The Microbiome Requires A Genetically Susceptible Host To Induce Central Nervous System Autoimmunity

While the risk of developing multiple sclerosis (MS) is recognized to have both genetic and environmental components, little is known about these complex interactions. The microbiome has recently been recognized as an environmental factor that contributes to MS. In Montgomery et al. (1), the authors harnessed the natural genetic diversity between B6 mice, PWD/PhJ (PWD) wild-derived mice, and a panel of 27 B6.ChrPWD consomic mice to investigate gene plus microbiome interactions. They identified chromosomes that affected disease susceptibility and also identified microbes that increased disease severity in disease-susceptible hosts. They found that while the PWD mice are resistant to experimental autoimmune encephalomyelitis (EAE), these mice surprisingly harbor a microbiota that increases central nervous system (CNS) autoimmunity when transferred into the genetically susceptible B6 mice (Fig. 1). This study advances the field by illustrating an important point: that altered microbiota alone may not be sufficient to cause MS, but rather, a perfect storm of host genetic risk plus specific microbes triggers CNS autoimmunity.\n\n\n\nFig. 1. \nGenetic susceptibility to EAE shapes interactions with the microbiome. PWD mice are genetically resistant to EAE, whereas B6 mice are susceptible. However, transfer of the microbiota from PWD mice or colonization with PWD-enriched microbe L . reuteri worsens disease in B6 mice and increased inflammatory cytokines interleukin-17 (Th17) and interferon-gamma (IFNγ), highlighting the importance of gene × microbiome interactions.\n\n\n\nIn the last 5 years, several studies have identified alterations in the microbiome of patients with MS (2⇓–4), with consistent depletions in butyrate producing bacteria and elevations in Akkermansia and Clostridia . Furthermore, the transfer of microbiota from patients with MS can increase disease incidence in spontaneous models of the disease (5, 6), demonstrating that alterations in the microbiome are not just a bystander of disease but may actually contribute to MS. Germfree mice … \n\n[↵][1]1To whom correspondence may be addressed. Email: hweiner{at}rics.bwh.harvard.edu.\n\n [1]: #xref-corresp-1-1