Abstract：
Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease.
摘要：
肠上皮层的通透性增加与多种肠和肠外疾病的发病机理和延续有关。用受控剂量的蠕虫感染人类，例如人类钩虫（称为钩虫疗法），被提议作为许多相同疾病的治疗方法。蠕虫诱导其宿主的免疫调节变化，从而降低上皮通透性，它被强调为蠕虫治疗疾病的潜在机制。尽管如此,慢性蠕虫感染对上皮通透性的影响尚不清楚。这项研究使用慢性感染的肠蠕虫Heligmosomoides多回揭示了感染过程中肠紧密连接蛋白表达和上皮通透性的变化。在急性感染阶段（感染后1周），观察到肠上皮通透性增加。与这一发现一致，空肠claudin-2上调，三细胞蛋白下调。相比之下,在慢性感染阶段（感染后6周），结肠claudin-1上调，上皮通透性降低。重要的是,这项研究还调查了一个小型人类队列中上皮通透性的变化，这些人类队列受到人类钩虫的实验挑战，美洲健忘。它显示出在急性感染阶段（感染后8周）小肠通透性增加的趋势，在慢性感染阶段（感染后24周），结肠和整个肠道通透性降低，提示人类和小鼠之间的保守的上皮反应。总之,我们的研究结果证明了慢性蠕虫感染过程中上皮通透性的动态变化，并提供了另一种合理的机制，通过该机制可以利用慢性蠕虫感染来治疗疾病。
