Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milano, Italy.
Division of Immunology, Transplantation and Infectious Disease, IRCCS Ospedale San Raffaele, Milano, Italy.
Gut. 2023 Oct;72(10):1838-1847. doi: 10.1136/gutjnl-2022-328375. Epub 2023 Feb 14.
Ulcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by the genus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis.
HBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing and correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors.C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control, with or without antibiotic treatment. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, chromatin immunoprecipitation assay with sequencing and RNA-sequencing were performed on models of the gut barrier. HBx-silencing experiments were performed and .
HBx was detected in about 45% of patients with UC and found to induce colonic inflammation in mice, while its silencing reverted the colitis phenotype . HBx acted as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering both innate and adaptive mucosal immunity and .
This study described HBx as a contributor to the UC pathogenesis and provides a new perspective on the virome as a target for tailored treatments.
溃疡性结肠炎（UC）是一种病因不明的慢性炎症性疾病。肠道病毒组失调是 UC 进展的基础，但它在疾病早期阶段的作用尚未完全了解。因此，我们试图研究肝炎病毒 X 蛋白（HBx）等病毒相关蛋白在 UC 发病机制中的作用。
通过 RT-PCR 和 Sanger 测序评估 UC 患者来源的血液和肠道黏膜中的 HBx 阳性，并通过多变量分析将其与临床特征相关联。对健康供体的 HBx 过表达内镜活检进行转录组学分析。C57BL/6 小鼠接受脂质体偶联的 HBx 编码质粒或对照质粒的黏膜内注射，伴或不伴抗生素治疗。对 HBx 处理和对照动物的结肠样本进行多维流式细胞术分析。对肠道屏障模型进行跨上皮电阻测量、增殖测定、染色质免疫沉淀测序和 RNA 测序。进行了 HBx 沉默实验。
约 45%的 UC 患者检测到 HBx，并在小鼠中发现其诱导结肠炎症，而其沉默则使结肠炎表型逆转。HBx 作为上皮细胞的转录调节剂，引起屏障渗漏，并改变固有和适应性黏膜免疫。
本研究将 HBx 描述为 UC 发病机制的一个促成因素，并为病毒组作为靶向治疗提供了新视角。
