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

摘要

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.