Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis

Abstract

ABSTRACTBackgroundMultiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown.MethodsIn a longitudinal study, disability status and associated clinical features in 60 MS patients were tracked over 4.2 ± 0.97 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression.ResultsWe found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 45 bacterial species were associated with worsening disease, including a marked depletion inAkkermansia,Lachnospiraceae,andOscillospiraceae, with an expansion ofAlloprevotella,Prevotella-9, andRhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed a significant enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2production (linked toAkkermansia), and a depletion in SCFA metabolism (linked toLachnospiraceaeandOscillospiraceae). Further, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to robustly predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status.ConclusionsThese results demonstrate the utility of the gut microbiome for predicting disease progression in MS. Further, analysis of the inferred metagenome revealed that oxidative stress, vitamin K2and SCFAs are associated with progression.Abstract Figure