肠道细菌 III 型分泌系统会加重小鼠结肠炎,并可作为克罗恩病的生物标志物。

IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
EBioMedicine Pub Date : 2024-09-01 Epub Date: 2024-08-30 DOI:10.1016/j.ebiom.2024.105296
Jun Xu, Peijie Li, Zhenye Li, Sheng Liu, Huating Guo, Cammie F Lesser, Jia Ke, Wenjing Zhao, Xiangyu Mou
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引用次数: 0

摘要

背景:肠系膜脂肪组织(mAT)增生,即所谓的爬行脂肪,是克罗恩病(CD)的病理特征之一。在我们之前报告的队列中,我们观察到肺部牛肝菌是爬行脂肪中最丰富、最普遍的细菌:方法:采用全基因组测序和 T3SS 同源物鉴定 mAT 衍生的肺褶菌。在体外和小鼠结肠炎模型中,功能性 III 型分泌系统(T3SS)介导了肺结核嗜血杆菌的致病潜能。此外,还引入了 T3SS Finder 管道,以评估 CD 患者、溃疡性结肠炎患者和结直肠癌患者粪便中的肠道细菌 T3SS 同源物:在这里,我们揭示了源自 mAT 的肺结核嗜血杆菌具有功能性 T3SS,通过 T3SS 加剧小鼠结肠炎,并在巨噬细胞和上皮细胞中通过一种不依赖于 Caspase 的机制表现出 T3SS 依赖性细胞毒性,这证明了携带 T3SS 的肺结核嗜血杆菌具有致病潜力。元基因组分析表明,与健康对照组相比,克罗恩病患者粪便中Achromobacter的丰度有所增加。对各种肠道疾病中微生物 vT3SS 总丰度的综合比较表明,vT3SS 基因在克罗恩病、溃疡性结肠炎和结直肠癌患者的粪便样本中都有特异性富集,在新招募的克罗恩病队列中发现并验证了 10 个基于 T3SS 基因的克罗恩病生物标志物。此外,研究还发现纯肠内营养(EEN)治疗(一种可改善 CD 患者症状的干预措施)与粪便样本中 T3SS 基因患病率的显著降低有关:这些发现凸显了T3SS在CD中的致病意义,并确定了特定的T3SS基因,这些基因有可能成为诊断和监测CD患者临床状况的生物标志物:本研究得到国家重点研发计划(2020YFA0907800)、中国博士后科学基金(2023M744089)、国家自然科学基金(32000096)、深圳市科技计划(KQTD20200820145822023、RCIC20231211085944057和ZDSYS20220606100803007)的资助、国家临床重点学科、广东省消化疾病临床研究中心(2020B1111170004)、中国克罗恩病及结肠炎基金会清风科研基金(CCCF-QF-2022B71-1)和中山大学附属第六医院临床研究1010项目1010CG(2023)-08。这些资助为本研究的数据收集、分析、解释、患者招募等工作提供了有力支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Gut bacterial type III secretion systems aggravate colitis in mice and serve as biomarkers of Crohn's disease.

Background: Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat, is a pathologic characteristic of Crohn's disease (CD). In our previously reported cohort, we observed that Achromobacter pulmonis was the most abundant and prevalent bacteria cultivated from creeping fat.

Methods: A whole genomic sequencing and identification of T3SS orthologs of mAT-derived A. pulmonis were used. A functional type III secretion system (T3SS) mediated the pathogenic potential of A. pulmonis in vitro and in mouse colitis model. Furthermore, a T3SS Finder pipeline was introduced to evaluate gut bacterial T3SS orthologs in the feces of CD patients, ulcerative colitis and colorectal cancer patients.

Findings: Here, we reveal that mAT-derived A. pulmonis possesses a functional T3SS, aggravates colitis in mice via T3SS, and exhibits T3SS-dependent cytotoxicity via a caspase-independent mechanism in macrophages and epithelial cells, which demonstrated the pathogenic potential of the T3SS-harboring A. pulmonis. Metagenomic analyses demonstrate an increased abundance of Achromobacter in the fecal of Crohn's disease patients compared to healthy controls. A comprehensive comparison of total microbial vT3SS abundance in various intestine diseases demonstrated that the specific enrichment of vT3SS genes was shown in fecal samples of CD, neither ulcerative colitis nor colorectal cancer patients, and ten T3SS gene-based biomarkers for CD were discovered and validated in a newly recruited CD cohort. Furthermore, treatment with exclusive enteral nutrition (EEN), an intervention that improves CD patient symptomatology, was found associated with a significant reduction in the prevalence of T3SS genes in fecal samples.

Interpretation: These findings highlight the pathogenic significance of T3SSs in the context of CD and identify specific T3SS genes that could potentially function as biomarkers for diagnosing and monitoring the clinical status of CD patients.

Funding: This work is supported by the National Key Research and Development Program of China (2020YFA0907800), the China Postdoctoral Science Foundation (2023M744089), the National Natural Science Foundation of China (32000096), the Shenzhen Science and Technology Programs (KQTD20200820145822023, RCIC20231211085944057, and ZDSYS20220606100803007), National Key Clinical Discipline, Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Qingfeng Scientific Research Fund of the China Crohn's & Colitis Foundation (CCCF) (CCCF-QF-2022B71-1), and the Sixth Affiliated Hospital, Sun Yat-sen University Clinical Research 1010 Program 1010CG(2023)-08. These funding provided well support for this research work, which involved data collection, analysis, interpretation, patient recruitment and so on.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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