Ewaschuk Julia, Endersby Ryan, Thiel David, Diaz Hugo, Backer Jody, Ma Mang, Churchill Thomas, Madsen Karen
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Hepatology. 2007 Sep;46(3):841-50. doi: 10.1002/hep.21750.
A breakdown in intestinal barrier function and increased bacterial translocation are key events in the pathogenesis of sepsis and liver disease. Altering gut microflora with noninvasive and immunomodulatory probiotic organisms has been proposed as an adjunctive therapy to reduce the level of bacterial translocation and prevent the onset of sepsis. The purpose of this study was to determine the efficacy of a probiotic compound in attenuating hepatic and intestinal injury in a mouse model of sepsis. Wild-type and interleukin-10 (IL-10) gene-deficient 129 Sv/Ev mice were fed the probiotic compound VSL#3 for 7 days. To induce sepsis, the mice were injected with lipopolysaccharide (LPS) and D-galactosamine (GalN) in the presence and absence of the peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor GW9662. The mice were killed after 6 hours, and their colons were removed for the measurement of the cytokine production and epithelial function. The functional permeability was assessed by the mannitol movement and cyclic adenosine monophosphate-dependent chloride secretion in tissue mounted in Ussing chambers. The livers were analyzed for bacterial translocation, cytokine production, histological injury, and PPARgamma levels. The tissue levels of tumor necrosis factor alpha, interferon gamma, IL-6, and IL-12p35 ribonucleic acid were measured by semiquantitative reverse transcription polymerase chain reaction. Mice injected with LPS/GalN demonstrated a breakdown in colonic barrier function, which correlated with enhanced proinflammatory cytokine secretion, bacterial translocation, and significant hepatic injury. A pretreatment with oral probiotics prevented the breakdown in intestinal barrier function, reduced bacterial translocation, and significantly attenuated liver injury. The inhibition of PPARgamma with GW9662 abrogated the protection induced by probiotics.
Orally administered probiotics prevented liver and intestinal damage in a mouse model of sepsis through a PPARgamma-dependent mechanism.
肠道屏障功能破坏和细菌易位增加是脓毒症和肝脏疾病发病机制中的关键事件。有人提出用无创且具有免疫调节作用的益生菌改变肠道微生物群，作为辅助治疗手段来降低细菌易位水平并预防脓毒症的发生。本研究的目的是确定一种益生菌化合物在减轻脓毒症小鼠模型肝损伤和肠损伤方面的疗效。野生型和白细胞介素 -10（IL -10）基因缺陷的129 Sv/Ev小鼠喂食益生菌化合物VSL#3 7天。为诱导脓毒症，在存在和不存在过氧化物酶体增殖物激活受体γ（PPARγ）抑制剂GW9662的情况下，给小鼠注射脂多糖（LPS）和D -半乳糖胺（GalN）。6小时后处死小鼠，取出结肠用于测量细胞因子产生和上皮功能。通过在Ussing小室中安装的组织中的甘露醇转运和环磷酸腺苷依赖性氯离子分泌来评估功能通透性。分析肝脏的细菌易位、细胞因子产生、组织学损伤和PPARγ水平。通过半定量逆转录聚合酶链反应测量肿瘤坏死因子α、干扰素γ、IL -6和IL -12p35核糖核酸的组织水平。注射LPS/GalN的小鼠表现出结肠屏障功能破坏，这与促炎细胞因子分泌增加、细菌易位和显著的肝损伤相关。口服益生菌预处理可防止肠道屏障功能破坏，减少细菌易位，并显著减轻肝损伤。用GW9662抑制PPARγ可消除益生菌诱导的保护作用。
口服益生菌通过PPARγ依赖性机制预防脓毒症小鼠模型中的肝损伤和肠损伤。
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