The Bidirectional Interplay Between Substances of Abuse and Gut Microbiome Homeostasis

Specific gut microorganisms and their metabolic by-products have been identified as key regulators of host physiology, contributing to the modulation of the immune system, inflammatory processes, brain function, and behavior, which highlights the gut microbiome as a potential modulator of the neurobiological mechanisms involved in substance use disorders. This narrative review provides an updated overview of how drugs of abuse influence the composition and dynamics of the human gut microbiome and how bacterial dysbiosis may be a contributing factor to substance use disorders by modulating the communication between the gut and the brain. Thus, by examining commonly abused substances such as alcohol, psychostimulants, opioids, cannabinoids, and nicotine, this review aimed to deepen the understanding of the bidirectional relationship between the gut microbiome and substance use. There is evidence indicating that gut microbiome alterations may influence addiction through changes in gut-brain signaling. Furthermore, changes in the gut microbiome and its metabolites may not only result from substance use disorders, but could also modulate behavioral responses to drugs of abuse. Although the exact mechanisms by which the gut microbiome modulates behavioral responses to drugs of abuse are not fully understood, microbial products such as short-chain fatty acids, tryptophan metabolites, bile acids, and neurotransmitters have been suggested to play a role in this process by influencing the blood-brain barrier permeability, host immune activation, neural signaling, and gene expression. Therefore, manipulating the gut microbiome or its by-products may represent a promising approach for enhancing substance use disorder treatments, identifying individuals at increased risk of pathological drug use, and elucidating its role in substance-related behaviors.