An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis
An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis
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DOI：
10.1152/ajpgi.00078.2018
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发表时间：
2018-09-01
影响因子：
4.5
通讯作者：
Besner, Gail E.
中科院分区：
文献类型：
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作者：
Olson, Jacob K.;Navarro, Jason B.;Besner, Gail E.
目前用于预防坏死性小肠结肠炎（NEC）的益生菌疗法的一个显著缺点是需要至少每天施用，因为肠内施用后益生菌的持久性差。如果肠道已经受损，则增加益生菌引起菌血症或败血症的风险。我们先前表明，当罗伊氏乳杆菌（Lr）作为生物膜生长在右旋糖酐微球（DM）表面上时，其预防NEC的有效性得到增强。在这里，我们试图通过向DM中加入生物膜促进物质（蔗糖和麦芽糖）或通过突变Lr SOW基因（编码生物膜产生的核心酶）来操纵Lr生物膜状态来测试Lr给药的功效。使用NEC的动物模型，我们确定了Lr粘附于蔗糖或麦芽糖负载的DM显著减少组织损伤，改善宿主存活。与Lr粘附于未负载的DM相比，Lr降低了肠道通透性，减少了肠道炎症，并改变了肠道微生物组。当DM或GtfW不存在于Lr接种物中时，这些效应被消除。这表明，单剂量的Lr在其生物膜状态下降低NEC的发病率。重要的是，用蔗糖或麦芽糖预加载DM进一步增强了Lr以GtfW依赖的方式对NEC的保护，证明了该方法的可调性以及使用其他货物来增强未来益生菌制剂的潜力。新&值得注意的是以前的益生菌预防坏死性小肠结肠炎的临床试验结果不一。在这些研究中，益生菌以其无菌、自由生活的形式提供。我们已经开发了一种新的益生菌递送系统，其中罗伊氏乳杆菌（Lr）以其生物膜状态递送。在实验性坏死性小肠结肠炎模型中，与给予自由生活形式的Lr相比，该制剂显著降低了肠道炎症和通透性，提高了存活率，并保留了天然肠道微生物菌群。
One significant drawback of current probiotic therapy for the prevention of necrotizing enterocolitis (NEC) is the need for at least daily administration because of poor probiotic persistence after enteral administration. increasing the risk of the probiotic bacteria causing bacteremia or sepsis if the intestines are already compromised. We previously showed that the effectiveness of Lactobacillus reuteri (Lr) in preventing NEC is enhanced when Lr is grown as a biofilm on the surface of dextranomer microspheres (DM). Here we sought to test the efficacy of Lr administration by manipulating the Lr biofilm state with the addition of biofilm-promoting substances (sucrose and maltose) to DM or by mutating the Lr SOW gene (encoding an enzyme central to biofilm production). Using an animal model of NEC, we determined that Lr adhered to sucrose- or maltose-loaded DM significantly reduced histologic injury, improved host survival. decreased intestinal permeability, reduced intestinal inflammation, and altered the gut microbiome compared with Lr adhered to unloaded DM. These effects were abolished when DM or GtfW were absent from the Lr inoculum. This demonstrates that a single dose of Lr in its biofilm state de reases NEC incidence. Importantly, preloading DM with sucrose or maltose further enhances Lr protection against NEC in a GtfW-dependent fashion, demonstrating the tunability of the approach and the potential to use other cargos to enhance future probiotic formulations.NEW & NOTEWORTHY Previous clinical trials of probiotics to prevent necrotizing enterocolitis have had variable results. In these studies, probiotics were delivered in their planktonic, free-living form. We have developed a novel probiotic delivery system in which Lactobacillus reuteri (Lr) is delivered in its biofilm state. In a model of experimental necrotizing enterocolitis, this formulation significantly reduces intestinal inflammation and permeability, improves survival, and preserves the natural gut microflora compared with the administration of Lr in its free-living form.