Review ArticleGut dysbiosis and multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS). In the CNS of MS patients, multiple demyelinating lesions accompanied by lymphocyte infiltration and antibody and complement deposition develop repeatedly, which induces various neurological symptoms. Most patients with MS have a relapsing-remitting disease course (RRMS) during the early disease stage. However, some patients proceed to a progressive phase characterized by the accumulation of irreversible neurological disabilities in later disease stages [1]. It is assumed that MS pathogenesis is mediated through an autoimmune response where T cells become reactive to myelin autoantigens such as myelin basic protein (MBP) [2]. Although the pathogenesis of autoimmune responses to myelin autoantigens is still poorly understood, epidemiological studies have revealed that genetic and environmental factors are involved in the development of MS [3,4]. Genome-wide association studies of MS revealed that many genes associated with the differentiation, activation, and proliferation of CD4+ helper T cells are linked to MS susceptibility, which suggests that cellular autoimmunity is a major factor in MS pathogenesis [[5], [6], [7], [8]]. Accumulating evidence has indicated that IFN-γ-producing Th1 cells and pathogenic Th17 cells, capable of producing TNF-α and GM-CSF in addition to IL-17, IL-21 and IL-22, play an important role in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS [[9], [10], [11]]. The development of CNS autoimmunity is likely to be triggered by a shift in the delicate balance between pathogenic Th17/Th1 cells and immune regulatory cells such as Foxp3+ regulatory T cells (Treg cells). Additionally, most currently available disease-modifying treatments affect the proliferation, activation, or migration of T cells [12], which further indicates the important roles of T cells in the pathogenesis of MS. Recently, emerging evidence based on the efficacy of anti-CD20 therapy has indicated the importance of B cells in CNS inflammation. The presence of oligoclonal bands (OCB) in cerebrospinal fluid, a characteristic finding of MS, suggests the intrathecal production of immunoglobulin. Although the pathogenicity and autoantigen recognized by these intrathecal immunoglobulins are still unknown, many studies have reported that antibody-independent functions of B cells including antigen presentation, modulation of T cell responses, and cytokine production, are involved in MS pathology and can have pathogenic and protective effects [13].
Many environmental factors have been reported to be associated with the onset of MS, including vitamin D, obesity in early life, infection with Epstein–Barr virus, cigarette smoking, and salt intake [3]. Recently, the association of gut microbiota and various CNS diseases including neurodegenerative diseases, psychiatric diseases, and neuroinflammatory diseases such as MS have attracted attention [14,15]. In this review, we summarize recent findings about the interaction between the gut microbiota and MS and related diseases.
Section snippets
Gut microbiota and the immune system
The human body is colonized by many microbial cells. An estimated 3.8 × 1013 bacteria, which consist of hundreds of species, exist in the human intestinal tract and form a huge system termed the gut microbiota [16]. The intestinal tract is the largest immune organ in the body, containing about 100 billion lymphocytes. Because the intestinal mucosa is the entry point for many pathogens, the gut immune system must exclude these pathogens. Additionally, the gut immune system must be regulated
Gut dysbiosis in RRMS
Today, various neurological and psychiatric diseases, including Parkinson's disease, Alzheimer's disease, major depressive disorder, autism and MS, are thought to be associated with alterations in the composition of the gut microbiota, termed dysbiosis (Table 1) [71]. Cantarel et al. analyzed fecal samples from seven MS patients and eight healthy controls in the USA and reported a decrease of Faecalibacterium in MS patients [72]. They also investigated differences in the bacterial composition
Antibiotics and germ-free conditions
To elucidate an association between the gut microbiota and CNS autoimmunity, an experimental approach using an animal model has been studied extensively (Table 2). EAE, the most common animal model of MS, is characterized by T-cell mediated autoimmune inflammation and demyelination. Usually, EAE can be induced by active immunization with a myelin peptide (active EAE) or the adoptive transfer of encephalitogenic T cells (passive EAE). In the early 1990s it was reported that MBP-specific
Conclusion
To date, many studies have reported a relationship between the gut microbiota and MS or its animal models. Studies have reported that in the gut of MS patients, several genera of microbiota including Akkermansia and Streptococcus are increased, and various genera mainly belonging to Firmicutes or Bacteroidetes, are reduced. Of note, studies have reported a decrease in the SCFA-producing microbiome in MS patients, suggesting the importance of microbiota metabolites including SCFAs in MS
Declaration of Competing Interest
The authors declare no competing financial interests.
Acknowledgment
We thank J. Ludovic Croxford, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This work was supported by JSPS KAKENHI Grant Numbers JP24229006 and JP26293234, and by AMED under Grant Number JP18ek0109189.
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