The Gut-Brain Axis in Opioid Use Disorder: Exploring the Bidirectional Influence of Opioids and the Gut Microbiome-A Comprehensive Review

Abstract

Opioid Use Disorder is a chronic condition characterized by compulsive opioid use despite negative consequences, resulting in severe health risks such as overdose and contraction of infectious diseases. High dropout rates in opioid agonist therapy highlight the need for more effective relapse prevention strategies. Animal and clinical studies indicate that opioids influence gut microbiota, which in turn plays a critical role in addiction development and alters behavioral responses to opioids. This study provides a comprehensive review of the literature on the effects of opioids on the gut microbiome and explores the potential of microbiome manipulation as a therapeutic target in opioid addiction.

Keywords: addiction; gut-brain axis; microbiome; microbiota; opioid use disorder; opioids.

Figure 1

Literature search flow diagram.

Figure 2

Number of reviewed studies by examined opioid.

Figure 3

Number of reviewed studies by experimental species.

Figure 4

Number of reviewed animal studies by opioid administration route. Abbreviations: SubQ—subcutaneous; i.p.—intraperitoneal; IVSA—intravenous self-administration; i.m.—intramuscular.

Figure 5

Characteristics of opioids induced dysbiosis. Current studies show that opioid use is associated with gut dysbiosis, characterized by the expansion of potentially pathogenic bacteria and a decrease in potentially beneficial bacteria. Figure was created with BioRender.com.

Figure 6

Impact of opioids on gut barrier function, permeability, and systemic inflammation. Current studies suggest that opioid use compromises gut barrier integrity by reducing the expression and altering the organization of tight junction proteins like Zonula occludens (ZO)-1 and Claudin. The disruption of these proteins allows pathogens and microbial products to translocate into the bloodstream. Additionally, opioids can potentiate a dysbiotic microbiome and promote gut inflammation, leading to further gut barrier compromise. This leads to activation of macrophages and results in increased recruitment of neutrophils and monocytes. Activation of these immune cells contributes to the upregulation of pro-inflammatory cytokines and increased enterocyte apoptosis. Figure was created with BioRender.com.

Figure 7

Association between opioid use and increased systemic inflammation, contributing to morphine tolerance through the gut-brain axis. Current studies suggest that opioids induce changes in gut microbiota, leading to intestinal bacterial product binding to enterocyte or gut immune cell TLR2 (recognizing bacterial peptidoglycan) and TLR4 (recognizing lipopolysaccharide (LPS)) receptors. This cascade leads to elevated levels and release of pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6, IL-17, and IL-18), leading to local gut inflammation and contributing to the development of morphine tolerance via the gut-brain axis. Figure was created with BioRender.com.