Lactobacillus plantarum as a Novel Modulator of Immune and Behavioral Recovery in Substance Use Disorders: A Hypothesis

Substance Use Disorders (SUDs) are increasingly recognized as conditions driven by neuroimmune dysfunction, leading to neuroinflammation and immune dysregulation. Growing evidence highlights the microbiota–gut–brain axis as a critical regulator of central nervous system activity, particularly through the modulation of glial cells such as microglia and astrocytes. The gut microbiome provides key immunomodulatory signals, and its therapeutic exploitation through probiotics offers a promising avenue. In this study, we hypothesize that supplementation with Lactobacillus plantarum can attenuate neuroinflammation and improve immune tolerance in SUDs by restoring microbial balance and modulating neuroimmune activity via the gut–brain axis. Using an established animal model of SUD, we propose to investigate the impact of L. plantarum on gut microbial composition, systemic and central inflammatory markers, glial cell activation, and behavioral outcomes. We further suggest that probiotics containing Lactobacillus species, including L. plantarum, could serve as a transformative approach not only for SUD-associated neuroinflammation but also for other neurological disorders. Such interventions may represent a breakthrough in non-drug discovery strategies by reducing reliance on conventional pharmacological treatments. Importantly, probiotic-based therapies could enhance overall survival and quality of life in individuals with SUDs, as Lactobacillus species have been shown to suppress inflammatory pathways from early developmental stages. Lactobacillus species could regulate the gut-brain axis and impact neurodegenerative diseases. If validated, this work could position L. plantarum and related probiotic strains as novel microbiome-based adjuncts for managing SUDs and open broader therapeutic possibilities for neuropsychiatric and neurodegenerative conditions.