Investigating how xenobiotics interact with phages to shift energy balance

项目概要 肥胖是一个主要的公共卫生问题，与多种并发症相关，例如代谢综合征、 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（SGA）会导致体重显着增加，从而增加肥胖风险。我们的实验室广泛研究 处方 SGA，利培酮，并表明与该药物相关的体重增加是由肠道介导的 微生物组。噬菌体或噬菌体在肠道中含量丰富，是肠道的重要介质 微生物群落组成。因此，我们研究了利培酮治疗如何影响肠道中的噬菌体 并发现利培酮治疗会导致噬菌体从细菌基因组中释放；这些噬菌体是 足以推动体重增加和微生物组组成的变化，而且它们也具有增加的潜力 与对照噬菌体相比，影响细菌宿主的代谢状态。 虽然我们知道噬菌体是利培酮诱导体重增加 (RIWG) 的重要贡献者，但我们尚未发现 以确定利培酮的存在如何诱导这些噬菌体的机制。温带噬菌体 通常是通过激活细菌 SOS 反应来诱导的，从而导致利培酮是一种假说 作为细菌应激源，诱导肠道细菌的 SOS 反应，最终导致释放 来自细菌基因组的噬菌体。该假设将在目标 1 中进行研究。 我们发现一种响应利培酮而释放噬菌体的细菌种类是罗伊氏柠檬酸杆菌。 此外，生物信息学分析表明，在利培酮治疗的动物中，罗伊氏乳杆菌显着减少， 表明它可能是瘦表型的重要贡献者。小鼠与利培酮联合治疗 罗伊氏乳杆菌阻止了 RIWG 并产生了与对照动物不同的微生物组。另外， 罗伊氏环素 (Rtc) 是罗伊氏乳杆菌某些菌株产生的一种特殊代谢产物，足以使 RIWG，表明罗伊氏乳杆菌通过释放 Rtc 来转移 RIWG。 Rtc 具有已知的抗菌作用 性质，并且与利培酮一样，是一种小分子异生素，导致 Rtc 使 RIWG 偏转的假设 通过差异改变噬菌体。该假设将在目标 2 中进行研究。 该项目的总体目标是了解异生素的存在如何催化改变 并确定这些改变如何导致能量通量的变化。这部作品 将于医学部微生物学和免疫学系 John Kirby 博士的实验室进行 威斯康星学院拥有高度协作和激励的环境，具备充分的能力来执行 拟议的目标。我们设计了一个有利于我的科学和专业成长的培训计划 最终将使我实现成为一名独立生物医学科学家的目标。总而言之， 这个项目对于我作为一名自闭症女性在生物医学研究（肥胖领域）的进步至关重要 研究，以及基于微生物组的疗法的产生，以治疗外源性体重增加。

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.