Simvastatin Improves Outcomes of Endotoxin-induced Coagulopathy by Regulating Intestinal Microenvironment

Min Xu,Meng-Yi Du,Jie Zhou,Yu Hu,Heng Mei,Li-Li Luo,Lu Tang

doi:10.1007/s11596-022-2526-3

Abstract

ObjectiveThe systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy, which is a strong predictor of mortality in patients with severe sepsis. Simvastatin plays an important role in reducing inflammation. In addition, the gut has long been hypothesized to be the “motor” of critical illness, driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation. Whether simvastatin plays a role in severe endotoxin-induced coagulopathy through the gut is unclear.MethodsIn this study, mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve h later, cytokine release, coagulation dysfunction, organ damage, and survival were assessed. Besides, the intestinal barrier, permeability, bacteria abundance, and translocation were evaluated.ResultsWe found that the severity of endotoxin-induced coagulopathy was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition, and improved survival time. Also, simvastatin reduced epithelial apoptosis and improved intestinal barrier function by upregulating antimicrobial peptides, lysozyme, and mucins. Simvastatin increased Lactobacillales counts, while the lipopolysaccharide group showed increased Desulfovibrio and Mucispirillum, which can produce harmful toxins. Finally, the decreased intestinal permeability in the simvastatin group caused reduced bacterial translocation in the organs and blood, both in terms of quantity and species.ConclusionSimvastatin improves the prognosis of severe endotoxemia, and the intestinal microenvironment participates in this process.

Highlights

Severe endotoxemia occurs frequently in intensive care unit (ICU) patients and is associated with serious complications like disseminated intravascular coagulation (DIC) and even multiple organ dysfunction syndrome (MODS)[1, 2]
A disturbance in the intestinal flora and increased intestinal permeability can promote the entrance of harmful bacteria and bacterial products into local and distant spaces that are difficult to reach under normal circumstances; potential outcomes include secondary infections, aggravated coagulopathy, and multiple organ dysfunction[5, 8]
Clinical and animal studies have demonstrated that statins have beneficial effects in terms of both morbidity and mortality in mild or moderate sepsis[12, 13], little is known about the changes in the intestinal tract in severe endotoxin-induced coagulopathy and whether simvastatin (SIM) can improve it by regulating intestinal microenvironment disorders

Summary

Introduction

Severe endotoxemia occurs frequently in intensive care unit (ICU) patients and is associated with serious complications like disseminated intravascular coagulation (DIC) and even multiple organ dysfunction syndrome (MODS)[1, 2]. A disturbance in the intestinal flora and increased intestinal permeability can promote the entrance of harmful bacteria and bacterial products into local and distant spaces that are difficult to reach under normal circumstances; potential outcomes include secondary infections, aggravated coagulopathy, and multiple organ dysfunction[5, 8]. In agreement with these findings, a correlation between gut barrier dysfunction and secondary lung injury has been reported[9]. This study aimed to evaluate the effects and mechanism of statins on the intestinal tract in an endotoxin mouse model

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Conclusion