PDF(Pubmed)
Abstract：
Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.
摘要：
色氨酸（Trp）是一种必需氨基酸，其新陈代谢是肠道稳态的关键看门人。然而，它的系统性影响，特别是动脉粥样硬化，仍然未知。在这里，我们显示高脂肪饮食（HFD）增加肠道吲哚胺2，3-双加氧酶1（IDO）的活性，它将Trp代谢从微生物群衍生的吲哚代谢物的产生转移到犬尿氨酸的产生。在HFD下，肠上皮细胞中IDO的特异性缺失导致肠道炎症，肠屏障受损，病变T淋巴细胞增加和动脉粥样硬化。这与5-羟色胺产生的增加和吲哚代谢物的减少有关，从而劫持了5-羟色胺途径的Trp。抑制肠5-羟色胺的产生或补充吲哚衍生物可减轻斑块炎症和动脉粥样硬化。总之,我们揭示了肠道IDO在微调Trp代谢中的关键作用，对动脉粥样硬化具有全身作用，为缓解肠道相关炎症性疾病的新治疗策略铺平了道路。
