Pediatric Gastroenterology and Liver Unit, Department of "Maternal-and-Child Health" and Urology, Sapienza University of Rome, Rome, Italy.
Mucosal Immunology and Biology Research Center, Center for Celiac Research and Treatment and Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, 175 Cambridge Street, CPZS - 574, Boston, MA, 02114, USA.
Dig Dis Sci. 2019 Jul;64(7):1748-1758. doi: 10.1007/s10620-019-05646-y.
For decades, the pathogenesis of a variety of human diseases has been attributed to increased intestinal paracellular permeability even though scientific evidence supporting this hypothesis has been tenuous. Nevertheless, during the past decade, there have been a growing number of publications focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately causing chronic inflammation, including autoimmunity, in genetically predisposed individuals. The gut mucosa works as a semipermeable barrier in that it permits nutrient absorption and also regulates immune surveillance while retaining potentially harmful microbes and environmental antigens within the intestinal lumen. Celiac disease (CD), a systemic, immune-mediated disorder triggered by gluten in genetically susceptible individuals, is associated with altered gut permeability. Pre-clinical and clinical studies have shown that gliadin, a prolamine component of gluten that is implicated in CD pathogenesis, is capable to disassembling intercellular junctional proteins by upregulating the zonulin pathway, which can be inhibited by the zonulin antagonist larazotide acetate. In this review, we will focus on CD as a paradigm of chronic inflammatory diseases in order to outline the contribution of gut paracellular permeability toward disease pathogenesis; moreover, we will summarize current evidence derived from available clinical trials of larazotide acetate in CD.
数十年来，尽管支持这一假说的科学证据一直很薄弱，但人们还是将多种人类疾病的发病机制归因于肠道细胞旁通透性的增加。然而，在过去十年中，越来越多的研究集中在人类遗传学、肠道微生物组和蛋白质组学上，这些研究表明，黏膜屏障功能的丧失，特别是在胃肠道中，可能会显著影响抗原的运输，最终导致慢性炎症，包括遗传易感性个体的自身免疫。肠道黏膜作为半渗透屏障发挥作用，它允许营养物质吸收，同时调节免疫监视，同时将潜在的有害微生物和环境抗原保留在肠腔内部。乳糜泻（CD）是一种由遗传易感个体中的麸质引发的全身性、免疫介导的疾病，与肠道通透性改变有关。临床前和临床研究表明，麦醇溶蛋白是麸质中的一种醇溶蛋白，它与 CD 的发病机制有关，能够通过上调紧密连接蛋白来破坏细胞间连接蛋白，而这种作用可以被紧密连接蛋白拮抗剂拉扎otide 乙酸盐抑制。在这篇综述中，我们将以 CD 为范例，探讨慢性炎症性疾病，概述肠道细胞旁通透性在疾病发病机制中的作用；此外，我们将总结目前从 CD 中可用的 larazotide 乙酸盐临床试验中获得的证据。
