乌头酸脱羧酶1下调结肠炎,维持肠道代谢组和微生物组的稳态

Kara M. McNamara , Yvonne L. Latour , Caroline V. Hawkins , Kamery J. Williams , Daniel P. Barry , Margaret M. Allaman , Alberto G. Delgado , Sergei V. Chetyrkin , M Wade Calcutt , M. Blanca Piazuelo , M. Kay Washington , Shilin Zhao , Lori A. Coburn , Alain P. Gobert , Keith T. Wilson
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引用次数: 0

摘要

背景:辅助性脱羧酶1 (ACOD1)与先天免疫和炎症反应有关。我们确定了ACOD1在结肠炎症和结肠炎相关癌(CAC)中的作用。方法对人类炎症性肠病转录组学数据集和储存的RNA样本进行询问。C57BL/6野生型(WT)和Acod1 - / -型小鼠分别感染啮齿柠檬酸杆菌(Citrobacter rodentium)或给予1或2个周期的4%葡聚糖硫酸钠(DSS)作为结肠炎模型。对于CAC,小鼠给予12.5 mg/kg偶氮氧甲烷(AOM),然后给予3个周期的4% DSS。评估临床和组织学参数。组织和粪便分别用于代谢组学和16S微生物组学分析。结果与对照组相比,sacod1在溃疡性结肠炎(UC)和克罗恩病(CD)组织中的表达升高。C. rodentium感染仅在Acod1 - / -小鼠中引起体重减轻,与野生型相比,其组织学损伤增加。在DSS结肠炎中,我们观察到与野生型小鼠相比,Acod1 - / -小鼠的结肠长度减少,组织学损伤增加。aom - dss处理的Acod1 - / -动物表现出更多的炎症和损伤,但肿瘤发生无差异。与野生型结肠组织相比,Acod1 - / -代谢组发生了改变,在结肠炎期间,嘌呤代谢受到的影响最为显著。16S微生物组分析显示门、属差异显著;值得注意的是,Acod1 - / -小鼠的拟杆菌门增加,变形菌门减少,表明一种生态失调状态。结论虽然ACOD1在人类炎症性肠病(IBD)组织中升高,但我们的数据表明,该酶在急性和慢性实验性结肠炎中具有保护作用,并与预防肠道生态失调和稳定代谢组有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Aconitate decarboxylase 1 downregulates colitis and maintains homeostasis of the gut metabolome and microbiome

Background & Aims

Aconitate decarboxylase 1 (ACOD1) is implicated in innate immunity and inflammatory responses. We determined the role of ACOD1 in colon inflammation and colitis-associated carcinoma (CAC).

Methods

Human inflammatory bowel disease transcriptomic datasets and banked RNA samples were interrogated. C57BL/6 wild-type (WT) and Acod1–/– mice were infected with Citrobacter rodentium or given one or two cycles of 4% dextran sulfate sodium (DSS) as models of colitis. For CAC, mice were given 12.5 mg/kg azoxymethane (AOM) followed by 3 cycles of 4% DSS. Clinical and histological parameters were assessed. Tissues and stool were used for metabolomic and 16S microbiome analyses, respectively.

Results

ACOD1 expression is increased in ulcerative colitis (UC) and Crohn’s disease (CD) tissues compared to controls. C. rodentium infection caused body weight loss only in Acod1–/– mice, which had increased histologic injury versus wild-type. In DSS colitis, we observed decreased colon length and increased histologic injury in Acod1–/– versus wild-type mice. AOM-DSS-treated Acod1–/– animals exhibited more inflammation and injury but no difference in tumorigenesis. There was an altered metabolome in Acod1–/– versus wild-type colon tissues, and during colitis, purine metabolism was most markedly affected. 16S microbiome analysis revealed significant differences in phyla and genera; notably an increase in Bacteroidetes and decrease in Proteobacteria in Acod1–/– mice, indicating a dysbiotic state.

Conclusions

While ACOD1 is increased in human inflammatory bowel disease (IBD) tissues, our data indicate that this enzyme has a protective role in acute and chronic experimental colitis and is associated with prevention of intestinal dysbiosis and stabilization of the metabolome.
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Gastro hep advances
Gastro hep advances Gastroenterology
CiteScore
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