Background and Objective: Multiple sclerosis (MS) is a complex inflammatory disease in whichmyelin destruction (demyelination) occurs in the central nervous system, affecting approximatelytwo and a half million people worldwide. Considering that intestinal microbiome changes canplay an important role in the etiology of chronic diseases, the purpose of this study is toinvestigate the effect of probiotic supplementation on systemic inflammation, intestinalmicrobiome, and mental health in patients with MS.Methods: In a double-blind clinical trial study that was designed and conducted for a period of ۲۴weeks, ۷۰ patients with MS were randomly divided into two groups receiving probiotics orplacebo. Patients in the intervention group received two capsules containing several strains of probioticsdaily, and patients in the control group received the same amount of placebo. Finally, factors related tosystemic inflammation and mental health were investigated at the beginning and end of the study.Results: In this research, ۶۵ patients were included in the final analysis, and except for theduration of the disease, no significant differences were observed in terms of baseline variablesbetween the two groups. However, during the comparison of probiotic supplements compared toplacebo, a significant decrease was reported in the serum levels of inflammatory factors. Also, inthe intervention group, a significant increase in FOXP۳ and TGF-b levels was observed. On theother hand, the level of the gut microbiome and some factors related to mental health also hadsignificant changes.Conclusion: The results of our study showed that probiotics supplementation can have beneficial effectson the serum levels of some factors related to systemic inflammation, gut microbiome, and mental health.