MS is a chronic autoimmune neurodegenerative disease characterized by different forms. The most common is the relapsing-remitting (RR)MS showing a significant dysregulation of immune homeostasis [5,6].~Disease progression occurring during MS, is not only driven by infiltrating T cells destroying myelin during relapses, indeed proinflammatory molecules can also trigger a glutamate-induced excitotoxic synaptopathy promoting neurodegenerative processes and negatively influencing disease course [1,2].~Inflammation, synaptopathy and neurodegeneration are intermingled with reparative processes in different proportions, making the MS course unpredictable and the treatment approach challenging [1]. Lifestyle habits can contribute to the heterogeneity of MS pathophysiology [3]. In this context, the gut microbiota is emerging as a key sensor of lifestyle indeed it is continuously modulated by many factors, particularly dietary habits, and by controlling the immune system homeostasis can influence the onset and progression of MS [5,6].~HFD exacerbates MS by promoting neuroinflammation and affects gut microbiota inducing dysbiosis [3,7] Gut dysbiosis in MS is associated with increased microglia activation and imbalance between pathogenic Th1/Th17 and tolerogenic regulatory T (Treg cells) [4], however its effects on immune-mediated synaptopathy and their underlying mechanisms in MS have not yet been investigated.~Considering that excitotoxic synaptic dysfunctions are reversible and can be only partially controlled by the currently available disease-modifying treatments (DMTs), they represent an attractive therapeutic target in MS [1,2]. Microbiota manipulation by dietary prebiotics and probiotics (Pre-Pro) supplementation may be an attractive candidate for enhancing the efficacy and the anti-synaptotoxic action of DMTs and could result in a safer and more effective therapeutic strategy to improve the management of overall health and well-being of MS patients.~This clinical study will be performed to verify whether the gut-microbiota manipulation can counteract synaptic alterations, neuroinflammation and degeneration by switching the immune system towards a more tolerogenic phenotype thus improving MS cognitive and clinical outcomes.~To verify our hypothesis, we will perform clinical and experimental studies to dissect at cellular and molecular level the effect and the mechanism of action of Pre-Pro supplementation during MS [6,8,9].~The following objectives will be addressed by evaluating the effects of a dietary supplementation of prebiotics and probiotics (Pre-Pro) in RRMS patients on~clinical disability and disease course;~immune cell homeostasis;~inflammation-driven synaptopathy and its molecular determinants.~This project aims at investigating for the first time the impact of gut-microbiota modulation on MS course associated with excitotoxic synaptopathy. The multidisciplinary approach will provide the unique opportunity to dissect immunoregulatory and synaptic effects of the prolonged Pre-Pro intake at both cellular and molecular levels. Moreover, the possible identification of novel molecular actors controlling the immune-brain axis shaped by the microbiota will open new opportunities for expanding the current treatment options for MS.~Overall, the results of this project will provide robust scientific groundwork for an integrative medicine based on Pre-Pro supplementation in addition to first line drug treatments for MS to counteract synaptopathy-driven disease progression.
Inflammatory synaptopathy is a prominent pathogenic process in multiple sclerosis (MS) induced by imbalanced immune system homeostasis. Its persistence causes excitotoxic neuronal damage, leading to motor and cognitive deficits. Although many advances have been made in MS treatment, the development of effective strategies for managing disease progression driven by excitotoxic synaptic dysfunctions is of great significance. Gut dysbiosis is commonly associated with both MS and obesity and high-fat diet (HFD) can exacerbate disease by acting on gut microbiota.~Since gut microbiota can shape the immune response and brain functions, we propose to target gut dysbiosis by dietary supplementation of prebiotics and probiotics (Pre-Pro) to treat synaptopathy in both human and experimental model of MS, even when exacerbated by HFD. Overall, this project aims at unveiling the anti-inflammatory and neuroprotective pathways activated by Pre-Pro supplementation to modulate the immune-synaptic axis.