The commensal microbiota has emerged as a key factor influencing human health and has been associated with several diseases, including those of the central nervous system (CNS). To investigate the role of the microbiome in multiple sclerosis (MS), a complex autoimmune disorder shaped by a multitude of genetic and environmental factors, we recruited a cohort of 34 monozygotic twin pairs discordant for MS, and compared their gut microbial composition by 16S ribosomal RNA sequencing of stool samples. While no major differences in the microbial profiles between MS-affected twins and their healthy co-twins were detected, a significant increase in some taxa (including Akkermansia) was seen in affected untreated subjects. To search for possible functional differences, we used a transgenic mouse model, in which spontaneous anti-CNS autoimmunity is dependent on the commensal gut flora. Germ-free mice colonized with microbiota from MS-affected twins, developed the MS-like disease with a significantly higher incidence than mice colonized with healthy twin-derived microbiota. Although alpha diversity was reduced compared to human donors, the microbial profiles of the colonized mice showed high intraindividual, remarkable temporal stability and a high transfer rate,. Analysis of the transplanted mouse microbiome at the level of individual taxa revealed several differences, including a significantly reduced abundance of the potentially autoimmune-protective genus Sutterella in mice colonized with MS-twin-derived microbiota. These findings provide first evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. This model lends itself to identify protective and pathogenic microbial component in human MS.

There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the central nervous system. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intra-individual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 compared to immune cells from mice colonized with healthy twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy twin fecal samples increased disease incidence. These findings provide first evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.