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

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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.