Abstract
Gut microbiota dysbiosis has been implicated in MS and other immune diseases, although it remains unclear how manipulating the gut microbiota may affect the disease course. Using a well-established model of progressive MS triggered by intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), we sought to determine whether dysbiosis induced by oral antibiotics (ABX) administered on pre-symptomatic and symptomatic phases of the disease influences its course. We also addressed the effects of microbiota recolonization after ABX withdrawn in the presence or absence of probiotics. Central and peripheral immunity, plasma acetate and butyrate levels, axon damage and motor disability were evaluated. The cocktail of ABX prevented motor dysfunction and limited axon damage in mice, which had fewer CD4+ and CD8+ T cells in the CNS, while gut microbiota recolonization worsened motor function and axonal integrity. The underlying mechanisms of ABX protective effects seem to involve CD4+CD39+ T cells and CD5+CD1d+ B cells into the CNS. In addition, microglia adopted a round amoeboid morphology associated to an anti-inflammatory gene profile in the spinal cord of TMEV mice administered ABX. The immune changes in the spleen and mesenteric lymph nodes were modest, yet ABX treatment of mice limited IL-17 production ex vivo. Collectively, our results provide evidence of the functional relevance of gut microbiota manipulation on the neurodegenerative state and disease severity in a model of progressive MS and reinforce the role of gut microbiota as target for MS treatment.
Highlights
Multiple sclerosis (MS) is a chronic demyelinating and inflammatory neurodegenerative disease of the central nervous system (CNS), and one of the most prevalent neurological diseases
Behavior in the activity cage and rotarod performance indicated that oral ABX administration for 15 days before the appearance of symptoms apparently prevented the motor dysfunction that develops in Theiler’s murine encephalomyelitis virus (TMEV) mice (Figure 1B)
ABX induced a decrease in the relative abundance of Oscillospira, Ruminococcus, Anaeroplasma Mucispirillum and Bilophila, and Sutterella, while there was an increase in Anaerococcus, Streptococcus, Bacillus, Flavobacterium, Prevotella, Acinetobacter, Ochrobactrum, and Corynebacterium
Summary
Multiple sclerosis (MS) is a chronic demyelinating and inflammatory neurodegenerative disease of the central nervous system (CNS), and one of the most prevalent neurological diseases. In susceptible strain of mice the intracranial inoculation of TMEV induces a biphasic disease characterized by an early acute disease associated with replication of the virus in the CNS gray matter that reach the peak at day 10 post infection. Autoimmunity in TMEV-induced demyelinating disease (TMEV-IDD) is first detected as a delayed type hypersensitivity response to the myelin proteolipid (PLP), PLP139−151 peptide around 60 days after the infection [8, 9]. The events triggering autoimmunity in MS are still not fully understood, yet it seems that genetic predisposition in conjunction with environment factors, including viral infection, could drive the onset and progress of the disease. The Theiler’s virus model brings together these genetic and environmental components of the disease in the context of virus-induced autoimmunity [10]
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