多発性硬化症における腸内細菌叢の株レベル解析から拓く次世代治療戦略

抄録

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which disability progressively accumulates. While current disease modifying therapies effectively suppress relapses, progression independent of relapse activity (PIRA) remains a major therapeutic challenge, particularly during transition to progressive MS. Increasing evidence suggests that the gut microbiome influences neuroinflammation through the gut–brain–immune axis.

Animal studies show that germ–free mice rarely develop experimental autoimmune encephalomyelitis (EAE), and antibiotic treatment attenuates disease severity. Human studies further demonstrate that transplantation of fecal microbiota from MS patients exacerbates EAE in recipient mice, indicating a causal contribution of intestinal microbes. Metagenomic analyses of MS fecal samples reveal functional alterations in progressive MS, including enrichment of bacterial DNA repair pathways consistent with adaptation to intestinal oxidative stress.

Strain–level analysis identified a disease–associated pathobiont, Tyzzerella nexilis. Within this species, only a specific lineage was enriched in progressive MS. This lineage contained a large number of mobile genetic elements with abundant sulfur and flagellar genes, induced intestinal Th17 responses, and exacerbated central nervous system inflammation and demyelination in EAE after monocolonization. These findings indicate that MS progression is associated not with microbial species per se but with functionally distinct bacterial strains.

These results support a therapeutic shift from broad microbiome modulation to selective targeting of pathogenic strains. Potential approaches include bacteriophage therapy, endolysin–based antibacterial strategies, and induction of antigen–specific mucosal IgA responses. Strain–level microbiome analysis therefore provides mechanistic insight into MS progression and suggests a framework for precision microbiome therapy aimed at preventing disability progression in MS.