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，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 翻了四倍这意味着产前和早期妊娠的儿童和年轻人人数迅速增加。 出生后阿片类药物暴露史。虽然已知长期使用吗啡会破坏肠道微生物组， 导致宿主免疫反应受损并增加炎症反应， 尚不清楚新生儿和护理期间的暴露对以后生活中阿片类药物相关合并症的影响。临床 对新生儿和幼儿期阿片样物质暴露的研究因母子相互作用而复杂化， 环境稳定性、遗传变异性和多种物质的使用，使动物模型更适合 确定新生儿和幼儿期阿片类药物暴露对随后的 在生命后期暴露于阿片类药物及其对阿片类药物相关合并症的影响。我们实验室以前的工作 我们的初步数据显示，吗啡会引起肠道微生物组和代谢组的变化。我们 最近表明阿片类药物诱导的微生物生态失调有助于镇痛耐受， 戒断行为这些作用在无菌小鼠和抗生素诱导的微生物耗竭中减弱 动物维持性阿片类药物如美沙酮和丁丙诺啡对母体微生物的影响 生态失调及其对胎儿和出生后肠脑轴发育的影响尚未被 研究了根据我们实验室发表的研究结果，这项提议的中心假设是， 在怀孕和哺乳期间，将导致母亲体内微生物生态失调，导致 后代中的微生物群。后代的微生物生态失调将导致肠道大脑失调 轴有助于阿片类药物相关的合并症在青春期和成年期。这个目标 补充是为多元化候选人提供研究培训，使候选人获得以下方面的专业知识： 将肠道微生物群与阿片类药物相关的几种行为和生物化学技术和概念 合并症这项研究的目的是确定产前检查的长期后果。 以及出生后早期暴露于吗啡和维持阿片类药物，美沙酮和丁丙诺啡的肠道 微生物组及其对行为结果和小胶质细胞炎性小体激活的影响。目标1：我们将 建立产前和产后暴露于吗啡、美沙酮和 丁丙诺啡将具有改变的a）肠道微生物组和B）代谢组，从而导致持续的 在青春期和成年期持续存在的肠脑轴中断。目标2：我们 建立产前和产后暴露于吗啡，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炎症 导致疼痛超敏反应并导致炎症诱导的行为共病 例如在青春期和成年期暴露于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.