Recent studies have demonstrated that commensal, probiotic, and pathogenic bacteria in the gastrointestinal tract can activate central nervous system (CNS) signaling systems, possibly through neural, endocrine and immune pathways, thus influencing brain function and behavior. This emerging concept of the microbiome–gut–brain axis suggests modulation of the gut microbiome as a potential novel therapeutic strategy for CNS disorders. In our laboratory, we selectively bred mice with strong features of dominance (Dom) and submissiveness (Sub) that represent opposite poles of the behavioral spectrum. We recently found that Dom and Sub mice possess differential gut microbiomes and that modulation of the gut microbiome alters their depressive-like behavior, potentially via inflammatory pathways. Our ongoing study is dedicated to the development of targeted microbiome modulations as a potential therapy for behavioral disorders.