Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV

摘要 在过去的十年中，在分娩和分娩时患有阿片类药物使用障碍的妇女人数超过了 翻了两番。这意味着产前和早产的儿童和年轻人的数量迅速增加。 出生后阿片类药物暴露史。虽然众所周知，长期使用吗啡会扰乱肠道微生物群 导致宿主免疫反应受损和炎症反应增加，阿片类药物的后果 新生儿和在哺乳期间接触阿片类药物相关的日后生活中的共病尚不清楚。临床 关于新生儿和儿童早期阿片类药物暴露的研究因母子相互作用而变得复杂， 环境稳定性、遗传多样性和多物质使用，为动物模型提供了更合适的 确定新生儿和儿童早期阿片类药物暴露的长期影响的工具 晚年接触阿片类药物及其对阿片类药物相关共病的影响。我们实验室以前的工作 我们的初步数据显示，吗啡引起肠道微生物组和代谢组的变化。我们 新近研究表明，阿片类药物诱导的微生物代谢失调有助于镇痛耐受并加重 戒断行为。这些影响在无菌小鼠和抗生素诱导的微生物耗尽时减弱 动物。维持性阿片类药物美沙酮、丁丙诺啡对母体微生物的影响 营养不良及其对胎儿和出生后肠道脑轴发育的影响尚未得到证实 学习。根据我们实验室公布的发现，这一提议的中心假设是阿片类药物的暴露 在怀孕和哺乳期间会导致母亲体内的微生物失调，从而导致垂直传播 后代中的非生物微生物群。后代中的微生物失调将导致肠道大脑的失调 导致青春期和成年期阿片类药物相关共病的轴心。这样做的目的是 补充是为多样性候选人提供研究培训，使候选人获得以下方面的专业知识 几种将肠道微生物区系与阿片类药物相关的行为和生化技术和概念联系起来 并存疾病。研究方案的目标是确定产前的长期后果 以及出生后早期对吗啡和维持性阿片类药物、美沙酮和丁丙诺啡的肠道暴露 微生物群及其对行为结局和小胶质细胞炎症小体激活的影响。目标1：我们将 确定出生前和出生后暴露于吗啡、美沙酮和 丁丙诺啡将有一个改变的a)肠道微生物组和b)代谢组导致持续 持续到青春期和成年期的肠道脑轴紊乱。目标2：我们将 确定出生前和出生后暴露于吗啡、美沙酮和 丁丙诺啡诱导小胶质细胞活化、炎性小体组装和持续性炎症 这会导致疼痛过敏，并导致炎症诱导的行为并存 例如，在青春期和成年期随后接触阿片类药物后的耐受性。

Abstract In the last decade the number of women with opioid use disorder at labor and delivery has more than quadrupled. This translates to a rapid rise in the number of children and young adults with prenatal and early postnatal history of opioid exposure. While it is known that chronic morphine use disrupts the gut microbiome leading to impaired host immune response and increases inflammatory responses, the consequences of opioid exposure in neonates and during nursing on opioid associated co-morbidities later in life are not known. Clinical studies of opioid exposure in neonates and early childhood are complicated by mother-child interactions, environmental stability, genetic variabilities and polysubstance use, lending animal models a more appropriate tool to determine the long-term effects of opioid exposure in neonates and early childhood on subsequent exposure to opioids later in life and its impact on opioid associated co-morbidities. Previous work from our lab and our preliminary data show that morphine induces changes in the gut microbiome and metabolome. We recently show that opioid induced microbial dysbiosis contributes to analgesictolerance and exacerbated withdrawal behavior. These effects are attenuated in germ free miceand antibiotic induced microbial depleted animals. The impact of maintenance opioids such methadone and buprenorphine on maternal microbial dysbiosis and its consequence on fetal and post-natal gut brain axis development has not been studied. Based on our lab's published findings, the central hypothesis of this proposal is that opioid exposure during pregnancy and nursing will result in microbial dysbiosis in the mother leading to vertical transmission of dysbiotic microbiome in off springs. Microbial dysbiosis in the off springs will leadto a dysregulated gut brain axis contributing to opioid associated co-morbidities in adolescence and adulthood. The goal of this supplement is to provide research training to the diversity candidate such that the candidate gains expertise in several behavioral and biochemical techniques and concepts that links the gut microbiota to opioid associated co-morbidities. The objective of the research proposal is to determine the long-term consequence of prenatal and early postnatal exposure to morphine and maintenance opioids, Methadone and Buprenorphine on the gut microbiome and its impact on behavioral outcomes and microglial inflammasome activation. AIM 1: We will establish that neonates that are prenatally and postnatally exposed to morphine, methadone and buprenorphine will have an altered a) gut microbiome and b) metabolome resulting in sustained disruption in the gut brain axisthat persists through adolescence and adulthood. Aim 2: We will establish that neonatesthat are prenatally and postnatally exposed to morphine, methadone and buprenorphine induces microglial activation, inflammasome assembly and sustained inflammation which lead to pain hypersensitization and contribute to inflammation induced behavioral co- morbidities such as tolerance following subsequent exposure to opioids in adolescence and adulthood.