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Researchers identified that epithelial cells in the ileum express MHC II to prime pathogenic Th17 cells, which then migrate to the CNS. Credit: Neuroscience News<\/p>\nSummary: For years, scientists have suspected that the gut plays a role in Multiple Sclerosis (MS), but the \u201csmoking gun\u201d linking the two has been elusive. A landmark study has finally identified the cellular mechanism: Intestinal Epithelial Cells (IECs)\u2014the cells lining your gut\u2014are acting as \u201caccidental\u201d messengers.<\/p>\n
The study found that in patients with MS, these gut cells abnormally express MHC II, a protein that \u201cpresents\u201d antigens to the immune system. This interaction mistakenly transforms ordinary immune cells into pathogenic Th17 cells, which then migrate from the gut directly to the central nervous system to attack the brain and spinal cord.<\/p>\n
Key Facts<\/p>\n
The Accidental Messenger: IECs do not normally \u201ctalk\u201d to the immune system in this way. In MS, they begin expressing MHC II, which \u201cprimes\u201d CD4+ T cells to become aggressive.The Th17 Migration: Using \u201cKaede\u201d protein tracking (which changes color under light), researchers proved that these gut-primed Th17 cells physically travel from the intestine to the spinal cord to drive neuroinflammation.Human Connection: The team used single-cell RNA sequencing on human biopsies to confirm that the same inflammatory patterns seen in mouse models are present in the intestines of human MS patients.New Treatment Target: Most current MS therapies target B cells in the blood; this study suggests that treating the gut environment or blocking the antigen-presenting activity of gut cells could stop MS at its source.<\/p>\n
Source: Keio University<\/p>\n
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). <\/p>\n
What makes our body turn against itself?<\/p>\n
Researchers identified that epithelial cells in the ileum express MHC II to prime pathogenic Th17 cells, which then migrate to the CNS. Credit: Neuroscience News<\/p>\n
Failure of the immune system to distinguish \u2018self\u2019 from \u2018non-self\u2019 entities leads to excessive autoimmune responses against self-proteins like myelin, which forms a protective covering on the neurons.<\/p>\n
Multiple factors influence the onset and progression of MS, including genetic susceptibility, environmental triggers, and, more recently, the gut microenvironment.<\/p>\n
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\u2013CNS axis, the cellular mechanisms that relay the gut-derived signals to the immune system to influence autoimmune inflammation in the CNS remain poorly understood.<\/p>\n
A recent study, made available online on March 27, 2026, in the journal\u00a0Science Immunology, uncovers a key mechanistic role for gut immune responses as initiators of neuroinflammation.<\/p>\n
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.<\/p>\n
\u201cIncreasing evidence shows that the gut microbiota influences neurological diseases such as Parkinson\u2019s, Alzheimer\u2019s, 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,\u201d said Dr. Sujino, explaining their motivation for the study.<\/p>\n
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.<\/p>\n
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\u2013CNS axis that may be active in human diseases.<\/p>\n
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+\u00a0T cells, and selective deletion of MHC II in IECs reduced pathogenic Th17 cell generation and disease severity.<\/p>\n
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+\u00a0T cells in the gut.<\/p>\n
Notably, in these assays, IECs induced Th17 polarization of activated CD4+\u00a0T cells. It became clear that the gut was a critical site for immune activation of pathogenic CD4+\u00a0T cells that polarized into pro-inflammatory Th17 cells.<\/p>\n
To investigate whether the Th17 cells directly contribute to the pool of autoreactive cells in the CNS, they used transgenic mice that express the\u00a0Kaede\u00a0protein, 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.<\/p>\n
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.<\/p>\n
This landmark study demonstrates that while systemic circulation allows T cell exchange across immune tissues, the epithelial\u2013immune interactions within the gut mucosal compartment can essentially shape effector T cell responses in the brain.<\/p>\n
\u201cWhile 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,\u201d explained Dr. Suzuki, emphasizing the therapeutic implications of their findings.<\/p>\n
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.<\/p>\n
Funding information
This work was supported by the Japan Science and Technology Agency (JST) through the Fusion Oriented Research for Disruptive Science and Technology (FOREST) program (grant number: 21457195); Grants-in-Aid from the Japan Society for the Promotion of Science (JSPS) (grant numbers: 20H00536, 20H03665, 21K18272, 23H02899, 23K27590, and 25K22627); the Japan Agency for Medical Research and Development (CREST grant number: 21gm1510002h0001); KGRI Challenge grant; Sakaguchi Memorial Foundation; and Miyarisan Pharmaceuticals.<\/p>\n
Key Questions Answered:Q: Why is my gut involved in a disease that attacks my brain?<\/p>\n
A: Think of your gut as the \u201ctraining ground\u201d for your immune system. This study shows that in MS, the gut lining makes a critical error during training. It shows the immune system the wrong \u201ctarget,\u201d creating a specialized force of inflammatory cells (Th17) that then leave the gut and travel specifically to your spine and brain to cause damage.<\/p>\n
Q: Does this mean a specific diet could cure MS?<\/p>\n
A: While the study highlights the \u201cgut microenvironment,\u201d it\u2019s more about the immune cells in the gut than just the food you eat. However, it opens the door for \u201cluminal\u201d therapies\u2014treatments that stay in the gut to fix these \u201ctraining errors\u201d without needing to suppress your entire immune system.<\/p>\n
Q: How did the scientists prove the cells actually moved from the gut to the brain?<\/p>\n
A: They used a fascinating technology called Kaede photoconversion. They used a special light to turn immune cells in the gut \u201cred\u201d and then waited. Later, they found those exact same red cells in the spinal cord, proving the gut is the primary \u201claunchpad\u201d for the attack.<\/p>\n
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this multiple sclerosis research news<\/p>\n
Author:\u00a0Tetyana Khatayeva<\/a>
Source:\u00a0Keio University<\/a>
Contact:\u00a0Tetyana Khatayeva \u2013 Keio University
Image:\u00a0The image is credited to Neuroscience News<\/p>\n