Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health
Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health
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吲哚胺2，3-双加氧酶的遗传缺陷促进肠道微生物群介导的代谢健康
DOI：
10.1038/s41591-018-0060-4
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发表时间：
2018-08-01
期刊：
影响因子：
82.9
通讯作者：
Taleb, Soraya
中科院分区：
文献类型：
--
作者：
Laurans, Ludivine;Venteclef, Nicolas;Taleb, Soraya
肠道菌群改变、肠道通透性、炎症和心脏代谢疾病之间的关联越来越清楚，但仍知之甚少（1，2）。吲哚胺2，3-双加氧酶是在许多类型的免疫细胞（包括巨噬细胞）中响应于炎症刺激而诱导的酶，并且催化色氨酸沿着犬尿氨酸途径的降解。吲哚胺2，3-双加氧酶活性因其抑制效应T细胞免疫和激活调节性T细胞而更为人所知（3，4）。然而，高吲哚胺2，3-双加氧酶活性预测更差的心血管结局（5 - 9），并可能促进动脉粥样硬化和血管炎症（6），表明在慢性炎症环境中的作用更复杂。吲哚胺2，3-双加氧酶活性在肥胖症中也增加（10 - 13），但其在代谢疾病中的作用仍未被探索。在这里，我们发现肥胖与肠道吲哚胺2，3-双加氧酶活性的增加有关，该活性使色氨酸代谢从吲哚衍生物和白细胞介素-22的产生转向犬尿氨酸的产生。吲哚胺2，3-双加氧酶缺失或抑制可改善胰岛素敏感性，保护肠粘膜屏障，降低内毒素血症和慢性炎症，并调节肝脏和脂肪组织中的脂质代谢。这些有益作用是由于色氨酸代谢向微生物群依赖性白细胞介素-22产生的重新布线，并且在用中和抗白细胞介素-22抗体治疗后被消除。总之，我们确定了吲哚胺2，3-双加氧酶在肠道色氨酸代谢微调中的意想不到的功能，对代谢疾病的微生物群依赖性控制具有重要影响，这表明吲哚胺2，3-双加氧酶是潜在的治疗靶点。
The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood(1,2). Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells(3,4). However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcomes(5-9) and may promote atherosclerosis and vascular inflammations(6), suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity(10-13), yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.