Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics

探索性试点研究展示预防抗生素相关腹泻的机制和益生菌的作用

• 批准号: 10264947
• 负责人: DANIEL J MERENSTEIN
• 金额: $ 47.2万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264947
• 关键词: Acetates; Address; Age; Amoxicillin; Anaerobic Bacteria; Antibiotics; Bacteria; Bifidobacterium; Butyrates; Clavulanate; Clinical; Clostridium; Colon; Consumption; Control Groups; Data; Development; Double-Blind Method; Ecosystem; Effectiveness; Eubacterium; Firmicutes; Future; Gastrointestinal Diseases; Goals; Health Benefit; Hour; Human; In Situ; In Vitro; Investigational Drugs; Liquid Chromatography; Liquid substance; Participant; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Pilot Projects; Prevention; Probiotics; Production; Protocols documentation; Randomized; Randomized Controlled Trials; Recombinant DNA; Recovery; Research; Respiratory Tract Infections; Role; Sampling; Shapes; Supplementation; Time; Translational Research; United States Food and Drug Administration; Up-Regulation; Volatile Fatty Acids; Yogurt; absorption; antibiotic-associated diarrhea; colon bacteria; commensal bacteria; comparative; fecal microbiota; feeding; gastrointestinal; gut homeostasis; gut microbiota; metatranscriptomics; microbial; microbiome; microbiota; microorganism; pathogen; phase I trial; prevent; restoration; safety study; tandem mass spectrometry

Abstract Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, the efficacy of many probiotic products used for AAD is not supported by rigorous independent research, and non-evidence-based clinical usage is common. Data from several studies suggest antibiotic-induced disruption of commensal colonic bacteria results in a significant reduction in short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption, ultimately resulting in AAD. The probiotic strain Bifidobacterium animalis subsp. lactis BB-12 (BB-12) has been shown to ameliorate a variety of gastrointestinal disease states and is known to produce acetate – the most abundant primary colonic SCFA – at concentrations of up to 50 mM in vitro. Thus, we hypothesize that the concurrent administration of BB-12 with antibiotics will protect against the development of AAD by the ability of BB-12 to both generate acetate directly, and increase other SCFAs through cross-feeding of certain bacteria in the Firmicutes phylum. For example, Clostridium, Eubacterium and Roseburia use acetate to produce butyrate, another common SCFA. The primary aim of the R61 phase (N=60) is to determine if BB-12 can mitigate antibiotic-induced reduction in SCFA concentration, as reflected in fecal acetate levels. We hypothesize that antibiotics will decrease fecal SCFAs, but BB-12 supplementation will protect against antibiotic-induced SCFA reduction, and/or be associated with quicker restoration to baseline SCFA levels as compared to control. Antibiotic administration also lowers total microbial counts and diversity in the gut microbiota, disrupting the homeostasis of the gut ecosystem and allowing colonization by pathogens. The secondary aim uses 16S rDNA profiling to determine if BB-12 inhibits antibiotic-induced disruption of the gut microbiota. We hypothesize that antibiotics will diminish the overall number and diversity of bacterial species present in the fecal microbiota, and concurrent BB-12 supplementation will minimize antibiotic-induced shifts in the microbiota, and/or will be associated with shorter recovery to baseline microbiota composition as compared to control. In the R33 phase (N=108), to further delineate the effects of BB-12 administration on the antibiotic-depleted gut microbiota, we will evaluate the timing of probiotic administration in four randomly assigned groups: 1) BB-12 yogurt consumed at the same time as the antibiotic; 2) control yogurt consumed at the same time as the antibiotic; 3) BB-12 yogurt consumed four hours after the antibiotic; and 4) control yogurt consumed four hours after the antibiotic. Our long-term goal is to determine the impact of BB-12 on a variety of gastrointestinal disease states and ages. Elucidation of the mechanism(s) of action will be integral in shaping the direction of future translational research on probiotic effectiveness.

抽象的 益生菌是活体生物 主人。益生菌治疗的最常见迹象之一是预防抗生素相关 腹泻（AAD）。不幸的是，许多用于AAD的益生菌的效率不支持 严格的独立研究和非证据的临床用法很常见。来自几项研究的数据 建议抗生素引起的共生结肠细菌破坏导致短暂降低 链脂肪酸（SCFA）的产生和NA依赖性滥用液的伴随降低，最终 导致AAD。益生菌菌株双歧杆菌动物亚种。乳酸BB-12（BB-12）已显示为 改善各种胃肠道疾病状态，并已知会产生醋酸盐 - 最丰富的 原发性结肠SCFA - 体外浓度高达50毫米。那我们假设并发 用抗生素给予BB-12将通过BB-12的能力来防止AAD的发展 两者都可以直接产生乙酸盐，并通过交叉喂养某些细菌中的某些细菌来增加其他SCFA Firmicutes门。例如，梭状芽胞杆菌，花生和罗斯伯里亚使用醋酸酯产生丁酸酯， 另一个常见的SCFA。 R61期的主要目的（n = 60）是确定BB-12是否可以减轻 抗生素诱导的SCFA浓度降低，如粪便中反映。我们假设这一点 抗生素会降低粪便SCFA，但补充BB-12将防止抗生素诱导的SCFA 与对照相比，还原和/或与基线SCFA水平更快地恢复。 抗生素给药还降低了肠道微生物群中的总微生物计数和多样性，从而破坏了 肠道生态系统的稳态，并允许病原体殖民化。次要目标使用16S rDNA 分析以确定BB-12是否抑制抗生素诱导的肠道菌群破坏。我们假设这一点 抗生素会减少粪便菌群中存在的细菌物种的总数和多样性， 并发补充BB-12将最大程度地减少抗生素诱导的微生物群的转移，并且/或将是/或将是 与对照相比，与基线菌群组成的恢复较短。在R33阶段 （n = 108），为了进一步描述BB-12给药对抗生素缺失的肠道微生物群的影响，我们 将评估四个随机分配组的益生菌给药的时间：1）BB-12 与抗生素同时食用； 2）控制酸奶与抗生素同时消耗； 3） BB-12酸奶在抗生素后四个小时消耗； 4）控制酸奶在四个小时后消耗 抗生素。我们的长期目标是确定BB-12对多种胃肠道疾病状态的影响 和年龄。阐明动作机制将在塑造未来方向上是不可或缺的 益生菌有效性的翻译研究。