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: 10222939
• 负责人: DANIEL J MERENSTEIN
• 金额: $ 43.34万
• 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/10222939
• 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; Homeostasis; 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 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.

摘要 益生菌是活的微生物，当给予足够的量时，对健康有益 主持人。益生菌治疗最常见的适应症之一是预防抗生素相关的 腹泻(AAD)。不幸的是，许多用于AAD的益生菌产品的疗效没有得到 严格的独立研究和非循证临床应用是常见的。来自几项研究的数据 提示抗生素诱导的共生结肠菌的破坏导致在短时间内显著减少 链脂肪酸(SCFA)的产生和伴随的钠依赖体液吸收的减少，最终 导致了AAD。益生菌动物双歧杆菌亚种。乳酸BB-12(BB-12)已被证明 改善各种胃肠道疾病状态，并已知产生醋酸盐--最丰富的 原代结肠SCFA-在体外浓度高达50 mM。因此，我们假设并发的 与抗生素一起使用BB-12将通过BB-12的能力来防止AAD的发展 两者都直接产生醋酸盐，并通过交叉喂养某些细菌来增加其他SCFA 菲尔米特斯门。例如，梭状芽胞杆菌、真细菌和Roseburia使用醋酸盐来生产丁酸盐， 另一种常见的SCFA。R61阶段(N=60)的主要目标是确定BB-12是否可以缓解 抗生素诱导的SCFA浓度降低，反映在粪便醋酸盐水平上。我们假设 抗生素会减少粪便中的SCFA，但补充BB-12可以防止抗生素诱导的SCFA 减少，和/或与与对照相比更快地恢复到基线SCFA水平有关。 抗生素的使用也降低了肠道微生物区系中的微生物总数和多样性，扰乱了 肠道生态系统的动态平衡，并允许病原体的定居。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微生物区系的破坏。我们假设 抗生素将减少粪便微生物区系中细菌物种的总数和多样性， 同时补充BB-12将最大限度地减少抗生素引起的微生物区系变化，和/或将 与对照相比，微生物区系组成恢复到基线水平的时间更短。在R33阶段 (n=108)，为了进一步描述BB-12给药对抗生素耗竭的肠道微生物区系的影响，我们 将评估四组随机分配的益生菌给药时间：1)BB-12酸奶 与抗生素同时食用；2)控制酸奶与抗生素同时食用；3) BB-12酸奶在抗生素注射后4小时饮用；4)对照组酸奶在抗生素注射后4小时饮用 抗生素。我们的长期目标是确定BB-12对各种胃肠道疾病状态的影响 和年龄。对作用机制的阐明(S)将是塑造未来方向不可或缺的一部分 益生菌有效性的翻译研究。