Abstract

Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.

摘要

色氨酸是一种必需氨基酸，在肠道中通过三种不同的代谢途径。肠道微生物群中的吲哚途径、肠嗜铬细胞中的血清素系统以及免疫细胞和肠壁中的犬尿氨酸途径是肠道中色氨酸代谢的三个臂。临床、体内和体外研究表明，这些武器中的每一个对 IBD 都有显着影响。这篇综述解释了色氨酸的不同代谢物如何参与 IBD 和结直肠癌的病理生理学，这是 IBD 的主要并发症。吲哚代谢物可缓解结肠炎并预防结肠直肠癌，而血清素组则遵循更复杂和受体特异性的模式。吲哚代谢物和犬尿氨酸与芳烃受体 (AHR) 相互作用以诱导 T 调节细胞分化、限制 Th17 和 Th1 反应并产生抗炎介质。Kynurenine 减少肿瘤浸润性 CD8+ 细胞并介导肿瘤细胞免疫逃避。血清素系统还增加了结直肠癌细胞的增殖和转移，而吲哚代谢物可以显着降低结直肠癌的生长。色氨酸代谢物的靶向治疗可改善 IBD 和结直肠癌的治疗，例如补充吲哚代谢物如 indole-3-carbinol (I3C)、抑制犬尿氨酸单加氧酶 (KMO) 和选择性刺激或抑制特定 5-羟色胺能受体可减轻结肠炎. 此外，将解释如何补充吲哚代谢物，抑制吲哚胺 2,3-双加氧酶 1 (IDO1)、KMO 和血清素受体可以预防结直肠癌。此外，还将深入讨论色氨酸代谢物和细胞内信号通路之间的广泛分子相互作用。