The effect of the intestinal microbiome on the gut–brain axis has received considerable attention, strengthening the evidence that intestinal bacteria influence emotions and behavior. The colonic microbiome is important to health and the pattern of composition and concentration varies extensively in complexity from birth to adulthood. That is, host genetics and environmental factors are complicit in shaping the development of the intestinal microbiome to achieve immunological tolerance and metabolic homeostasis from birth. Given that the intestinal microbiome perseveres to maintain gut homeostasis throughout the life cycle, epigenetic actions may determine the effect on the gut–brain axis and the beneficial outcomes on mood. Probiotics are postulated to exhibit a range of positive health benefits including immunomodulating capabilities.LactobacillusandBifidobacteriumare genera of bacteria found in the intestines and so far, the benefits afforded by ingesting bacteria such as these as probiotics to people with mood disorders have varied in efficacy. Most likely, the efficacy of probiotic bacteria at improving mood has a multifactorial dependency, relying namely on several factors that include the agents used, the dose, the pattern of dosing, the pharmacotherapy used, the characteristics of the host and the underlying luminal microbial environment (e.g., gut dysbiosis). Clarifying the pathways linking probiotics with improvements in mood may help identify the factors that efficacy is dependent upon. Adjunctive therapies with probiotics for mood disorders could, through DNA methylation molecular mechanisms, augment the intestinal microbial active cohort and endow its mammalian host with important and critical co-evolutionary redox signaling metabolic interactions, that are embedded in bacterial genomes, and that in turn can enhance beneficial mood dispositions.