Multiple sclerosis, the microbiome, TLR2, and the hygiene hypothesis

Highlights

• The microbiome is an important component of the “environment”, and one function of the microbiome is to seed the systemic circulation with microbial products that regulate innate immunity through the induction of a relative level of TLR2 tolerance

• Circulating levels of microbiome-derived microbial products are deficient in MS, resulting in decreased innate immune regulation in MS

• A significant percentage of MS patients demonstrate enhanced peripheral blood responses to TLR2 ligands, consistent with decreased innate immune regulation

• In murine models of MS, inducing TLR2 tolerance via administration of low dose microbial products inhibits CNS inflammation and enhances CNS remyelination, suggesting that TLR2 tolerance induction represents a potential dual-pronged treatment for MS

Take Home Messages

• Genetic and twin concordance studies indicate that the etiology of MS involves a significant environmental component

• The microbiome is an important component of the “environment”

• One function of the microbiome is to seed the systemic circulation with microbial products that regulate innate immunity through TLR2 tolerance induction

• Circulating levels of microbiome-derived microbial products are deficient in MS, resulting in decreased innate immune regulation in MS

• A significant percentage of MS patients demonstrate enhanced peripheral blood responses to TLR2 ligands, consistent with decreased innate immune regulation

• In murine models of MS, inducing TLR2 tolerance via administration of low dose microbial products inhibits CNS inflammation and enhances CNS remyelination

• TLR2 tolerance induction represents a potential dual-pronged treatment for MS

Abstract

The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the “Hygiene Hypothesis,” have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too “clean” lack the requisite exposure to “immune-tolerizing” microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS.

Our central hypothesis is that the microbiome in MS represents a “defective environment” that fails to provide normal levels of “TLR2-tolerizing” bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.