Tunable Native Probiotic Formulations for the Treatment of NEC.

用于治疗 NEC 的可调节天然益生菌制剂。

• 批准号: 9883801
• 负责人: MICHAEL T BAILEY
• 金额: $ 31.79万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883801
• 关键词: Adherence; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Antimicrobial Effect; Bacteria; Biological Process; Clinical; Communities; Data; Development; Disease; Dose; Effectiveness; Extracellular Matrix; Formulation; Gastric Acid; Goals; Health Promotion; Histamine Production; In Vitro; Incidence; Infant; Inflammatory Response; Injury; Intestinal Mucosa; Intestines; Lactobacillus reuteri; Maltose; Microbial Biofilms; Microspheres; Morbidity - disease rate; Multiple Organ Failure; Necrosis; Necrotizing Enterocolitis; Neonatal; Outcome; Patients; Permeability; Premature Infant; Probiotics; Production; Property; Rattus; Research; Resistance; Risk; Shock; Structure; Sucrose; System; Testing; Therapeutic; Therapeutic Intervention; antimicrobial; base; biomaterial compatibility; design; extracellular; gut colonization; gut microbiome; improved; in vitro Assay; in vivo; inflammatory disease of the intestine; innovation; insight; microbiome; mortality; neonate; novel; novel strategies; prebiotics; premature; prevent; targeted delivery; therapeutic effectiveness; therapy outcome; virtual

Despite decades of research, the morbidity and mortality of necrotizing enterocolitis (NEC) remain unchanged. An altered intestinal microbiome and intestinal inflammation may predispose prematures to NEC. Probiotics may protect the intestines from NEC, however, they have to be delivered in high numbers with repeated dosing for any effect. We have developed a novel, tunable delivery system in which Lactobacillus reuteri (Lr) administered in a protective biofilm on biocompatable microspheres provides persistent probiotic benefits from just a single dose, greatly reducing experimental NEC. Our long-term goal is to identify novel strategies to protect neonates from NEC. The current overall objective is to identify a novel probiotic-based therapy protective against experimental NEC. Our central hypothesis is that administering Lr in a biofilm state with biocompatible microspheres that can be loaded with beneficial luminal cargo significantly improves its ability to colonize the intestines, reduce intestinal inflammation, and decrease the incidence of NEC. The rationale is that identification of an optimal probiotic delivery system will lead to maximally beneficial treatment of NEC. Elucidating the attributes of Lr that prevent NEC will also provide insight into factors essential for NEC development. We will objectively test our central hypothesis by pursuing the following specific aims: 1) To determine the impact of our Lr formulation in protection of the intestines from NEC. 2) Tuning the beneficial activities (biofilm formation, antimicrobial and anti-inflammatory effects) of Lr to optimize our therapeutic formulation. 3) To determine whether tuning the properties of Lr alters its ability to protect the intestines from NEC. Expected outcomes include identification of the most effective Lr delivery system to reduce NEC, and determination of the relative importance of anti-inflammatory and anti-microbial effects of Lr in protection from NEC. The significance is a better understanding of the effects of probiotics on protection of intestines, allowing the best design of clinical probiotic-based therapies for NEC. This will have a positive impact in terms of providing improved therapeutic interventions for patients at risk of developing NEC, in addition to fundamentally advancing our understanding of the mechanisms by which Lr exerts its beneficial intestinal effects. This research is innovative because it involves a novel probiotic formulation that: (i) requires only a single dose for beneficial effects on NEC and (ii) is a platform by which mechanisms of probiosis can be studied through targeted delivery of prebiotic substrates in well defined microspheres.

尽管经过几十年的研究，坏死性小肠结肠炎（NEC）的发病率和死亡率仍然很低， 保持不变。肠道微生物组的改变和肠道炎症可能使 不成熟的NEC益生菌可以保护肠道免受NEC的侵害，但是，它们必须 以高数量重复给药以达到任何效果。我们开发了一部小说， 可调递送系统，其中罗伊氏乳杆菌（Lr）在保护性生物膜中施用于 生物相容性微球仅从单剂量提供持久的益生菌益处， 大大降低了实验NEC。我们的长期目标是确定新的战略， NEC的新生儿。目前的总体目标是确定一种新的益生菌为基础的治疗 对实验性NEC有保护作用。我们的中心假设是， 具有生物相容性微球的生物膜状态 显著提高其在肠道定植的能力，减少肠道炎症， 降低NEC的发生率。基本原理是，确定最佳益生菌 递送系统将导致NEC的最大有益治疗。阐明的属性 防止NEC的LR也将提供对NEC发展的必要因素的洞察。 我们将通过追求以下具体目标来客观地检验我们的中心假设： 1)确定我们的Lr制剂在保护肠道免受NEC影响方面的影响。 2)调节有益活性（生物膜形成、抗菌和抗炎 Lr的作用），以优化我们的治疗配方。 3)为了确定调整Lr的属性是否会改变其保护 NEC的肠。 预期成果包括确定最有效的激光发射系统， NEC，并确定抗炎和抗微生物的相对重要性 Lr对NEC的保护作用。其意义在于更好地理解 益生菌对肠道的保护作用，使临床设计的最佳益生菌为基础 治疗NEC。这将在提供改善的治疗方面产生积极的影响。 对有发生NEC风险的患者进行干预，除了从根本上推进我们的 了解Lr发挥其有益肠道作用的机制。这 研究是创新的，因为它涉及一种新的益生菌制剂，该制剂：（i）仅需要 单剂量对NEC的有益作用，和（ii）是一个平台，通过该平台益生菌的机制 可以通过在良好限定的微球中靶向递送益生元底物来研究。

项目成果

Lactobacillus reuteri in Its Biofilm State Improves Protection from Experimental Necrotizing Enterocolitis.

• DOI: 10.3390/nu13030918
• 发表时间: 2021-03-12
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Al-Hadidi A;Navarro J;Goodman SD;Bailey MT;Besner GE
• 通讯作者: Besner GE

A novel probiotic therapeutic in a murine model of Clostridioides difficile colitis.

• DOI: 10.1080/19490976.2020.1814119
• 发表时间: 2020-11-09
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Shelby RD;Janzow GE;Mashburn-Warren L;Galley J;Tengberg N;Navarro J;Conces M;Bailey MT;Goodman SD;Besner GE
• 通讯作者: Besner GE

Next-Generation Probiotic Therapy to Protect the Intestines From Injury.

• DOI: 10.3389/fcimb.2022.863949
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

Enhanced Probiotic Potential of Lactobacillus reuteri When Delivered as a Biofilm on Dextranomer Microspheres That Contain Beneficial Cargo.

• DOI: 10.3389/fmicb.2017.00489
• 发表时间: 2017
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Navarro JB;Mashburn-Warren L;Bakaletz LO;Bailey MT;Goodman SD
• 通讯作者: Goodman SD

Antibacterial and anti-inflammatory effects of Lactobacillus reuteri in its biofilm state contribute to its beneficial effects in a rat model of experimental necrotizing enterocolitis.

罗伊氏乳杆菌在其生物膜状态下的抗菌和抗炎作用有助于其在实验性坏死性小肠结肠炎大鼠模型中发挥有益作用。

• DOI: 10.1016/j.jpedsurg.2021.09.001
• 发表时间: 2022
• 期刊: Journal of pediatric surgery
• 影响因子: 2.4
• 作者: Shelby,RitaD;Mar,Pamela;Janzow,GraceE;Mashburn-Warren,Lauren;Tengberg,Natalie;Navarro,JasonB;Allen,JacobM;Wickham,Joseph;Wang,Yijie;Bailey,MichaelT;Goodman,StevenD;Besner,GailE
• 通讯作者: Besner,GailE