The role of gut microbiota in shaping the relapse-remitting and chronic-progressive forms of multiple sclerosis in mouse models

K Alexa Orr Gandy,Mitzi Nagarkatti,Jiajia Zhang,Prakash Nagarkatti

doi:10.1038/s41598-019-43356-7

Abstract

Using a mouse model of multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), we evaluated the role of gut microbiota in modulating chronic-progressive (CP) versus relapse-remitting (RR) forms of the disease. We hypothesized that clinical courses of EAE may be shaped by differential gut microbiota. Metagenomic sequencing of prokaryotic 16S rRNA present in feces from naïve mice and those exhibiting CP-EAE or RR-EAE revealed significantly diverse microbial populations. Microbiota composition was considerably different between naïve strains of mice, suggesting microbial components present in homeostatic conditions may prime mice for divergent courses of disease. Additionally, there were differentially abundant bacteria in CP and RR forms of EAE, indicating a potential role for gut microbiota in shaping tolerant or remittance-favoring, and pathogenic or pro-inflammatory-promoting conditions. Furthermore, immunization to induce EAE led to significant alterations in gut microbiota, some were shared between disease courses and others were course-specific, supporting a role for gut microbial composition in EAE pathogenesis. Moreover, using Linear Discriminant Analysis (LDA) coupled with effect size measurement (LEfSe) to analyze microbial content, biomarkers of each naïve and disease states were identified. Our findings demonstrate for the first time that gut microbiota may determine the susceptibility to CP or RR forms of EAE.

Highlights

Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model of the neurodegenerative disease multiple sclerosis (MS) and is characterized by CD4+ T cell-mediated autoimmune destruction of protective myelin sheaths surrounding neurons in the central nervous system (CNS)[1]
We hypothesized that differential susceptibility to EAE and the distinct clinical forms of the disease seen in SJL/J and C57BL/6 mice may result from differences in gut microbial composition in these strains and that encephalitogenic immunization would cause dysbiosis of the gut microbiome with unique bacteria emerging that influence the disease
At the peak of disease, stool was collected from mice exhibiting the chronic progressive (CP-EAE; MOG-induced EAE in C57BL/6 strain) or relapse remitting (RR-EAE; PLPinduced EAE in SJL/J strain) form of EAE, or from naïve mice (C57BL/6 or SJL/J)

Summary

Introduction

Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model of the neurodegenerative disease multiple sclerosis (MS) and is characterized by CD4+ T cell-mediated autoimmune destruction of protective myelin sheaths surrounding neurons in the central nervous system (CNS)[1]. Immunization with myelin proteolipid protein peptide (PLP139–151), in the SJL/J strain of mouse, leads to a relapse-remitting course of disease (RR-EAE), similar to RRMS4. It is unclear why these two strains of mice exhibit differing disease courses; it is generally believed that this may result from the differential induction of pro-inflammatory Th1/Th17 cells versus anti-inflammatory Tregs[5]. We hypothesized that differential susceptibility to EAE and the distinct clinical forms of the disease seen in SJL/J and C57BL/6 mice may result from differences in gut microbial composition in these strains and that encephalitogenic immunization would cause dysbiosis of the gut microbiome with unique bacteria emerging that influence the disease.

Methods

Results

Conclusion