Nowadays, the multiple character of the bipolar disorder (BD) etiology has become obvious comprising oxidative stress, mitochondrial dysfunction, inflammation etc. Gut microbiota alterations are implicated in the mentioned processes. Normalizing of microbiota with probiotics may have antidepresssant or antipsychotic effects and used as adjunct in therapy of BD. Using the experimental (rat) model of dexamphetamine-induced bipolar disorder (BD) we have shown alterations of the microbiota viz., reduced number of beneficial resident microbes, and an elevation that of Candida albicans, as well as manifestation of Staphylococcus aureus and hemolytic E. coli pathogenic bacteria. Changes in microbiota were accompanied by bacterial translocation contributing to anxiety-like behavior and brain histopathological changes observed. We have found for the first time upregulation of the arginase isoforms and a concomitant decrease in the nitric oxide (NO) synthase activity in the cytoplasm and mitochondria of the brain corticolimbic system regions. Simultaneous stimulation of lipid peroxidation processes and reduction in the creatine kinase cytoplasmic and mitochondrial activity were also detected suggesting that BD is associated with impaired brain cellular energy buffering and transfer. Animals were orally gavaged with mixture in equal amounts of the selected probiotics 6 x 109 CFU/ml per day (Lactobacillus rhamnosus B-7701, L. salivarius ВКПМ В-6778, L. plantarum ЦМПМ В-2353, L. acidophilus ИНМИА 9602, Bifidobacterium bifidum ВКПМ AC-1666, and Escherichia coli М17) with psycho-, and antifungal activities; for two weeks before and 24 days with dexamphetamine treatment. Probiotics exhibited antimanic, anxiolytic and antidepressant effects, presumably, via normalization of microbiota and a subsequent restoration of intracellular arginine/ornithine and arginine/NO conversions and inhibition of lipid peroxidation processes. They protected also against of swelling, intensive proliferation and aberrant morphology observed in the brain regions following experimental BD. The results obtained will help to expand understanding of pathogenesis of BD assessing competing L-arginine metabolic pathways and mechanisms of probiotics effects, as well as open opportunity of developing unique microbial-based strategies for the treatment of BD supporting the idea that correction of microbiome might be included in future strategies in prevention and treatment of psychiatric disorders.