A recent study uncovered a key mechanistic role for gut immune responses as initiators of neuroinflammation in multiple sclerosis. The findings may provide an improved understanding of the gut mucosal immune responses, which may help the development of better therapeutics for MS.

Multiple factors influence the onset and progression of MS, including genetic susceptibility, environmental triggers, and, more recently, the gut microenvironment. Patients with MS exhibit alterations in their gut microbiota, while the gut microbiota and microbial metabolites play a pivotal role in shaping the chronic autoreactive immune responses. However, in trying to define this gut–central nervous system axis, the cellular mechanisms that relay the gut-derived signals to the immune system to influence autoimmune inflammation in the CNS remain poorly understood.

Building on their previous observation that mild intestinal inflammation exists in experimental autoimmune encephalomyelitis, a mouse model of MS; researchers at the School of Medicine, at Keio University, Japan, set out to test whether similar inflammation is present in patients with MS. By performing single-cell RNA sequencing on intestinal biopsies, the team noted inflammatory Th17 cells accumulate in the mouse model, as well as in the intestine of patients with MS, suggesting a conserved gut–central nervous system axis may be active in human diseases.

In both EAE mice and patients with MS, intestinal epithelial cells upregulated antigen presentation pathways. Particularly, epithelial cells in the ileum had higher expression of major histocompatibility complex class II that presents antigens to CD4+ T cells, and selective deletion of MHC II in intestinal epithelial cells which reduced pathogenic Th17 cell generation and disease severity.

Intestinal epithelial cells do not typically present antigens to immune cells. The team tested the antigen presentation function of intestinal epithelial cells. Their findings demonstrate intestinal epithelial cells can directly present antigens in an MHC II-dependent manner to prime CD4+ T cells in the gut. Notably, intestinal epithelial cells induced Th17 polarization of activated CD4+ T cells. It became clear the gut was a critical site for immune activation of pathogenic CD4+ T cells polarized into proinflammatory Th17 cells.

To investigate whether the Th17 cells directly contribute to the pool of autoreactive cells in the central nervous system, they used transgenic mice that express the Kaede protein, which, upon exposure to violet light, undergoes photoconversion from green to red fluorescence. This model allowed for precise tracking of pathogenic Th17 cells induced in the intestinal lamina propria that then migrate to the spinal cord and drive neuroinflammation.

Taken together, the study suggests a critical role for MHC II expressed by intestinal epithelial cells in the expansion of pathogenic Th17 cells that subsequently migrate to the central nervous system during EAE, providing a mechanistic link between gut immune responses and autoimmune neuroinflammatory diseases. The findings suggest that while systemic circulation allows T cell exchange across immune tissues, the epithelial–immune interactions within the gut mucosal compartment can essentially shape effector T cell responses in the brain.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, while current therapies for MS often target B cells, the authors said their study highlights the gut as an important therapeutic site. Modulating intestinal microbiota or antigen-presenting activity of intestinal epithelial cells represents new approaches to treating autoimmune neurological diseases.

The study was published in the journal Science Immunology.