College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6045, United States.
Med Hypotheses. 2009 Dec;73(6):1045-7. doi: 10.1016/j.mehy.2009.06.058. Epub 2009 Aug 4.
Clostridium difficile associated disease (CDAD), a common type of antibiotic associated diarrhea, is increasing in frequency and affecting patients outside of traditional populations. At one time CDAD exclusively occurred in hospitalized patients or frail elderly patients receiving antibiotic therapy. It is now occurring more commonly in younger patients who are relatively healthy and may not be receiving antibiotics. Co-factors that might explain this increase incidence and changing demographic are of great public health interest. Recent investigations have identified gastric acid suppression, particularly via proton pump inhibitors, as a risk factor for the development of CDAD by mechanisms which are not entirely clear. C. difficile toxin comes as two major forms that are closely related, toxin A and toxin B and both are able to produce CDAD. These toxins have a glucosyltransferase domain that glucosylates actived Rho, a small GTP binding protein involved in multiple cellular signaling pathways. Glucosylation inactivates Rho and modifies cell cycle, cytoskeletal and inflammatory pathways. The lipid lowering drugs called statins also inhibit Rho but at an earlier step in the Rho pathway. Statins inhibit the isoprenylation of Rho and therefore inhibits membrane anchoring a key step in Rho signaling. We propose that statins potentiate C. difficile toxin effects on colonic epithelium which leads to an increased risk of CDAD. We present preliminary data from a retrospective cohort which demonstrated an increased rate of CDAD in patients receiving statins compared to non-statin controls. The weight of the evidence leads to our hypothesis that statins interact with C difficile toxin A and B causing an increase in the rate and severity of CDAD.
艰难梭菌相关性疾病（CDAD），一种常见的抗生素相关性腹泻，其发病率正在上升，且影响范围已超出传统人群。曾有一段时间，CDAD 仅发生在住院患者或接受抗生素治疗的体弱老年患者中。而现在，越来越多相对健康且可能未接受抗生素治疗的年轻患者也会出现这种疾病。对于解释这种发病率上升和人口统计学变化的共同因素，人们非常关注其对公共卫生的影响。最近的调查研究已经确定，胃酸抑制（特别是通过质子泵抑制剂）是导致 CDAD 发展的一个风险因素，其发病机制尚不完全清楚。艰难梭菌毒素有两种主要形式，密切相关，即毒素 A 和毒素 B，两者均能引起 CDAD。这些毒素具有一个葡萄糖基转移酶结构域，该结构域能够使 Rho 发生葡萄糖基化，而 Rho 是一种参与多种细胞信号通路的小 GTP 结合蛋白。葡萄糖基化会使 Rho 失活，并改变细胞周期、细胞骨架和炎症通路。被称为他汀类的降脂药物也能抑制 Rho，但在 Rho 通路的早期阶段。他汀类药物抑制 Rho 的异戊烯化，从而抑制 Rho 信号通路中的膜锚定这一关键步骤。我们提出，他汀类药物增强了艰难梭菌毒素对结肠上皮的作用，从而增加了 CDAD 的风险。我们提供了一项回顾性队列研究的初步数据，该研究表明，接受他汀类药物治疗的患者发生 CDAD 的比率高于未接受他汀类药物治疗的对照组。越来越多的证据支持我们的假设，即他汀类药物与艰难梭菌毒素 A 和 B 相互作用，导致 CDAD 的发生率和严重程度增加。
