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

摘要 益生菌是活的微生物，当以足够的量施用时， 主持人益生菌治疗最常见的适应症之一是预防与益生菌相关的 腹泻（AAD）。不幸的是，许多用于AAD的益生菌产品的功效并不被 严格的独立研究和非循证临床使用是常见的。来自多项研究的数据 提示，抗生素诱导结肠细菌的破坏导致了短时间内的显著降低， 链脂肪酸（SCFA）的产生和伴随的钠依赖性液体吸收的减少，最终 导致AAD。益生菌菌株Bifidobacterium animalis subsp.乳酸BB-12（BB-12）已被证明 改善各种胃肠道疾病状态，并已知产生乙酸盐-最丰富的 原代结肠SCFA -体外浓度高达50 mM。因此，我们假设， BB-12与抗生素一起给药将通过BB-12的能力防止AAD的发展， 两者都直接产生乙酸盐，并通过交叉喂养某些细菌来增加其他SCFA。 厚壁菌门例如，梭菌属（Clostridium）、真杆菌属（Eubacterium）和罗斯拜瑞氏菌属（Roseburia）使用乙酸盐来产生丁酸盐， 另一种常见的SCFA。R61阶段（N=60）的主要目的是确定BB-12是否可以缓解 粪便中乙酸盐水平反映了粪便诱导的SCFA浓度降低。我们假设 抗生素将减少粪便SCFA，但BB-12补充剂将防止抗生素诱导的SCFA 减少，和/或与更快恢复到基线SCFA水平相关联。 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，破坏了肠道微生物的生长。 肠道生态系统的稳态和允许病原体的定植。第二个目的是使用16 S rDNA 分析以确定BB-12是否抑制肠道微生物群的益生菌诱导的破坏。我们假设 抗生素将减少粪便微生物群中存在的细菌物种的总数和多样性， 并且同时补充BB-12将最小化微生物群中的益生菌诱导的变化，和/或将 与对照相比，与基线微生物群组成的较短恢复相关。在R33阶段 （N=108），为了进一步描述BB-12给药对消化道消耗的肠道微生物群的影响，我们 将在四个随机分配的组中评估益生菌施用的时间：1）BB-12酸奶 与抗生素同时食用; 2）与抗生素同时食用的对照酸奶; 3） BB-12酸奶在抗生素后四小时食用;和4）对照酸奶在抗生素后四小时食用。 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。阐明行动机制将是确定未来发展方向的组成部分。 益生菌有效性的转化研究。

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.