Facultad de Medicina, Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago 755000, Chile.
Escuela de Medicina Veterinaria, Facultad de Agronomía e Ingeniería Forestal, Facultad de Ciencias Biológicas y Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Nutrients. 2024 Oct 27;16(21):3655. doi: 10.3390/nu16213655.
IL-33, a pleiotropic cytokine, has been associated with a plethora of immune-related processes, both inflammatory and anti-inflammatory. T regulatory (Treg) cells, the main leukocyte population involved in immune tolerance, can be induced by the administration of IL-33, the local microbiota, and its metabolites. Here, we demonstrate that IL-33 drastically induces the production of intestinal metabolites involved on tryptophan (Trp) metabolism.
naïve mice were treated with IL-33 for 4 days and leukocyte populations were analyzed by flow cytometry, and feces were processed for microbiota and intestinal metabolites studies. Using a murine skin transplantation model, the effect of Kynurenic acid (KA) on allograft survival was tested.
Under homeostatic conditions, animals treated with IL-33 showed an increment in Treg cell frequencies. Intestinal bacterial abundance analysis indicates that IL-33 provokes dysbiosis, demonstrated by a reduction in and an increment in genera. Furthermore, metabolomics analysis showed a dramatic IL-33 effect on the abundance of intestinal metabolites related to amino acid synthesis pathways, highlighting molecules linked to Trp metabolism, such as kynurenic acid (KA), 5-Hydroxyindoleacetic acid (5-HIAA), and 6-Hydroxynicotinic acid (6-HNA), which was supported by an enhanced expression of and mRNA in MLN cells, which are two enzymes involved on KA synthesis. Interestingly, animals receiving KA in drinking water and subjected to skin transplantation showed allograft acceptance, which is associated with an increment in Treg cell frequencies.
Our study reveals a new property for IL-33 as a modulator of the intestinal microbiota and metabolites, especially those involved with Trp metabolism. In addition, we demonstrate that KA favors Tregs in vivo, positively affecting skin transplantation survival.
白细胞介素 33（IL-33）是一种多功能细胞因子，与众多免疫相关过程有关，包括炎症和抗炎过程。调节性 T 细胞（Treg）是参与免疫耐受的主要白细胞群，可以通过给予 IL-33、局部微生物群及其代谢物来诱导。在这里，我们证明 IL-33 可剧烈诱导参与色氨酸（Trp）代谢的肠道代谢物的产生。
用 IL-33 处理 naive 小鼠 4 天，通过流式细胞术分析白细胞群，处理粪便以进行微生物群和肠道代谢物研究。使用小鼠皮肤移植模型，测试犬尿氨酸（KA）对同种异体移植物存活的影响。
在稳态条件下，用 IL-33 处理的动物显示 Treg 细胞频率增加。肠道细菌丰度分析表明，IL-33 引发了肠道菌群失调，表现为减少 和增加 属。此外，代谢组学分析显示，IL-33 对与氨基酸合成途径相关的肠道代谢物的丰度有显著影响，突出了与 Trp 代谢相关的分子，如犬尿氨酸（KA）、5-羟色吲哚乙酸（5-HIAA）和 6-羟基烟酸（6-HNA），这得到了 MLN 细胞中 和 mRNA 表达增强的支持，这两种酶都参与 KA 的合成。有趣的是，在饮用水中接受 KA 并接受皮肤移植的动物表现出同种异体移植物接受，这与 Treg 细胞频率增加有关。
我们的研究揭示了 IL-33 作为肠道微生物群和代谢物的调节剂的新特性，特别是那些与 Trp 代谢有关的代谢物。此外，我们证明 KA 在体内有利于 Tregs，从而正向影响皮肤移植的存活。
