Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis

项目摘要 靶向肠粘膜和微生物组以预防新生儿迟发性脓毒症。晚发型败血症 (LOS)是早产儿发病和死亡的主要原因，被认为是由 肠道微生物的系统性传播。发育中的肠道微生物组的扰动（生态失调） 早产儿比足月儿更常见，被认为是导致其升高的基础。 对LOS的敏感性，虽然导致这种情况的机制还没有很好的理解。我们最近 开发了一种新的新生儿LOS小鼠模型，该模型证实了长期以来临床上对直接LOS的怀疑。 生态失调和LOS之间的联系。我们发现，通过改变发育中的微生物组来防止生态失调， 我们能够防止LOS。这种保护作用与内源性Ligilaclactin的丰度有关。 （以前的乳杆菌）鼠，其中一些菌株被证明是有效的，在防止LOS时， 作为益生菌使用。然而，值得注意的是，即使是密切相关的L。鼠类分离物差异很大 在它们的益生菌功效中，乳杆菌的其他菌株也是如此，包括许多菌株， 商业益生菌。此外，我们还发现L.防止生态失调的鼠 和LOS改变了肠上皮的氧状态，这表明这些菌株可能调节 肠道氧化还原状态，以防止兼性厌氧菌的生长，可以呼吸氧气或其他 呼吸末端电子受体。尽管成年人中驱动生态失调的主要机制增加了， 细菌呼吸底物的可用性，使兼性厌氧菌胜过专性厌氧菌 厌氧微生物在健康微生物组中占主导地位，我们的初步研究表明， 在炎症或感染条件下使成人肠易患生态失调的因素至少部分地 与未成熟的新生儿肠道中的不同。因此，我们认为新生儿的肠道是 易受微生态失调的影响，其机制与先前成人的特征不同， 肠的发育不成熟和发育中的肠道微生物组的早期不稳定。这里我们 将采取团队科学的方法来阐明新生儿生态失调的宿主和微生物决定因素， 易患LOS，结合两个实验室在肠道生物学方面互补的专业知识， 免疫（韦弗），微生物遗传学和细菌呼吸（格雷）与合作者谁是领导者 在微生物基因组学（朱莉塞格雷），炎症相关的肠道生态失调（塞巴斯蒂安冬季）和消化学 （Namasivayan Ambalavanan）.通过确定发展中国家特有的生态失调机制， 我们将为更合理地设计益生菌和益生元提供基础， 预防早产儿LOS的治疗干预。

PROJECT SUMMARY Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis. Late-onset sepsis (LOS) is a leading cause of morbidity and mortality in premature infants and is thought to be caused by the systemic spread of commensal microbes. Perturbation in the developing intestinal microbiome (dysbiosis) is far more common in premature infants than in full-term infants and is thought to underlie their heightened susceptibility to LOS, although the mechanisms that predispose to this are not well understood. We recently developed a new murine model of neonatal LOS, which has confirmed the long-held clinical suspicion of a direct link between dysbiosis and LOS. We discovered that, by altering the developing microbiome to prevent dysbiosis, we were able to prevent LOS. This protection correlated with the abundance of endogenous Ligilactobacillus (formerly Lactobacuillus) murinus, some isolates of which proved to be effective in preventing LOS when administered as probiotics. Remarkably, however, even closely-related L. murinus isolates differed considerably in their probiotic efficacy, as did other strains of Lactobacilli—including a number of strains that are components of commercial probiotics. Moreover, we have found that probiotic strains of L. murinus that prevented dysbiosis and LOS altered the oxygen status of the intestinal epithelium, suggesting that these strains may modulate intestinal redox status to prevent the outgrowth of facultative anaerobes that can respire oxygen or other respiratory terminal electron acceptors. Although a major mechanism driving dysbiosis in adults is increased availability of substrates of bacterial respiration that allows facultative anaerobes to outcompete the obligate anaerobes that predominate in a healthy microbiome, our preliminary studies indicate that mechanisms that predispose the adult intestine to dysbiosis under conditions of inflammation or infection are at least partially disparate with those in the immature neonatal intestine. We therefore posit that the neonatal intestine is susceptible to dysbiosis via mechanisms distinct from those previously characterized in adults, reflecting developmental immaturity of the intestines and early instability of the developing intestinal microbiome. Here, we will take a team science approach to elucidate both host and microbial determinants of neonatal dysbiosis that predispose to LOS, marrying the efforts of two labs with complementary expertise in intestinal biology and immunity (Weaver), and microbial genetics and bacterial respiration (Gray) with collaborators who are leaders in microbial genomics (Julie Segre), inflammation-associated gut dysbiosis (Sebastian Winter) and neonatology (Namasivayan Ambalavanan). Through the identification of mechanisms of dysbiosis unique to the developing intestines and microbiome we will provide a foundation for more rational design of probiotics and prebiotics for therapeutic interventions that prevent LOS in premature infants.