The Gut Microbiota in Addiction Biology: A Systematic Review of Substance-Induced Dysbiosis and Gut–Brain Axis Alterations

Background: Growing evidence suggests that chronic substance use disrupts the gut microbiota composition and function, which can contribute to intestinal dysfunction, systemic inflammation, and gut–brain axis dysregulation. However, current evidence remains fragmented and heterogenous, with most studies focusing on individual substances rather than substance-specific microbial signatures. Objective: Therefore, this systematic review synthesizes recent evidence (2019–2025) to characterize the impact of chronic substance use, including alcohol, nicotine, opioids, cocaine, and methamphetamine, on the gut microbiota composition and functional integrity. Methods: Following the PRISMA 2020 guidelines, a total of 91,421 records were identified before screening through searches conducted across electronic databases and publisher platforms, including PubMed, Web of Science, ProQuest, and BSCOhost, among others. After duplication removal and application of the predefined eligibility criteria, 60 studies were selected for qualitative analysis. Results: The findings revealed an interspecies similarity in which chronic substance exposure generally induced dysbiosis characterized by a depletion of beneficial short-chain fatty acid (SCFA)-producing taxa, such as Lactobacillus, Akkermansia, and Faecalibacterium, alongside the enrichment of opportunistic pathogens such as Escherichia-Shigella. Alcohol emerged as a particularly potent ecological driver, consistently reducing the richness and diversity of the microbial community. Mechanistically, these alterations are linked to impaired intestinal barrier function, increased lipopolysaccharide translocation, and the activation of systemic inflammatory pathways. Furthermore, substance-specific metabolic fingerprints were identified, including disruptions in glutamate pathways for cocaine and trimethylamine N-oxide precursors for methamphetamine. Preclinical evidence from fecal microbiota transplantation and germ-free models suggests that these microbial shifts actively modulate reward sensitivity and neuroplasticity through the gut–brain axis. Conclusion: Collectively, the data presented in this study support a shift from reductionist addiction models toward a systems-level framework, positioning the gut microbiome as a pivotal, modifiable component of addiction biology and a promising target for novel therapeutic interventions.