Circadian Regulation of Antibiotic Resistance in the Microbiome

项目摘要 人类必须调节与近100万亿肠道细菌的共生关系， 抗生素抗性基因及其传播机制。尽管抗生素的使用不断增加 关于体内调节抗生素耐药性发展的宿主因子知之甚少。 初步调查显示，哺乳动物的生物钟可能是这样一个因素。既往体内研究 已经证明，生物钟驱动微生物组组成的每日节律， 与昼夜周期同步。然而，在昼夜节律时间尺度上微生物组中的基因表达是 大部分未开发。为此，对小鼠微生物组进行了全面的研究。 昼夜光循环这些数据显示，除了微生物丰度的日常节律外， 在昼夜光周期中，微生物组中发生转录节律。事实上，抗生素耐药性 水平基因转移系统显示了一些最重要的转录节律， 微生物组，每天在4小时窗口内达到峰值表达。这些初步数据表明， 微生物组中的转录在体内是时间结构化的。这些昼夜节律是 受宿主生物钟调节的特性。因此，这项建议旨在了解 通过检查微生物组中细菌昼夜转录的体内调节， 水平基因转移和宿主生物钟对抗生素耐药性传播的影响。采取 总之，这项工作提出了昼夜节律钟在微生物组中的转录， 周期，可能揭示了哺乳动物抗生素耐药性发展的调节因子。

Project Summary Humans must regulate a symbiotic relationship with almost 100 trillion intestinal bacteria which readily harbor antibiotic resistance genes and the mechanisms that spread them. Despite the relentless rise of antibiotic resistant infections little is known about the host factors that regulate antibiotic resistance development in vivo. Preliminary investigations revealed that the mammalian circadian clock may be such a factor. Prior in vivo studies have demonstrated that the circadian clock drives daily rhythms in microbiome composition which are synchronized to the day-night cycle. However, gene expression in the microbiome at circadian time scales is largely unexplored. To this end, a comprehensive study of the mouse microbiome was performed across the day-night light cycle. These data revealed that beyond daily rhythms of microbe abundances, extensive transcriptional rhythms occur in the microbiome across the day-night light cycle. Indeed, antibiotic resistance and horizontal gene transfer systems showed some of the most significant transcriptional rhythms in the microbiome, reaching peak expression within a 4-hour window each day. These preliminary data demonstrated that transcription in the microbiome is temporally structured in vivo. These diurnal (daily) rhythms are characteristic of regulation by the host’s circadian clock. Therefore, this proposal seeks to understand mechanisms driving diurnal bacterial transcription in the microbiome by examining the in vivo regulation of horizontal gene transfer and the impact of the host circadian clock on the spread of antibiotic resistance. Taken together, this work proposes the circadian clock synchronizes transcription in the microbiome to the day-night cycle, potentially revealing a mammalian regulator of antibiotic resistance development.