Recent research demonstrates that the composition of the gut microbiome is a master regulator of key neurophysiological processes that are affected in depression. Indeed, contemporary studies showed that faecal microbiota is altered in patients with major depressive disorder (MDD). Furthermore, it has also been shown that supplementation of probiotics ameliorated depressive symptoms in unmedicated patients with mild to moderate depression. However, no study has yet explored the efficacy of a probiotic-based therapy in patients with severe MDD in addition to a standard antidepressant treatment. As dietary and lifestyle interventions may be a desirable, effective, pragmatical and non-stigmatizing prevention and adjuvant therapy (in addition to antidepressant treatment) in depression, this project is aimed at investigating for the first time if probiotic supplementation compared to a placebo treatment improves the effect of standard antidepressant medication on depressive symptoms (i.e. better and faster remission) in patients with severe MDD. Furthermore, this study will further test if probiotic supplementation modulates immune signalling and inflammatory processes (macrophage migration inhibitory factor and interleukin 1 beta), hypothalamic-pituitaryadrenal (HPA) axis responses (saliva cortisol), neurogenesis (brain-derived neurotrophic factor (BDNF) expression), the release of appetite-regulating hormones (leptin and ghrelin), the composition of gut microbiota (in particular levels of Enterobacteriaceae, Alistipes and Faecalibacterium) and brain perfusion, structure and activation and if these changes are associated with the probiotic-induced effect on depressive symptoms.