Lacy Brian E, Rosenbaum David, Edelstein Susan, Kozuka Kenji, Williams Laura A, Kunkel David C
Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.
Ardelyx, Inc, Waltham, MA, USA.
Clin Exp Gastroenterol. 2024 Jun 6;17:173-183. doi: 10.2147/CEG.S455101. eCollection 2024.
Increased intestinal permeability has been identified as one of the many pathophysiological factors associated with the development of irritable bowel syndrome (IBS), a common disorder of gut-brain interaction. The layer of epithelial cells that lines the intestine is permeable to a limited degree, and the amount of paracellular permeability is tightly controlled to enable the absorption of ions, nutrients, and water from the lumen. Increased intestinal permeability to macromolecules can be triggered by a variety of insults, including infections, toxins from food poisoning, or allergens, which in turn cause an inflammatory response and are associated with abdominal pain in patients with IBS. This review article discusses increased intestinal permeability in IBS, focusing on IBS with constipation (IBS-C) through the lens of a patient case with a reported prior diagnosis of "leaky gut syndrome" upon initial contact with a gastrointestinal specialist. We review advantages and disadvantages of several methods of measuring intestinal permeability in patients and discuss when measuring intestinal permeability is appropriate in the therapeutic journey of patients with IBS-C. Furthermore, we discuss a possible mechanism of restoring the intestinal barrier to its healthy state through altering intracellular pH by inhibiting sodium-hydrogen exchanger isoform 3 (NHE3). Tenapanor is a minimally absorbed, small-molecule inhibitor of NHE3 that has been approved by the US Food and Drug Administration for the treatment of IBS-C in adults. Preclinical studies showed that tenapanor may restore the intestinal barrier in IBS-C by affecting the conformation of tight junction proteins via NHE3 inhibition to block the paracellular transport of macromolecules from the intestinal lumen. Testing for increased permeability in patients with IBS-C who experience abdominal pain may help inform the choice of therapeutics and alter patients' misconceptions about "leaky gut syndrome".
肠通透性增加已被确认为与肠易激综合征（IBS）发展相关的众多病理生理因素之一，IBS是一种常见的肠-脑互动障碍。肠道内衬的上皮细胞层具有一定程度的通透性，细胞旁通透性的量受到严格控制，以实现从肠腔吸收离子、营养物质和水分。多种损伤可引发肠道对大分子的通透性增加，包括感染、食物中毒毒素或过敏原，进而引发炎症反应，并与IBS患者的腹痛相关。本文通过一名患者的病例来探讨IBS中肠通透性增加的情况，该患者在初次接触胃肠专科医生时被诊断为“肠漏综合征”。我们回顾了几种测量患者肠通透性方法的优缺点，并讨论了在IBS-C患者的治疗过程中何时测量肠通透性是合适的。此外，我们还讨论了通过抑制钠氢交换体3（NHE3）改变细胞内pH值来恢复肠道屏障至健康状态的可能机制。替那帕诺是一种吸收极少的NHE3小分子抑制剂，已被美国食品药品监督管理局批准用于治疗成人IBS-C。临床前研究表明，替那帕诺可能通过抑制NHE3影响紧密连接蛋白的构象，从而阻止大分子从肠腔的细胞旁转运，恢复IBS-C患者的肠道屏障。对有腹痛症状的IBS-C患者进行通透性增加检测，可能有助于指导治疗选择，并改变患者对“肠漏综合征”的误解。
