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

针对肠粘膜和微生物组预防新生儿迟发性脓毒症

• 批准号: 10317586
• 负责人: Michael Jeffrey Gray
• 金额: $ 70.52万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317586
• 关键词: Adult; Alabama; Anaerobic Bacteria; Anaerobiosis; Animal Model; Antibiotics; Automobile Driving; Biology; Cell Maturation; Cells; Child; Clinical; Collaborations; Development; Disease; Dose; Enterobacteriaceae; Epithelial; Epithelial Cells; Family; Foundations; Future; Genes; Genetic; Genetic Transcription; Goals; Immune; Immunity; Incidence; Infant; Infection; Inflammation; Intervention; Intestinal Mucosa; Intestines; Klebsiella pneumoniae; Lactobacillus; Link; Mediating; Metagenomics; Microbial Genetics; Molecular; Morbidity - disease rate; Neonatal; Neonatology; Outcome; Oxidants; Oxidation-Reduction; Oxygen; Pathway interactions; Patients; Predisposition; Premature Infant; Prevention; Probiotics; Research; Research Personnel; Respiration; Sampling; Science; Sepsis; Signal Transduction; Staphylococcaceae; Testing; Therapeutic Intervention; Translating; Variant; Work; age related; base; clinically relevant; commensal bacteria; commensal microbes; design; dysbiosis; electron donor; enteric infection; gut dysbiosis; gut microbes; gut microbiome; high risk infant; host microbiome; human disease; inflammatory disease of the intestine; insight; interdisciplinary approach; intestinal epithelium; lactic acid bacteria; late onset sepsis; microbial; microbial genomics; microbiome; microbiota; mortality; mouse model; neonate; novel; pathobiont; prebiotics; prevent; programs; respiratory

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.

项目概要 针对肠粘膜和微生物组预防新生儿迟发性脓毒症。迟发性败血症 （LOS）是早产儿发病和死亡的主要原因，被认为是由 共生微生物的系统性传播。发育中的肠道微生物组的扰动（菌群失调）远非如此 早产儿比足月儿更常见，被认为是早产儿体重增加的原因 LOS 的易感性，尽管导致这种情况的机制尚不清楚。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怀疑的直接证据 生态失调和 LOS 之间的联系。我们发现，通过改变正在发育的微生物组来防止生态失调， 我们能够防止 LOS。这种保护与内源性 Ligilactobacillus 的丰度相关 （以前称为鼠乳杆菌），其中一些分离株被证明可有效预防 LOS 作为益生菌施用。然而，值得注意的是，即使是密切相关的 L. murinus 分离株也存在很大差异 其益生菌功效，以及其他乳酸菌菌株（包括许多作为其组成部分的菌株） 商业益生菌。此外，我们还发现鼠乳杆菌益生菌菌株可以防止菌群失调 LOS 改变了肠上皮的氧状态，表明这些菌株可能调节 肠道氧化还原状态，以防止可以呼吸氧气或其他物质的兼性厌氧菌的生长 呼吸末端电子受体。尽管驱动成人生态失调的一个主要机制有所增加 细菌呼吸底物的可用性使兼性厌氧菌能够战胜专性厌氧菌 厌氧菌在健康微生物组中占主导地位，我们的初步研究表明，其机制 在炎症或感染的情况下，至少部分地使成人肠道易发生菌群失调 与未成熟的新生儿肠道不同。因此我们推测新生儿肠道是 通过与先前在成人中描述的机制不同的机制，容易出现生态失调，反映 肠道发育不成熟和发育中肠道微生物组的早期不稳定。在这里，我们 将采取团队科学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，将两个实验室的努力结合起来，在肠道生物学和 免疫（Weaver），以及微生物遗传学和细菌呼吸（Gray）与领导者的合作者 微生物基因组学 (Julie Segre)、炎症相关肠道菌群失调 (Sebastian Winter) 和新生儿学 （纳马西瓦扬·安巴拉瓦南）。通过识别发育中独特的生态失调机制 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 的治疗干预措施。