A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis

Abstract

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Microbiota Signaling Pathways that Influence Neurologic Disease

“…Intriguingly, effective control of EAE has only been achieved when high-dose, broadspectrum antibiotics are applied before the onset of symptoms. In one study of relapsing-remitting EAE, later antibiotic treatment did not reduce the severity of EAE relapses, suggesting that the interaction between the microbiota and the immune system play a key role in disease initiation [84]. Few studies have examined the use of antibiotics in the MS population.…”

The Microbiome and Neurologic Disease: Past and Future of a 2-Way Interaction

“…In this context, the disease promoted changes in the microbiota. Similarly, treatment with antibiotics at early stages of disease (from day 0 to 14) resulted in reduced severity of disease, indicating the bidirectional association between disease and the microbiota [24]. The induction of EAE in mice has remarkable cellular and molecular effects on the intestinal barrier by promoting the induction of a Bleaky gut^and accumulation of proinflammatory Th17 and Th1 cells, concomitant with reductions in regulatory T cells in the intestinal mucosa [25].…”

“…We recently proposed that in CNS inflammatory diseases the association with the gut microbiota is bidirectional [24]. In nonobese diabetic mice, the induction of EAE promoted a significant change in the overall structure of the gut microbiota, which was more significant in mice that developed severe disease compared with mice that did not develop or developed a milder form of disease.…”

Assessment of urinary 3-indoxyl sulfate as a marker for gut microbiota diversity and abundance of Clostridiales

“…Besides the described findings in the areas of allo-HCT and CDI, current publications on the significant role of gut microbiota diversity in the pathophysiology of a diverse range of other medical conditions, e.g. hepatic encephalopathy, tumor growth and multiples sclerosis [25][26][27][28][29] , suggest that protection of microbiota diversity may emerge as a new focus of antimicrobial stewardship besides protection from development of antibiotic resistance.…”