Multiple sclerosis: the gut as an unexpected driver of neuroinflammation

By Elodie Vaz | Published on April 10, 2026 | 4 min read


Multiple sclerosis (MS) is a chronic and disabling neurological disease characterized by an immune-mediated attack on the central nervous system (CNS). This autoimmune response primarily targets myelin, a protective sheath essential for proper nerve impulse conduction.

At the root of this dysregulation is the immune system’s inability to distinguish “self” from “non-self,” leading to inflammatory reactions against the body’s own components. While genetic and environmental factors are involved, attention is increasingly turning to an unexpected player: the gut microbiota.

Alterations in this microbial ecosystem have been observed in patients with MS, suggesting a role in modulating immune responses. However, the cellular mechanisms linking the gut to brain inflammation have remained largely unclear.

Deciphering the gut–brain axis in MS

A study published on March 27, 2026, in Science Immunology, led by Professors Shohei Suzuki and Tomohisa Sujino at Keio University, aimed to elucidate the mechanisms by which intestinal immune responses contribute to neuroinflammation.

“Growing evidence shows that the gut microbiota influences neurological diseases […] However, the mechanisms linking gut microbes, intestinal immunity, and brain inflammation remain unclear. We sought to identify how intestinal immune responses contribute to neuroinflammatory diseases,” explained Professor Tomohisa Sujino in a press release.

A translational approach from mice to humans

The researchers relied on the experimental autoimmune encephalomyelitis (EAE) mouse model, widely used to study MS, and compared these findings with observations in patients.

Using single-cell RNA sequencing analyses on intestinal biopsies, they identified an accumulation of inflammatory Th17 lymphocytes in both mice and MS patients.

In parallel, co-culture experiments were conducted to assess the ability of intestinal epithelial cells to present antigens to T lymphocytes. Additionally, transgenic mice expressing the Kaede protein—with modifiable fluorescence—were used to track the migration of immune cells from the gut to the CNS.

The gut as a site of pathogenic T cell activation

The results reveal a central role for intestinal epithelial cells in activating pathogenic immune responses. Contrary to their classical function, these cells express major histocompatibility complex class II (MHC II) molecules and present antigens to CD4+ T lymphocytes.

This interaction promotes the differentiation of these lymphocytes into pro-inflammatory Th17 cells, known to be involved in autoimmune diseases. Deletion of MHC II in intestinal epithelial cells reduced both the generation of these pathogenic lymphocytes and disease severity in the mouse model.

Tracking experiments showed that these Th17 lymphocytes, activated in the gut, subsequently migrate to the spinal cord, where they directly contribute to neuroinflammation.

Thus, the gut appears to be a key “priming” site for pathogenic T cells, establishing a mechanistic link between mucosal immunity and CNS inflammation.

A new therapeutic target to explore

These findings highlight a critical role for the intestinal epithelial interface in modulating systemic immune responses. They suggest that the gut environment does not merely influence immunity but actively participates in the generation of autoreactive cells involved in MS.

“While current MS treatments often target B cells, our study highlights the gut as an important therapeutic target,” emphasized Professor Shohei Suzuki. “Modulating the gut microbiota or the antigen-presenting activity of intestinal epithelial cells represents new approaches for treating autoimmune neurological diseases.”

By shedding light on the gut–brain axis, this study proposes a paradigm shift in the management of neuroinflammatory diseases. Ultimately, targeting immune interactions at the level of the intestinal mucosa could help prevent the generation of pathogenic cells upstream—before they even reach the central nervous system.      

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