Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS). During the early stage of MS, most patients exhibit a relapsing-remitting disease course (relapsing-remitting MS (RRMS)). However, at the later stages of the disease, some patients enter a secondary-progressive phase characterized by the accumulation of irreversible neurological disabilities (secondary-progressive MS (SPMS)) [
1]. Although the etiology and pathogenesis of MS remain to be elucidated, epidemiological studies have revealed that both genetic and environmental factors are involved in its development [
2]. It has long been postulated that MS is an autoimmune disease mediated by T cells reactive to myelin autoantigens, such as myelin basic protein [
3]. Recent genome-wide association studies revealed a major role for cellular autoimmunity in MS because many genes associated with the differentiation, activation, and proliferation of CD4
+ helper T cells have been linked to MS susceptibility [
4‐
7]. The efficacy of therapy to block the entry of T cells into the CNS of MS patients also supports the importance of T cells in the pathogenesis of relapsing-remitting RRMS [
8]. However, the therapeutic effect of these drugs is limited in SPMS and the insufficiency of remyelination and subsequent degeneration of neurons persist in the brain of SPMS patients [
9]. Therefore, unraveling the mechanism of impaired remyelination might contribute to the development of a novel therapy for progressive MS.
Recently, the association of gut microbiota and various CNS diseases including neurodegenerative diseases, psychiatric diseases, and neuroinflammatory diseases such as MS have attracted attention [
10‐
12]. We and other groups have reported the presence of dysbiosis in the gut microbiota of MS patients [
13‐
20]. We found a reduction in bacteria belonging to
Clostridia clusters IV and XIVa, which produce short-chain fatty acids (SCFAs) in MS patients [
13]. Jangi et al. also reported that a SCFA-producing genus,
Butyricimonas, was reduced in treated and untreated MS patients, suggesting the reduction of
Butyricimonas may not be a secondary phenomenon of MS [
14]. SCFAs are defined as groups of fatty acids with fewer than six carbons, especially acetate, propionate, and butyrate [
21]. Indigestible dietary fiber usually metabolized by microbiota in the cecum and colon and SCFAs are major metabolites produced from microbial fermentative activity. SCFAs were reported to have many important roles in the maintenance of gut health, the control of energy metabolism, and regulation of the immune system [
22,
23]. Several reports have demonstrated that SCFAs regulate gut immunity by inducing regulatory T cells (Treg cells) through the inhibition of histone deacetylase (HDAC) [
24‐
26]. Butyrate was also reported to act as a ligand of the G-protein-coupled receptor, GPR109a, expressed on dendritic cells (DC), and to induce the production of retinoic acid and IL-10, which lead to the expansion of Treg cells [
27]. We and other groups recently revealed that the oral administration of SCFAs ameliorated the disease severity of experimental autoimmune encephalomyelitis (EAE), an animal model of MS [
28,
29]. Various effects of SCFAs on the CNS have also been shown. The permeability of the blood-brain barrier (BBB) was increased in germ-free mice and restored by the colonization of SCFA-producing bacteria [
30]. In germ-free mice, microglia in the brain had an immature phenotype and branched cell shape and oral treatment with SCFAs restored microglial immaturity and malformation [
31]. However, the relationship between gut microbiota or SCFAs and demyelination or remyelination remains unclear. The prevalence of MS but not neuromyelitis optica (NMO), an autoimmune astrocytopathy induced by anti-aquaporin-4 (AQP4) antibody, has increased in Japan over the last 30 years [
32]. Therefore, we hypothesized that dysbiosis caused by dietary change is involved in demyelination and/or remyelination.
In this study, we revealed that the oral administration of non-absorbing antibiotics significantly exacerbated cuprizone-induced demyelination and the oral administration of butyrate significantly ameliorated cuprizone-induced demyelination. We further demonstrated that butyrate treatment significantly suppressed lysolecithin (LPC)-induced demyelination and increased remyelination in association with the enhanced differentiation of immature oligodendrocytes. In addition, the depletion of microglia did not affect the butyrate-mediated suppression of demyelination and enhancement of remyelination, suggesting that butyrate directly affected the maturation of oligodendrocytes. Our findings report a new mechanism related to how the gut environment affects homeostasis in the CNS.