The effects of adolescent alcohol use on oral microbiota and the brain

PROJECT SUMMARY Research on the microbiome-brain axis indicates strong bidirectional communication systems between the microbiome (including the oral microbiota) and the brain. In adults, the microbiome-brain axis is implicated in the development and maintenance of alcohol use disorder (AUD) and has been examined as a potential AUD treatment target; however, similar research is lacking during adolescence. In our recent review of the adolescent oral and gut microbiota, we found that the adolescent microbiome may be vulnerable to alcohol use. It is important to investigate if the microbiome-brain axis findings from the adult literature can be replicated in adolescents who use alcohol, or if the developmental aspect of adolescence incurs differential effects. The genus Lactobacillus is of particular interest in the adult AUD field and provides an ideal initial target for extending microbiome-brain research into adolescence. Lactobacillus shows a lower relative abundance in relation to adult alcohol use; has been proposed as a treatment option for adult AUD; and administration in a preclinical model resulted in brain metabolite alterations (glutamate, GABA, and N-acetylaspartate or NAA) measured with proton magnetic resonance spectroscopy (MRS). Combined, these findings indicate that alcohol related alterations to Lactobacillus may led to brain metabolite level alterations through the microbiome-brain axis. Investigating the microbiome-brain axis during adolescence will provide insights into a critical piece of the AUD trajectory, as well as potential prevention (e.g., vulnerability markers) and intervention (e.g., pre/probiotics) targets. The overarching hypothesis is that the adolescent microbiome-brain axis is impacted by alcohol use. This application proposes an initial assessment of this hypothesis through novel research that will collect (1) salivary samples to assess the oral microbiome, with Lactobacillus as the primary genus of interest, and (2) Glu, GABA, and NAA brain metabolite levels within the dorsal anterior cingulate cortex via MRS. The oral microbiome was selected for this age range due to increased feasibility and conserved scientific integrity (e.g., resembles the upper gastrointestinal tract and sensitive to alcohol). We will recruit 126 adolescents (ages 14-18) with no/low alcohol use (n=42), recent moderate alcohol use (n=42), or recent heavy alcohol use (n=42). The proposed research plan in this NIAAA K01 application will serve as essential hands-on training to promote Dr. Kirkland’s career development in adolescent alcohol use through five distinct career objectives: (1) become proficient in oral microbiome data collection, analysis, and interpretation; (2) develop foundational knowledge of the adolescent microbiome, specifically its development, the potential effects of alcohol, and its connection to the central nervous system through the microbiome-brain axis; (3) gain experience in lab management skills to foster independence; (4) continue training in responsible conduct of research; and (5) enhance scientific writing, grant writing skills, and science communication skills. The mentorship and research skills gained through this application will set Dr. Kirkland up to be a successful and prolific NIH-supported independent researcher.