Linking the gut microbiome to microglial activation in opioid use disorder

Abstract

Substance use disorder (SUD) is a physical and psychological disorder globally prevalent today that has resulted in over 107,000 drug overdose deaths in 2021 in the United States alone. This manuscript reviews the potential relationship between opioid use disorder (OUD), a prevalent subset of SUD, and the microglia, the resident macrophages of the central nervous system (CNS), as they have been found to become significantly more activated during opioid exposure. The inflammatory response mediated by the microglia could contribute to the pathophysiology of SUDs, in particular OUD. Further understanding of the microglia and how they respond to not only signals in the CNS but also signals from other areas of the body, such as the gut microbiome, could explain how the microglia are involved in drug use. Several studies have shown extensive communication between the gut microbiome and the microglia, which may be an important factor in the initiation and development of OUD. Particularly, strategies seeking to manipulate and restore the gut microbiome have been shown to reduce microglial activation and attenuate inflammation. In this review, we discuss the evidence for a link between the microglia and OUD and how the gut microbiome might influence microglial activation to drive the disorder and its associated behaviors. Understanding this connection between microglia and the gut microbiome in the context of drug use may present additional therapeutic targets to treat the different stages of drug use.

Keywords: OUD; SUD; microbiome; microglia; opioids.

FIGURE 1

Microglia-neuron interaction in an opioid context. This figure depicts the general mechanism by which morphine may impact neuronal signaling via the microglia. Either LPS from a dysbiotic microbiome or morphine itself binds to microglial TLR4, prompting the release of proinflammatory cytokines such as TNFα and IL-1β. These cytokines bind to local astrocytes, causing glutamate release. Glutamate binds to neuronal AMPA receptors, which are differentially expressed in the hippocampus (HPC) and NAc, causing altered neuronal signaling. Alterations in neuronal signaling can lead to addictive behaviors, neuroinflammation, systemic inflammation, and further stress on the gut microbiome.

FIGURE 2

Routes of communication between the gut microbiome and the brain. This figure visually depicts the different routes of communication between the gut microbiome and the brain. Microbial communication with secreted neurotransmitters (NT) and microbiome-derived EVs allow for the transfer of bacterial products into the CNS. The gut microbiome can influence brain activity through the HPA axis by influencing the secretion of its various hormones. The vagus nerve acts as a neuroanatomical connection between the gut and the CNS, as gut bacterial products and metabolites such as LPS and SCFAs can bind to their receptive receptors expressed on the vagus nerve and send signals to brain.

FIGURE 3

Gut-brain communication in SUDs. This figure visually summarizes how drug induced changes to the microbiome may be related to cellular changes in the brain during drug use. Drug use causes a disruption of gut homeostasis, resulting in a dysbiotic state of the microbiome. The microbial change in the gut may alter the communications sent from the gut to the nervous system through the vagus nerve, the HPA axis, or extracellular vesicles. The communication between the gut and the nervous system may contribute to the increase of microglial activation, which alters astrocyte and neuron signaling, potentially modifying behaviors comorbid with drug use.