Multiple sclerosis (MS) is a debilitating neurological disorder caused by malfunctioning immune responses that target the brain and spinal cord of the central nervous system (CNS). What makes our body turn against itself? Failure of the immune system to distinguish 'self' from 'non-self' entities leads to excessive autoimmune responses against self-proteins like myelin, which forms a protective covering on the neurons.
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–CNS axis, the cellular mechanisms that relay the gut-derived signals to the immune system to influence autoimmune inflammation in the CNS remain poorly understood.
A recent study, made available online on March 27, 2026, in the journal Science Immunology , uncovers a key mechanistic role for gut immune responses as initiators of neuroinflammation. This study was led by Dr. Shohei Suzuki, Assistant Professor, Division of Gastroenterology and Hepatology, and Dr. Tomohisa Sujino, Associate Professor, School of Medicine, at Keio University, Japan.
"Increasing evidence shows that the gut microbiota influences neurological diseases such as Parkinson's, Alzheimer's, and MS. However, the mechanisms linking gut microbes, intestinal immunity, and brain inflammation remain unclear. We were keen to identify how gut immune responses contribute to neuroinflammatory diseases," said Dr. Sujino, explaining their motivation for the study.
Building on their previous observation that mild intestinal (ileal) inflammation exists in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, the authors set out to test whether similar inflammation is present in patients with MS. By performing single-cell RNA sequencing on intestinal biopsies, the team identified that inflammatory Th17 cells accumulate in the mouse EAE model as well as in the intestine of patients with MS, suggesting a conserved gut–CNS axis that may be active in human diseases.
In both EAE mice and patients with MS, intestinal epithelial cells (IECs) upregulated antigen presentation pathways. Particularly, epithelial cells in the ileum had higher expression of major histocompatibility complex class II (MHC II) that presents antigens to CD4+ T cells, and selective deletion of MHC II in IECs reduced pathogenic Th17 cell generation and disease severity.
IECs do not typically present antigens to immune cells. So, the team conducted co-culture assays to test the antigen presentation function of IECs. Their findings demonstrate that IECs can directly present antigens in an MHC II-dependent manner to prime CD4+ T cells in the gut. Notably, in these assays, IECs induced Th17 polarization of activated CD4+ T cells. It became clear that the gut was a critical site for immune activation of pathogenic CD4+ T cells that polarized into pro-inflammatory Th17 cells.
To investigate whether the Th17 cells directly contribute to the pool of autoreactive cells in the CNS, they used transgenic mice that express the Kaede protein, which undergoes photoconversion from green to red fluorescence upon exposure to violet light. 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, this study reveals a critical role for MHC II expressed by IECs in the expansion of pathogenic Th17 cells that subsequently migrate to the CNS during EAE, providing a mechanistic link between gut immune responses and autoimmune neuroinflammatory diseases. This landmark study demonstrates 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.
"While current therapies for MS often target B cells, our study highlights the gut as an important therapeutic site. Modulating intestinal microbiota or antigen-presenting activity of IECs represents new approaches to treating autoimmune neurological diseases," explained Dr. Suzuki, emphasizing the therapeutic implications of their findings.
Let us hope that an improved understanding of the gut mucosal immune responses will help the development of better therapeutics for debilitating neurological disorders like MS.
