Regulation of Inflammatory Responses in the Central Nervous System by Gut Microbiota

Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation and demyelination in the central nervous system (CNS) that leads to multiple symptoms such as visual disturbance and quadriplegia. Although the etiology of MS remains elusive, it is thought that both genetic and environmental factors are involved and that autoreactive Th17 cells play a pivotal role in disease development. Recently, several groups have reported that MS patients have a distinct microbiota compared to healthy subjects. Studies using the experimental autoimmune encephalomyelitis (EAE), an animal model of MS, have also demonstrated that disease development and severity are attenuated when mice are raised under a germ-free condition. These results indicate that some gut microbes promote the inflammatory responses in the CNS of MS patients and EAE mice. It is, however, unknown what kind of gut microbes are involved in and how they regulate the inflammation in the CNS. In the present study, we demonstrated that two specific gut bacteria coordinately act to promote the CNS inflammation in EAE mice. In EAE mice, myelin-specific Th17 cells migrate from the periphery to the CNS to initiate neuroinflammation. We first found that myelin-specific Th17 cells are recruited to the small intestine and activated by gut bacteria there during EAE development. The Erysipelotrichaceae strain acts like an adjuvant for the Th17 responses increasing the pathogenicity of the autoreactive T cells, and myelin-specific T cells cross-react with UvrA expressed in Lactobacillus reuteri and proliferate upon the stimulation. It is worthy of note that mono-colonization of germ-free mice with these bacteria did not or only slightly increased the susceptibility and clinical symptoms of EAE, pointing to the importance of the synergic effects of their pathogenic functions in fully activating autoimmune T cells. Taken together, our results imply that the microbiota of the small intestine is a potential target for the prevention and treatment of MS. Further studies using human microbes and autoreactive T cells are needed to confirm our findings in MS patients, because mouse and human gut microbes and target myelin epitopes are different