Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis
Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis
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粘性阿克曼原虫及其外蛋白AMUC_1100对结肠炎患者色氨酸代谢的调节作用
DOI：
10.1039/d1fo02172a
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发表时间：
2021-09-01
期刊：
影响因子：
6.1
通讯作者：
Zhang, Zhan
中科院分区：
文献类型：
--
作者：
Gu, Zhenyang;Pei, Wenlong;Zhang, Zhan
饮食干预，包括膳食成分，营养素和益生菌，发挥抗炎作用的溃疡性结肠炎（UC）。我们以前的研究表明，Akkermansia muciniphila（Akk）是一种很有前途的益生菌，可以通过调节免疫反应来预防结肠炎。然而，它是否可以恢复结肠炎期间异常的色氨酸（Trp）代谢仍不清楚。在本研究中，UC和结肠炎小鼠患者的非靶向血清代谢组学显示Trp代谢被激活，这通过来自验证队列和动物研究的Trp代谢物的定量得到证实。粪便宏基因组和血清代谢组的综合分析显示Akk和三种Trp代谢物之间存在显著关联。活的Akk、巴氏灭菌的Akk和Amuc_1100未能恢复结肠炎小鼠中参与5-羟色胺途径的Trp代谢物的减少。然而，活的Akk、巴氏灭菌的Akk和Amuc_1100增加犬尿氨酸（Kyn），但降低2-吡啶甲酸（PIC）水平和PIC/Kyn比率，而不调节参与Trp代谢的任何基因，表明它们可以独立于结肠组织抑制Kyn途径（KP）。此外，它们可以显著恢复由粪便微生物群介导的Trp代谢的富集。具体而言，活的Akk、巴氏灭菌的Akk和Amuc_1100可以显著抵消吲哚乙酸（IAA）水平的降低。巴氏灭菌的Akk显着升高血清中吲哚丙烯酸（IA）的水平。此外，活的Akk、巴氏灭菌的Akk和Amuc_1100可以上调芳香烃受体（AhR）靶向基因，包括CYP 1A 1、IL-10和IL-22，表明Akk可以通过调节Trp代谢激活AhR信号传导，从而减轻结肠炎症。
Dietary interventions, including dietary ingredients, nutrients and probiotics, exert anti-inflammatory effects in ulcerative colitis (UC). Our previous study showed that Akkermansia muciniphila (Akk), a promising probiotic, could protect against colitis via the regulation of the immune response. However, whether it can restore aberrant tryptophan (Trp) metabolism during colitis remains unclear. In this study, untargeted serum metabolomics of patients with UC and colitis mice showed that Trp metabolism was activated, which was confirmed by quantification of Trp metabolites from a validation cohort and animal study. Integrative analysis of faecal metagenomes and serum metabolomes revealed significant associations between Akk and three Trp metabolites. Live Akk, pasteurised Akk and Amuc_1100 failed to restore the reduction in Trp metabolites involved in the serotonin pathway in colitis mice. However, live Akk, pasteurised Akk and Amuc_1100 increased kynurenine (Kyn) but decreased 2-picolinic acid (PIC) levels and the PIC/Kyn ratio without regulating any of the genes involved in Trp metabolism, suggesting that they could suppress the Kyn pathway (KP) independent of colon tissue. In addition, they could significantly restore the enrichment of Trp metabolism mediated by faecal microbiota. Specifically, live Akk, pasteurised Akk and Amuc_1100 could significantly offset the reduction in indoleacetic acid (IAA) levels. Pasteurised Akk significantly elevated the serum levels of indole acrylic acid (IA). In addition, live Akk, pasteurised Akk and Amuc_1100 could upregulate aryl hydrocarbon receptor (AhR) targeted genes, including CYP1A1, IL-10 and IL-22, suggesting that Akk could activate AhR signaling by regulating Trp metabolism, thereby attenuating colonic inflammation.