Prenatal Opioid Exposure and Inflammation: The Role of the Microbiome and Epigenome.

产前阿片类药物暴露和炎症：微生物组和表观基因组的作用。

• 批准号: 10235840
• 负责人: Yaa Abu
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10235840
• 关键词: Address; Adult; Affect; Age; Animal Model; Anti-Inflammatory Agents; Attenuated; Birth; Blood Circulation; Brain region; Cells; Chronic; Data; Development; Distress; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Equilibrium; Exposure to; Goals; Histones; Human; Hydromorphone; Immune; Immune System Diseases; Immune response; Immune system; Immunosuppression; Impairment; Incidence; Infant; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Intestines; Investigation; Life; Lysine; Maintenance; Measures; Mediating; Mediator of activation protein; Modeling; Modification; Molecular; Morbidity - disease rate; Morphine; Mus; National Institute of Drug Abuse; Neonatal; Neonatal Abstinence Syndrome; Neurologic Symptoms; Opioid; Phenotype; Play; Population; Pregnancy; Production; Promoter Regions; Recording of previous events; Regulation; Reporting; Role; Streptococcus pneumoniae; Syndrome; Systemic Inflammatory Response Syndrome; TLR4 gene; TNF gene; Taxonomy; Testing; United States; Woman; brain tissue; cytokine; differential expression; dysbiosis; epigenetic regulation; epigenome; experience; fetal opioid exposure; functional disability; genomic locus; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; gut-brain axis; immunoregulation; in utero; insight; interest; macrophage; metabolome; microbial; microbiome; mortality; mouse model; neutrophil; offspring; opioid epidemic; opioid exposure; opioid use; opioid user; postnatal; prenatal; prenatal exposure; probiotic therapy; promoter; reproductive; response; systemic inflammatory response

Project Summary The heightened incidence of opioid use during pregnancy in the wake of the ongoing opioid crisis motivates this targeted investigation into the impact of prenatal opioid exposure. Here, we examine the molecular mechanisms through which prenatal opioid exposure produces systemic inflammation and immunosuppressive phenotypes later in life. This result is consistent with systemic inflammatory response syndrome (SIRS) followed by the corresponding compensatory anti-inflammatory response syndrome (CARS) that restricts harmful systemic immune responses. Recent studies have implicated the role of microbial dysbiosis in systemic inflammation and epigenetic modifications of macrophages in CARS-mediated immunosuppression. Specifically, adult models have shown that following chronic opioid exposure, gut microbial dysbiosis initiates TLR4-induced systemic inflammation. Opioid use during pregnancy results in gut dysbiosis that is strongly correlated with diversity and taxonomy of the infant microbiome. Taken together, it is plausible that prenatal opioid exposure results in neonatal gut microbial dysbiosis which contributes to systemic inflammation. Surprisingly, probiotic therapy does not fully attenuate opioid-induced immune dysfunction, suggesting other mechanisms at play that contribute to immunosuppressive phenotypes following SIRS such as epigenetic modifications of macrophages. H3K9me2 modifications in the IL-1β and TNFα promoters of macrophages following SIRS have commonly been described; adult models of chronic opioid use have largely limited their analysis of these modifications to brain tissue where, promisingly, differential expression of H3K9me2 modifications in several brain regions has been shown. Given these preliminary findings, this project aims to study these modifications on a cellular level in intestinal macrophages. I hypothesize that prenatal opioid exposure results in microbial dysbiosis, which contributes to systemic inflammation; additionally, opioid-induced systemic inflammation that persists postnatally alters the epigenome of intestinal macrophages which further perpetuates immune dysfunction. To date, there have been no reported studies on how prenatal opioid exposure affects the gut microbiome or how opioid-induced inflammation leads to epigenetic modifications of macrophages. Thus, the goal of this project is to characterize immune dysfunction following prenatal opioid exposure and to define underlying mechanisms through the following two Specific Aims. Aim 1. Determine how alterations in the gut microbiome following prenatal opioid exposure contribute to systemic inflammation by examining gut microbial and metabolome composition, gut barrier integrity, and TLR4-induced systemic inflammation. Aim 2. Characterize immune dysfunction following prenatal opioid exposure and the effects of opioid-induced inflammation on H3K9me2 modifications in intestinal macrophages. Collectively, this proposal will contribute an in-depth understanding of immune dysfunction following prenatal opioid exposure and will provide the first insights into epigenetic and microbiome regulation of immune dysfunction.

项目摘要 在持续的阿片类药物危机之后，妊娠期间阿片类药物使用的发生率增加， 对产前阿片类药物暴露的影响进行有针对性的调查。在这里，我们研究了 通过产前阿片类药物暴露产生全身性炎症和免疫抑制表型 在以后的人生中。这一结果与全身炎症反应综合征（SIRS）一致， 相应的代偿性抗炎反应综合征（汽车），限制有害的全身性 免疫反应。最近的研究表明，微生物生态失调在全身性炎症中的作用， CAR介导的免疫抑制中巨噬细胞的表观遗传修饰。特别是成人模特 已经表明，在慢性阿片类药物暴露后，肠道微生物生态失调启动TLR 4诱导的全身性 炎症怀孕期间使用阿片类药物导致肠道生态失调，这与多样性和 婴儿微生物组的分类。综上所述，产前阿片类药物暴露可能导致 新生儿肠道微生物生态失调，导致全身性炎症。令人惊讶的是，益生菌疗法 不能完全减弱阿片类药物诱导的免疫功能障碍，这表明其他机制在起作用，有助于 SIRS后的免疫抑制表型，如巨噬细胞的表观遗传修饰。H3K9me2 SIRS后巨噬细胞的IL-1β和TNFα启动子的修饰已被普遍描述; 慢性阿片样物质使用的成人模型在很大程度上限制了他们对脑组织的这些修饰的分析， 有希望的是，已经显示了H3 K9 me 2修饰在几个脑区域中的差异表达。给定 这些初步的发现，这个项目的目的是研究这些修改在细胞水平上，在肠道 巨噬细胞我假设产前阿片类药物暴露导致微生物生态失调， 有助于全身炎症;此外，阿片类药物诱导的全身炎症持续存在 出生后改变了肠道巨噬细胞的表观基因组， 功能障碍到目前为止，还没有关于产前阿片类药物暴露如何影响肠道的研究报告。 微生物组或阿片类药物诱导的炎症如何导致巨噬细胞的表观遗传修饰。因此 该项目的目标是描述产前阿片类药物暴露后的免疫功能障碍，并定义 通过以下两个具体目标的基本机制。目标1。确定肠道的变化 通过检查肠道微生物，产前阿片类药物暴露后的微生物组有助于全身性炎症 和代谢组组成、肠屏障完整性和TLR 4诱导的全身性炎症。目标2. 描述产前阿片类药物暴露后的免疫功能障碍以及阿片类药物诱导的免疫功能障碍的影响。 炎症对肠巨噬细胞中H3 K9 me 2修饰的影响。总的来说，这项建议将有助于 深入了解产前阿片类药物暴露后的免疫功能障碍，并将提供第一个 对免疫功能障碍的表观遗传和微生物组调节的见解。