Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, Albuquerque, NM, United States.
Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico, Albuquerque, NM, United States.
Front Cell Infect Microbiol. 2022 May 26;12:882498. doi: 10.3389/fcimb.2022.882498. eCollection 2022.
Tight junctions (TJs) are essential components of intestinal barrier integrity and protect the epithelium against passive paracellular flux and microbial translocation. Dysfunctional TJ leads to leaky gut, a condition associated with diseases including inflammatory bowel disease (IBD). Sulfate-Reducing Bacteria (SRB) are minor residents of the gut. An increased number of , the most predominant SRB, is observed in IBD and other diseases associated with leaky gut. However, it is not known whether contributes to leaky gut. We tested the hypothesis that (DSV) may induce intestinal permeability . Snail, a transcription factor, disrupts barrier function by affecting TJ proteins such as occludin. Intestinal alkaline phosphatase (IAP), a host defense protein, protects epithelial barrier integrity. We tested whether DSV induced permeability in polarized Caco-2 cells snail and if this effect was inhibited by IAP. Barrier integrity was assessed by measuring transepithelial electric resistance (TEER) and by 4kDa FITC-Dextran flux to determine paracellular permeability. We found that DSV reduced TEER, increased FITC-flux, upregulated snail protein expression, caused nuclear translocation of snail, and disrupted occludin staining at the junctions. DSV-induced permeability effects were inhibited in cells knocked down for snail. Pre-treatment of cells with IAP inhibited DSV-induced FITC flux and snail expression and DSV-mediated disruption of occludin staining. These data show that DSV, a resident commensal bacterium, can contribute to leaky gut and that snail may serve as a novel therapeutic target to mitigate DSV-induced effects. Taken together, our study suggests a novel underlying mechanism of association of bloom with diseases with increased intestinal permeability. Our study also underscores IAP as a novel therapeutic intervention for correcting SRB-induced leaky gut inhibition of snail.
紧密连接（TJs）是肠道屏障完整性的重要组成部分，可防止上皮细胞被动通过细胞旁通道和微生物易位。TJ 功能障碍导致肠道渗漏，这种情况与包括炎症性肠病（IBD）在内的多种疾病有关。硫酸盐还原菌（SRB）是肠道的次要居民。在 IBD 和其他与肠道渗漏相关的疾病中，观察到数量增加，最主要的 SRB。然而，尚不清楚是否会导致肠道渗漏。我们检验了这样一个假设，即（DSV）可能会引起肠道通透性增加。Snail 是一种转录因子，通过影响紧密连接蛋白（如 Occludin）来破坏屏障功能。肠道碱性磷酸酶（IAP）是一种宿主防御蛋白，可保护上皮屏障的完整性。我们测试了 DSV 是否会诱导极化的 Caco-2 细胞通透性增加，并观察到这种作用是否被 IAP 抑制。通过测量跨上皮电阻（TEER）和 4kDa FITC-右旋糖酐通量来评估屏障完整性，以确定细胞旁通透性。我们发现 DSV 降低了 TEER，增加了 FITC 通量，上调了 snail 蛋白表达，导致 snail 核转位，并破坏了 Occludin 在连接处的染色。在敲低 snail 的细胞中，DSV 诱导的通透性作用受到抑制。细胞先用 IAP 预处理可抑制 DSV 诱导的 FITC 通量和 snail 表达以及 DSV 介导的 Occludin 染色破坏。这些数据表明，DSV，一种常驻共生菌，可能导致肠道渗漏，而 snail 可能成为一种新的治疗靶点，以减轻 DSV 诱导的作用。总之，我们的研究表明，与肠道通透性增加相关疾病中 bloom 的一个新的潜在机制。我们的研究还强调了 IAP 作为一种新的治疗干预措施，可纠正 SRB 诱导的肠道渗漏和抑制 snail。
