Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Physiol Rev. 2011 Jan;91(1):151-75. doi: 10.1152/physrev.00003.2008.
The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a "leaky gut" in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.
传统上，人们认为胃肠道的主要功能仅限于消化和吸收营养物质以及电解质和水的动态平衡。然而，对胃肠道的解剖和功能排列进行更仔细的分析表明，这个器官的另一个极其重要的功能是通过屏障机制调节大分子在环境和宿主之间的运输。肠道上皮屏障与肠道相关淋巴组织和神经内分泌网络一起，通过细胞间紧密连接控制着对非自身抗原的耐受性和免疫性之间的平衡。迄今为止，zonulin 是唯一描述的细胞间紧密连接的生理调节剂，它参与大分子的运输，因此参与了耐受/免疫反应的平衡。当具有遗传易感性的个体中精细调节的 zonulin 途径失调时，可能会发生肠道和肠道外自身免疫、炎症和肿瘤性疾病。鉴于人们对“肠漏”在针对肠道和肠道外器官的多种病理状况的发病机制中的作用的兴趣增加，这一新范式颠覆了这些疾病发展的传统理论，并表明如果通过重新建立 zonulin 依赖性肠道屏障功能来防止基因和环境触发因素之间的相互作用，这些过程可以被阻止。
