Investigating how xenobiotics interact with phages to shift energy balance

研究异生素如何与噬菌体相互作用以改变能量平衡

• 批准号: 10749135
• 负责人: Alexis B Kazen
• 金额: $ 4.77万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2025-08-21
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749135
• 关键词: 16S ribosomal RNA sequencing; Animals; Antipsychotic Agents; Bacteria; Bacterial Genome; Bacteriophages; Basal metabolic rate; Binding; Bioinformatics; Biomedical Research; Cardiovascular Diseases; Control Animal; DNA; Data; Development; Drug Prescriptions; Environment; Etiology; Feces; Future; Gene Expression Profiling; Generations; Goals; Growth; Health; Homeostasis; Immunology; Individual; Knowledge; Laboratories; Lactobacillus reuteri; Machine Learning; Mediating; Mediator; Metabolic; Metabolic syndrome; Microbiology; Molecular; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Production; Property; Public Health; Research; Risk; Risk Factors; Risperidone; Role; SOS Response; Supplementation; Syndrome; Testing; Therapeutic; Thinness; Time; Training; Viral; Weight; Weight Gain; Wisconsin; Woman; Work; Xenobiotics; antimicrobial; autistic; biomarker identification; biomedical scientist; comorbidity; comparison control; design; energy balance; experimental study; gut bacteria; gut microbiome; gut microbiota; medical schools; metagenomic sequencing; microbial; microbiome; microbiome analysis; microbiome composition; model organism; mutant; obesity development; obesity risk; obesogenic; particle; prevent; response; reutericyclin; stressor; targeted treatment; treatment group

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.

项目摘要 肥胖是一个主要的公共卫生问题，与几种合并症有关，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。我们的实验室研究了 处方SGA，利培酮，并已表明，体重增加与这种药物是由肠道介导的 微生物组噬菌体，或称噬菌体，在肠道中含量很高，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内的炎症， 并发现利培酮治疗导致细菌基因组中的β-内酰胺酶释放;这些β-内酰胺酶是 足以驱动体重增加和微生物组组成的变化，并且它们也具有增加的潜力 与对照组相比，它们能影响宿主的代谢状态。 虽然我们知道，脂肪酸是利培酮诱导的体重增加（RIWG）的重要贡献者，但我们还没有 以确定利培酮的存在如何机械地诱导这些震颤。温和噬菌体 通常是通过激活细菌SOS反应诱导的，导致利培酮是 作为细菌应激因子，诱导肠道细菌的SOS反应，最终导致释放 从细菌基因组中分离出来。这一假设将在目标1中加以研究。 我们发现，利培酮作用下释放β-内酰胺酶的一种细菌是罗伊氏硅乳杆菌。 进一步的生物信息学分析表明，L.在利培酮处理的动物中罗伊氏菌显著减少， 这表明它可能是瘦型的重要贡献者。小鼠与利培酮的共治疗 和L. reuteri阻止了RIWG并产生了与对照动物不同的微生物组。此外，本发明还 罗伊环素（reutericyclin，Rtc）是由L. reuteri，足以使 RIWG，建议L. reuteri通过发布RTC来改变RIWG的方向。RTC有已知的抗菌剂 和利培酮一样，它是一种小分子异生素，这导致了Rtc偏离RIWG的假设。 通过差异性地改变噬菌体组。目标2将研究这一假设。 这个项目的总体目标是了解外源性物质的存在如何催化改变 并确定这些改变如何有助于能量通量的变化。这项工作 将在医学部微生物学和免疫学系的John Kirby博士的实验室进行 威斯康星州，一个高度协作和刺激的环境，是装备精良，以执行 提出的目标。我们设计了一个培训计划，这将有利于我的科学和专业成长 并最终将使我能够实现成为一名独立的生物医学科学家的目标。总的来说， 这个项目是我作为一个自闭症女性在生物医学研究领域的基础， 研究，并产生基于微生物组的治疗外源性诱导的体重增加。