Probiotic neuroimmune modulation of morphine tolerance - The vast majority of adults in the US have taken an opioid drug for pain relief. Oral opioids have revolutionized our ability to treat post-surgical pain and, thereby, drastically shortened post-surgical hospital stays. However, recently there has been an unprecedented increase in the number of patients taking oral opioids for pain who have developed an opioid use disorder (OUD). In fact, more than 280 people per day died of an opioid overdose in 2021(1). While the dramatic increase in OUD has coincided with the much-reported increase in opioid prescriptions, it is still true that only a fraction of patients who are prescribed opioids for pain develop an OUD. If we could identify those pain patients most at risk prior to opioid treatment, we could potentially stem the tide of opioid abuse and overdose death. Recent studies have shown that alterations in the gut microbiome can influence a plethora of central nervous systems disorders, leading to widespread acceptance of the concept of a gut-microbiome-brain axis(2, 3) . It is compelling that, coincident with the increase in opioid prescriptions, there has also been a large increase in the routine and often unnecessary use of oral antibiotics—a trend that that has altered the gut microbiome of an entire generation. Not surprisingly, given the widespread expression of opioid receptors in the gut, opioids have been shown to alter the gut microbiome. Furthermore, alterations in the microbiome have been shown to alter opioid analgesia and reward, suggesting that opioids influence the gut- brain axis(4-8). However, to date, no studies have examined whether the gut microbiome influences the development of OUDs. In our preliminary studies, we capitalized on both behavioral variability in a mouse model of antinociceptive tolerance and OUD, and mouse microbiome variability, both innate and in response to morphine, to identify microbial biomarkers of OUD. One such biomarker we identified is Akkermansia muciniphila (AKK), a key gut commensal of mammals that promotes gut homeostasis and has emerged as an important biological intervention in diseases with diverse etiologies. Specifically, we found a significantly higher abundance of Akkermansia muciniphila (AKK) in mice that did not develop antinociceptive tolerance to morphine during voluntary chronic oral morphine use. This discovery led to our central hypothesis, to be tested here, that AKK protects against the development of OUDs. Here we will interrogate the molecular mechanisms by which AKK protects against OUD (Aim 1) and assess how AKK supplementation impacts dynamics of microbiome community interactions and final composition in a morphine-exposed gut (Aim 2). Together these studies could inform development of immediate and non-invasive therapeutic strategies to extend the analgesic efficacy of opioids for chronic pain conditions while reducing the development of OUD.
