of Immunology (Baltimore, Md. : 1950), vol. 170, no. 8, pp. 3939–3943, 2003. View at: Publisher Site | Google Scholar
  48. R. Hontecillas and J. Bassaganya-Riera, “Peroxisome proliferator-activated receptor γ is required for regulatory CD4+ T cell-mediated protection against colitis,” Journal of Immunology, vol. 178, no. 5, pp. 2940–2949, 2007. View at: Publisher Site | Google Scholar
  49. D. Ishikawa, A. Okazawa, D. Corridoni et al., “Tregs are dysfunctional in vivo in a spontaneous murine model of Crohn's disease,” Mucosal Immunology, vol. 6, no. 2, pp. 267–275, 2013. View at: Publisher Site | Google Scholar
  50. M. Mohammadnia-Afrouzi, A. Zavaran Hosseini, A. Khalili, S. Abediankenari, V. Hosseini, and I. Maleki, “Decrease of CD4+CD25+CD127lowFoxP3+regulatory T cells with impaired suppressive function in untreated ulcerative colitis patients,” Autoimmunity, vol. 48, no. 8, pp. 556–561, 2015. View at: Publisher Site | Google Scholar
  51. M. C. Fantini and G. Monteleone, “Update on the therapeutic efficacy of Tregs in IBD,” Inflammatory Bowel Diseases, vol. 23, no. 10, pp. 1682–1688, 2017. View at: Publisher Site | Google Scholar
  52. J. Cho, S. Kim, D. H. Yang et al., “Mucosal immunity related to FOXP3+ regulatory T cells, Th17 cells and cytokines in pediatric inflammatory bowel disease,” Journal of Korean medical science, vol. 33, no. 52, 2018. View at: Publisher Site | Google Scholar
  53. Y. Lu, N. M. Kim, Y. W. Jiang et al., “Cambogin suppresses dextran sulphate sodium-induced colitis by enhancing Treg cell stability and function,” British Journal of Pharmacology, vol. 175, no. 7, pp. 1085–1099, 2018. View at: Publisher Site | Google Scholar
  54. R. N. Fedorak, A. Gangl, C. O. Elson et al., “Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease,” Gastroenterology, vol. 119, no. 6, pp. 1473–1482, 2000. View at: Publisher Site | Google Scholar
  55. A. Majowicz, S. van der Marel, A. A. te Velde et al., “Murine CD4+CD25- cells activated in vitro with PMA/ionomycin and anti-CD3 acquire regulatory function and ameliorate experimental colitis in vivo,” BMC gastroenterology, vol. 12, no. 1, 2012. View at: Publisher Site | Google Scholar
  56. P. Desreumaux, A. Foussat, M. Allez et al., “Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease,” Gastroenterology, vol. 143, no. 5, pp. 1207–1217.e2, 2012. View at: Publisher Site | Google Scholar
  57. N. Ohkura, M. Hamaguchi, H. Morikawa et al., “T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development,” Immunity, vol. 37, no. 5, pp. 785–799, 2012. View at: Publisher Site | Google Scholar
  58. F. Karlsson, N. E. Martinez, L. Gray, S. Zhang, I. Tsunoda, and M. B. Grisham, “Therapeutic evaluation of ex vivo-generated versus natural regulatory T-cells in a mouse model of chronic gut inflammation,” Inflammatory Bowel Diseases, vol. 19, no. 11, pp. 2282–2294, 2013. View at: Publisher Site | Google Scholar
  59. D. Haribhai, W. Lin, B. Edwards et al., “A central role for induced regulatory T cells in tolerance induction in experimental colitis,” Journal of Immunology (Baltimore, Md. : 1950), vol. 182, no. 6, pp. 3461–3468, 2009. View at: Publisher Site | Google Scholar
  60. C. Asseman, S. Fowler, and F. Powrie, “Control of experimental inflammatory bowel disease by regulatory T cells,” American Journal of Respiratory and Critical Care Medicine, vol. 162, supplement_3, pp. S185–S189, 2000. View at: Publisher Site | Google Scholar
  61. P. Trzonkowski, M. Bieniaszewska, J. Juścińska et al., “First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells,” Clinical Immunology, vol. 133, no. 1, pp. 22–26, 2009. View at: Publisher Site | Google Scholar
  62. A. Cebula, M. Seweryn, G. A. Rempala et al., “Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota,” Nature, vol. 497, no. 7448, pp. 258–262, 2013. View at: Publisher Site | Google Scholar
  63. M. Feuerer, J. A. Hill, K. Kretschmer, H. von Boehmer, D. Mathis, and C. Benoist, “Genomic definition of multiple ex vivo regulatory T cell subphenotypes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 13, pp. 5919–5924, 2010. View at: Publisher Site | Google Scholar
  64. J. B. Canavan, C. Scottà, A. Vossenkämper et al., “Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease,” Gut, vol. 65, no. 4, pp. 584–594, 2016. View at: Publisher Site | Google Scholar
  65. J. D. Fernstrom, “A perspective on the safety of supplemental tryptophan based on its metabolic fates,” The Journal of nutrition, vol. 146, no. 12, pp. 2601s–2608s, 2016. View at: Publisher Site | Google Scholar
  66. M. T. Yokoyama and J. R. Carlson, “Microbial metabolites of tryptophan in the intestinal tract with special reference to skatole,” The American Journal of Clinical Nutrition, vol. 32, no. 1, pp. 173–178, 1979. View at: Publisher Site | Google Scholar
  67. I. Cervenka, L. Z. Agudelo, and J. L. Ruas, “Kynurenines: tryptophan's metabolites in exercise, inflammation, and mental health,” Science, vol. 357, no. 6349, article eaaf9794, 2017. View at: Publisher Site | Google Scholar
  68. P. J. Kennedy, J. F. Cryan, T. G. Dinan, and G. Clarke, “Kynurenine pathway metabolism and the microbiota-gut-brain axis,” Neuropharmacology, vol. 112, Part B, pp. 399–412, 2017. View at: Publisher Site | Google Scholar
  69. D. A. Bender, “Biochemistry of tryptophan in health and disease,” Molecular Aspects of Medicine, vol. 6, no. 2, pp. 101–197, 1983. View at: Publisher Site | Google Scholar
  70. J. Gao, K. Xu, H. Liu et al., “Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism,” Frontiers in cellular and infection microbiology, vol. 8, p. 13, 2018. View at: Publisher Site | Google Scholar
  71. T. Nedi, P. J. White, I. M. Coupar, and H. R. Irving, “Effect of the 5-HT4 receptor agonist tegaserod on the expression of GRK2 and GRK6 in the rat gastrointestinal tract,” BMC research notes, vol. 11, no. 1, p. 362, 2018. View at: Publisher Site | Google Scholar
  72. D. Keszthelyi, F. J. Troost, and A. A. M. Masclee, “Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function,” Neurogastroenterology and Motility, vol. 21, no. 12, pp. 1239–1249, 2009. View at: Publisher Site | Google Scholar
  73. L. Apetoh, F. J. Quintana, C. Pot et al., “The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27,” Nature Immunology, vol. 11, no. 9, pp. 854–861, 2010. View at: Publisher Site | Google Scholar
  74. R. Gandhi, D. Kumar, E. J. Burns et al., “Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells,” Nature Immunology, vol. 11, no. 9, pp. 846–853, 2010. View at: Publisher Site | Google Scholar
  75. F. J. Quintana, A. S. Basso, A. H. Iglesias et al., “Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor,” Nature, vol. 453, no. 7191, pp. 65–71, 2008. View at: Publisher Site | Google Scholar
  76. A. Yeste, I. D. Mascanfroni, M. Nadeau et al., “IL-21 induces IL-22 production in CD4+ T cells,” Nature communications, vol. 5, no. 1, 2014. View at: Publisher Site | Google Scholar
  77. I. D. Mascanfroni, M. C. Takenaka, A. Yeste et al., “Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α,” Nature Medicine, vol. 21, no. 6, pp. 638–646, 2015. View at: Publisher Site | Google Scholar
  78. Q. Lv, C. Shi, S. Qiao et al., “Alpinetin exerts anti-colitis efficacy by activating AhR, regulating miR-302/DNMT-1/CREB signals, and therefore promoting Treg differentiation,” Cell death & disease, vol. 9, no. 9, p. 890, 2018. View at: Publisher Site | Google Scholar
  79. J. Xue, Q. Zhao, V. Sharma et al., “Aryl hydrocarbon receptor ligands in cigarette smoke induce production of interleukin-22 to promote pancreatic fibrosis in models of chronic pancreatitis,” Gastroenterology, vol. 151, no. 6, pp. 1206–1217, 2016. View at: Publisher Site | Google Scholar
  80. R. Fuertig, D. Azzinnari, G. Bergamini et al., “Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: both effects are reversed by inhibition of indoleamine 2,3-dioxygenase,” Brain, Behavior, and Immunity, vol. 54, pp. 59–72, 2016. View at: Publisher Site | Google Scholar
  81. Z. Huang, Y. Jiang, Y. Yang et al., “3,3-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction,” Molecular Immunology, vol. 53, no. 4, pp. 335–344, 2013. View at: Publisher Site | Google Scholar
  82. J. A. Goettel, R. Gandhi, J. E. Kenison et al., “AHR activation is protective against colitis driven by T cells in humanized mice,” Cell Reports, vol. 17, no. 5, pp. 1318–1329, 2016. View at: Publisher Site | Google Scholar
  83. W. H. Kim, H. S. Lillehoj, and W. Min, “Indole treatment alleviates intestinal tissue damage induced by chicken coccidiosis through activation of the aryl hydrocarbon receptor,” Frontiers in immunology, vol. 10, 2019. View at: Publisher Site | Google Scholar
  84. A. K. Ehrlich, J. M. Pennington, W. H. Bisson, S. K. Kolluri, and N. I. Kerkvliet, “TCDD, FICZ, and other high affinity AhR ligands dose-dependently determine the fate of CD4+ T cell differentiation,” Toxicological Sciences, vol. 161, no. 2, pp. 310–320, 2018. View at: Publisher Site | Google Scholar
  85. A. K. Ehrlich and N. I. Kerkvliet, “Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases?” Current opinion in Toxicology, vol. 2, pp. 72–78, 2017. View at: Publisher Site | Google Scholar
  86. S. Punj, P. Kopparapu, H. S. Jang et al., “Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease,” PloS one, vol. 9, no. 2, p. e88726, 2014. View at: Publisher Site | Google Scholar
  87. A. K. Ehrlich, J. M. Pennington, X. Wang et al., “Activation of the aryl hydrocarbon receptor by 10-cl-BBQ prevents insulitis and effector T cell development independently of Foxp3+ regulatory T cells in nonobese diabetic mice,” The Journal of Immunology, vol. 196, no. 1, pp. 264–273, 2015. View at: Publisher Site | Google Scholar
  88. P. B. Busbee, M. Rouse, M. Nagarkatti, and P. S. Nagarkatti, “Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders,” Nutrition Reviews, vol. 71, no. 6, pp. 353–369, 2013. View at: Publisher Site | Google Scholar
  89. N. I. Kerkvliet, L. B. Steppan, W. Vorachek et al., “Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes,” Immunotherapy, vol. 1, no. 4, pp. 539–547, 2009. View at: Publisher Site | Google Scholar
  90. N. B. Marshall and N. I. Kerkvliet, “Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells,” Annals of the New York Academy of Sciences, vol. 1183, no. 1, pp. 25–37, 2010. View at: Publisher Site | Google Scholar
  91. P. Terness, T. M. Bauer, L. Röse et al., “Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites,” The Journal of Experimental Medicine, vol. 196, no. 4, pp. 447–457, 2002. View at: Publisher Site | Google Scholar
  92. A. Curti, S. Trabanelli, C. Onofri et al., “Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells,” Haematologica, vol. 95, no. 12, pp. 2022–2030, 2010. View at: Publisher Site | Google Scholar
  93. Y. Chen and G. J. Guillemin, “Kynurenine pathway metabolites in humans: disease and healthy states,” International Journal of Tryptophan Research, vol. 2, pp. 1–19, 2009. View at: Publisher Site | Google Scholar
  94. H. Kawasaki, H. W. Chang, H. C. Tseng et al., “A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor,” Allergy, vol. 69, no. 4, pp. 445–452, 2014. View at: Publisher Site | Google Scholar
  95. M. Veldhoen, K. Hirota, A. M. Westendorf et al., “The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins,” Nature, vol. 453, no. 7191, pp. 106–109, 2008. View at: Publisher Site | Google Scholar
  96. P. Puccetti and U. Grohmann, “IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation,” Nature Reviews. Immunology, vol. 7, no. 10, pp. 817–823, 2007. View at: Publisher Site | Google Scholar
  97. J. D. Mezrich, J. H. Fechner, X. Zhang, B. P. Johnson, W. J. Burlingham, and C. A. Bradfield, “An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells,” Journal of Immunology, vol. 185, no. 6, pp. 3190–3198, 2010. View at: Publisher Site | Google Scholar
  98. S. Li, X. Han, N. Lyu et al., “Mechanism and prognostic value of indoleamine 2,3-dioxygenase 1 expressed in hepatocellular carcinoma,” Cancer Science, vol. 109, no. 12, pp. 3726–3736, 2018. View at: Publisher Site | Google Scholar
  99. L. I. Greene, T. C. Bruno, J. L. Christenson et al., “A role for tryptophan-2,3-dioxygenase in CD8 T-cell suppression and evidence of tryptophan catabolism in breast cancer patient plasma,” Molecular Cancer Research, vol. 17, no. 1, pp. 131–139, 2019. View at: Publisher Site | Google Scholar
  100. N. J. C. King and S. R. Thomas, “Molecules in focus: indoleamine 2,3-dioxygenase,” The International Journal of Biochemistry & Cell Biology, vol. 39, no. 12, pp. 2167–2172, 2007. View at: Publisher Site | Google Scholar
  101. A. Curti, S. Trabanelli, V. Salvestrini, M. Baccarani, and R. M. Lemoli, “The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology,” Blood, vol. 113, no. 11, pp. 2394–2401, 2009. View at: Publisher Site | Google Scholar
  102. M. D. Sharma, D. Y. Hou, Y. Liu et al., “Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes,” Blood, vol. 113, no. 24, pp. 6102–6111, 2009. View at: Publisher Site | Google Scholar
  103. M. D. Sharma, D. Y. Hou, B. Baban et al., “Reprogrammed Foxp3+ Regulatory T Cells Provide Essential Help to Support Cross-presentation and CD8+ T Cell Priming in Naive Mice,” Immunity, vol. 33, no. 6, pp. 942–954, 2010. View at: Publisher Site | Google Scholar
  104. F. Fallarino, U. Grohmann, S. You et al., “Tryptophan catabolism generates autoimmune-preventive regulatory T cells,” Transplant Immunology, vol. 17, no. 1, pp. 58–60, 2006. View at: Publisher Site | Google Scholar
  105. B. Sawitzki, C. I. Kingsley, V. Oliveira, M. Karim, M. Herber, and K. J. Wood, “IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo,” The Journal of Experimental Medicine, vol. 201, no. 12, pp. 1925–1935, 2005. View at: Publisher Site | Google Scholar
  106. T. Shizuma, H. Mori, and N. Fukuyama, “Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis,” The Turkish Journal of Gastroenterology, vol. 24, no. 1, pp. 30–35, 2013. View at: Publisher Site | Google Scholar
  107. J.-E. Ghia, N. Li, H. Wang et al., “Serotonin has a key role in pathogenesis of experimental colitis,” Gastroenterology, vol. 137, no. 5, pp. 1649–1660, 2009. View at: Publisher Site | Google Scholar
  108. Y. Liu, X. Wang, and C. A. Hu, “Therapeutic potential of amino acids in inflammatory bowel disease,” Nutrients, vol. 9, no. 9, p. 920, 2017. View at: Publisher Site | Google Scholar
  109. P. Rutgeerts, S. Vermeire, and G. Van Assche, “Biological therapies for inflammatory bowel diseases,” Gastroenterology, vol. 136, no. 4, pp. 1182–1197, 2009. View at: Publisher Site | Google Scholar
  110. J. Yin, M. Conlon, and S. W. Kim, “Nutrients and inflammatory diseases,” Mediators of inflammation, vol. 2017, Article ID 6134909, 2 pages, 2017. View at: Publisher Site | Google Scholar
  111. X. Bao, Z. Feng, J. Yao, T. Li, and Y. Yin, “Roles of Dietary Amino Acids and Their Metabolites in Pathogenesis of Inflammatory Bowel Disease,” Mediators of inflammation, vol. 2017, Article ID 6869259, 9 pages, 2017. View at: Publisher Site | Google Scholar
  112. T. Hashimoto, T. Perlot, A. Rehman et al., “ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation,” Nature, vol. 487, no. 7408, pp. 477–481, 2012. View at: Publisher Site | Google Scholar
  113. M. Ooi, S. Nishiumi, T. Yoshie et al., “GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis,” Inflammation research, vol. 60, no. 9, pp. 831–840, 2011. View at: Publisher Site | Google Scholar
  114. Y. Shiomi, S. Nishiumi, M. Ooi et al., “GCMS-based metabolomic study in mice with colitis induced by dextran sulfate sodium,” Inflammatory Bowel Diseases, vol. 17, no. 11, pp. 2261–2274, 2011. View at: Publisher Site | Google Scholar
  115. R. Schicho, A. Nazyrova, R. Shaykhutdinov, G. Duggan, H. J. Vogel, and M. Storr, “Quantitative metabolomic profiling of serum and urine in DSS-induced ulcerative colitis of mice by 1H NMR spectroscopy,” Journal of Proteome Research, vol. 9, no. 12, pp. 6265–6273, 2010. View at: Publisher Site | Google Scholar
  116. C. M. Forrest, P. Youd, A. Kennedy, S. R. Gould, L. G. Darlington, and T. W. Stone, “Purine, kynurenine, neopterin and lipid peroxidation levels in inflammatory bowel disease,” Journal of Biomedical Science, vol. 9, no. 5, pp. 436–442, 2002. View at: Publisher Site | Google Scholar
  117. C. M. Forrest, S. R. Gould, L. G. Darlington, and T. W. Stone, “Levels of purine, kynurenine and lipid peroxidation products in patients with inflammatory bowel disease,” Advances in Experimental Medicine and Biology, vol. 527, pp. 395–400, 2003. View at: Publisher Site | Google Scholar
  118. L. Zhou, H. Chen, Q. Wen, and Y. Zhang, “Indoleamine 2,3-dioxygenase expression in human inflammatory bowel disease,” European Journal of Gastroenterology & Hepatology, vol. 24, no. 6, pp. 695–701, 2012. View at: Publisher Site | Google Scholar
  119. E. E. Alexeev, J. M. Lanis, D. J. Kao et al., “Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor,” The American Journal of Pathology, vol. 188, no. 5, pp. 1183–1194, 2018. View at: Publisher Site | Google Scholar
  120. C. M. Whitfield-Cargile, N. D. Cohen, R. S. Chapkin et al., “The microbiota-derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy,” Gut Microbes, vol. 7, no. 3, pp. 246–261, 2016. View at: Publisher Site | Google Scholar
  121. S. C. Bischoff, R. Mailer, O. Pabst et al., “Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice,” American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 296, no. 3, pp. G685–G695, 2009. View at: Publisher Site | Google Scholar
  122. A. Rapalli, S. Bertoni, V. Arcaro et al., “Dual role of endogenous serotonin in 2,4,6-trinitrobenzene sulfonic acid-induced colitis,” Frontiers in pharmacology, vol. 7, 2016. View at: Publisher Site | Google Scholar
  123. C. J. Kim, J. A. Kovacs-Nolan, C. Yang, T. Archbold, M. Z. Fan, and Y. Mine, “L-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis,” The Journal of Nutritional Biochemistry, vol. 21, no. 6, pp. 468–475, 2010. View at: Publisher Site | Google Scholar
  124. J. Islam, S. Sato, K. Watanabe et al., “Dietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice,” The Journal of Nutritional Biochemistry, vol. 42, pp. 43–50, 2017. View at: Publisher Site | Google Scholar
  125. T. Zelante, R. G. Iannitti, C. Cunha et al., “Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22,” Immunity, vol. 39, no. 2, pp. 372–385, 2013. View at: Publisher Site | Google Scholar
  126. J. M. Lanis, E. E. Alexeev, V. F. Curtis et al., “Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia,” Mucosal Immunology, vol. 10, no. 5, pp. 1133–1144, 2017. View at: Publisher Site | Google Scholar
  127. A. Acovic, M. Gazdic, N. Jovicic et al., “Role of indoleamine 2,3-dioxygenase in pathology of the gastrointestinal tract,” Therapeutic advances in gastroenterology, vol. 11, p. 175628481881533, 2018. View at: Publisher Site | Google Scholar
  128. L. Etienne-Mesmin, B. Chassaing, and A. T. Gewirtz, “Tryptophan: a gut microbiota-derived metabolites regulating inflammation,” World Journal of Gastrointestinal Pharmacology and Therapeutics, vol. 8, no. 1, pp. 7–9, 2017. View at: Publisher Site | Google Scholar

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