Akkermansia muciniphila and its membrane protein ameliorates intestinal inflammatory stress and promotes epithelial wound healing via CREBH and miR-143/145.
Akkermansia muciniphila and its membrane protein ameliorates intestinal inflammatory stress and promotes epithelial wound healing via CREBH and miR-143/145.
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DOI：
10.1186/s12929-023-00935-1
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发表时间：
2023-06-07
影响因子：
11
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中科院分区：
文献类型：
--
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肠道上皮屏障是肠道微生物区系与宿主代谢系统相互作用的界面。粘液阿克曼氏菌是位于粘液层的结肠微生物区系中的关键成员，其丰度在炎症性肠病(IBD)患者的粪便微生物区系中选择性降低。本研究旨在探讨转录因子cAMP反应元件结合蛋白H(CREBH)和microRNA-143/145(miR-143/145)在肠炎性应激、肠屏障完整性和上皮再生中的调节机制。本研究采用CREBH基因敲除小鼠肠道内粘液A菌定植增加的新小鼠模型、上皮伤口愈合试验和多种分子生物学技术。结果用同方差双尾t检验进行分析。黏菌在小鼠肠道的定植增加，促进了肠道CREBH的表达，这与减轻葡聚糖硫酸钠(DSS)诱导的肠道内质网(ER)应激、肠屏障渗漏和血内毒素血症有关。CREBH基因缺失(CREBH-KO)显著抑制了与肠道屏障完整性相关的紧密连接蛋白的表达，包括Claudin5和Claudin8，但上调了Claudin2，这是一种提高肠道通透性的紧密连接蛋白，导致肠道高通透性和炎症。进一步结合miR-143/145的粘液弧菌上调CREBH通过胰岛素样生长因子(IGF)和Igfbp5信号通路促进肠上皮细胞(IEC)再生和伤口修复。此外，还将表达粘虫外膜蛋白基因Amuc_1100克隆到哺乳动物细胞表达载体中，并在猪和人的IECS中成功表达。Amuc_1100在IECS中的表达可能通过激活CREBH、抑制内质网应激、增强肠道屏障完整性和IEC再生相关基因的表达来概括粘菌对肠道健康的有益作用。这项研究揭示了粘液杆菌及其膜蛋白与宿主CREBH、IGF信号转导和miRNAs在减轻肠道炎症应激-肠道屏障通透性和促进肠道伤口愈合方面的新机制。这一新的发现可能为通过操纵宿主基因、肠道细菌及其生物活性成分之间的相互作用来开发治疗IBD的方法提供支持。网上版载有补充材料，可在10.1186/s12929-023-00935-1查阅。
The intestinal epithelial barrier is the interface for interaction between gut microbiota and host metabolic systems. Akkermansia muciniphila (A. muciniphila) is a key player in the colonic microbiota that resides in the mucus layer, whose abundance is selectively decreased in the faecal microbiota of inflammatory bowel disease (IBD) patients. This study aims to investigate the regulatory mechanism among A. muciniphila, a transcription factor cAMP-responsive element-binding protein H (CREBH), and microRNA-143/145 (miR-143/145) in intestinal inflammatory stress, gut barrier integrity and epithelial regeneration. A novel mouse model with increased colonization of A muciniphila in the intestine of CREBH knockout mice, an epithelial wound healing assay and several molecular biological techniques were applied in this study. Results were analysed using a homoscedastic 2-tailed t-test. Increased colonization of A. muciniphila in mouse gut enhanced expression of intestinal CREBH, which was associated with the mitigation of intestinal endoplasmic reticulum (ER) stress, gut barrier leakage and blood endotoxemia induced by dextran sulfate sodium (DSS). Genetic depletion of CREBH (CREBH-KO) significantly inhibited the expression of tight junction proteins that are associated with gut barrier integrity, including Claudin5 and Claudin8, but upregulated Claudin2, a tight junction protein that enhances gut permeability, resulting in intestinal hyperpermeability and inflammation. Upregulation of CREBH by A. muciniphila further coupled with miR-143/145 promoted intestinal epithelial cell (IEC) regeneration and wound repair via insulin-like growth factor (IGF) and IGFBP5 signalling. Moreover, the gene expressing an outer membrane protein of A. muciniphila, Amuc_1100, was cloned into a mammalian cell-expression vector and successfully expressed in porcine and human IECs. Expression of Amuc_1100 in IECs could recapitulate the health beneficial effect of A. muciniphila on the gut by activating CREBH, inhibiting ER stress and enhancing the expression of genes involved in gut barrier integrity and IEC’s regeneration. This study uncovers a novel mechanism that links A. muciniphila and its membrane protein with host CREBH, IGF signalling and miRNAs in mitigating intestinal inflammatory stress–gut barrier permeability and promoting intestinal wound healing. This novel finding may lend support to the development of therapeutic approaches for IBD by manipulating the interaction between host genes, gut bacteria and its bioactive components. The online version contains supplementary material available at 10.1186/s12929-023-00935-1.
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