Investigating how xenobiotics interact with phages to shift energy balance

项目摘要 肥胖是一个主要的公共卫生问题，与几种共病相关，如代谢综合征， 2型糖尿病和心血管疾病。许多处方药，包括第二代 抗精神病药物(SGAs)，通过导致体重显著增加而增加肥胖风险。我们的实验室广泛地研究 处方中的SGA，利培酮，并已表明与该药物相关的体重增加是由肠道调节的 微生物组。噬菌体，或称噬菌体，在肠道中含量非常丰富，是肠道的重要媒介。 微生物群落组成。因此，我们调查了利培酮治疗如何影响肠道内的噬菌体。 并发现利培酮治疗会导致细菌基因组中的噬菌体释放；这些噬菌体是 足以推动体重增加和微生物组组成的转变，而且它们也有更大的潜力 与对照噬菌体相比，影响其细菌宿主的代谢状态。 虽然我们知道噬菌体是利培酮诱导的体重增加(RIWG)的重要贡献者，但我们还没有 从机制上确定这些噬菌体是如何在利培酮存在下被诱导的。温带噬菌体 通常是通过激活细菌的SOS反应来诱导的，导致了利培酮是 作为细菌应激源，在肠道细菌中诱导SOS反应，最终导致 细菌基因组中的噬菌体。这一假设将在目标1中进行研究。 我们发现有一种细菌能对利培酮做出反应，释放噬菌体，那就是里氏利莫硅乳杆菌。 此外，生物信息学分析显示，在利培酮处理的动物中，路支杆菌显著枯竭， 这表明它可能是瘦肉型的一个重要因素。利培酮联合治疗小鼠的实验研究 而路氏乳杆菌抑制了RIWG，并产生了与对照动物不同的微生物群。另外， 鲁氏乳杆菌某些菌株产生的一种特殊代谢物reurcyclin(RTC)足以转移 RIWG，表明L.reuri通过释放RTC来偏转RIWG。RTC已知抗菌剂 性质，和利培酮一样，是一种小分子异生物质，导致假设RTC偏转RIWG 通过不同的方式改变噬菌体。这一假设将在目标2中进行研究。 这个项目的总体目标是了解外来生物的存在如何催化变化。 并确定这些变化如何导致能量通量的变化。这部作品 将在医学院微生物学和免疫学系约翰·柯比博士的实验室举行 威斯康星大学，一个高度协作和激励的环境，非常适合表演 建议的目标。我们设计了一个对我的科学和专业成长有利的培训计划 最终将使我达到成为一名独立生物医学科学家的目标。总而言之， 这个项目是我作为一名自闭症女性在生物医学研究、肥胖领域取得进步的基础。 针对外来生物引起的体重增加的研究和基于微生物组的治疗药物的产生。

Project Summary Obesity is a major public health concern associated with several co-morbidities, such as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Many prescription medications, including second-generation antipsychotics (SGAs), increase obesity risk by causing significant weight gain. Our lab studies the widely prescribed SGA, risperidone, and has shown that weight gain associated with this drug is mediated by the gut microbiome. Bacteriophages, or phages, are highly abundant in the gut and are important mediators of the gut microbial community composition. Thus, we investigated how risperidone treatment influences phages in the gut and found that risperidone treatment leads to the release of phages from bacterial genomes; these phages are sufficient to drive weight gain and shifts in microbiome composition, and they also have an increased potential to influence their bacterial hosts’ metabolic state compared to control phages. While we know that phages are important contributors to risperidone-induced weight gain (RIWG), we have yet to determine mechanistically how these phages are induced by the presence of risperidone. Temperate phages are often induced through activation of the bacterial SOS response, leading to the hypothesis that risperidone is acting as a bacterial stressor that induces the SOS response in gut bacteria, ultimately leading to the release of phages from the bacterial genomes. This hypothesis will be investigated in Aim 1. One bacterial species that we found to release phages in response to risperidone is Limosilactobacillus reuteri. Further, bioinformatics analysis revealed that L. reuteri is significantly depleted in risperidone-treated animals, suggesting that it may be an important contributor to a lean phenotype. Co-treatment of mice with risperidone and L. reuteri prevented RIWG and generated a microbiome distinct from that of control animals. Additionally, reutericyclin (Rtc), a specialized metabolite produced by some strains of L. reuteri, was sufficient to deflect RIWG, suggesting that L. reuteri deflects RIWG through the release of Rtc. Rtc has known antimicrobial properties and, like risperidone, is a small molecular xenobiotic leading to the hypothesis that Rtc deflects RIWG by differentially altering the phageome. This hypothesis will be investigated in Aim 2. The overall goal of this project is to understand how the presence of xenobiotics can catalyze alterations in the phageome and determine how these alterations can contribute to changes in energy flux. This work will take place in the laboratory of Dr. John Kirby in the Department of Microbiology & Immunology at the Medical College of Wisconsin, a highly collaborative and stimulating environment that is well equipped to perform the proposed aims. We have designed a training plan that will be beneficial for my scientific and professional growth and ultimately will position me to reach my goal of becoming an independent biomedical scientist. Altogether, this project is fundamental for my advancement as an autistic woman in biomedical research, the field of obesity research, and the generation of microbiome-based therapeutics for xenobiotic-induced weight gain.