Vedolizumab and the gut–CNS axis in multiple sclerosis: considering T cell licensing pathways

Abstract

Background:

The role of gut-mediated T cell licensing in multiple sclerosis (MS) remains incompletely understood.

Objective:

We hypothesized that T cell licensing in the gut contributes to MS pathogenesis and evaluated whether vedolizumab—an anti-α4β7 integrin, gut-selective monoclonal antibody approved for inflammatory bowel disease (IBD)—is associated with MS prevalence.

Design:

Retrospective observational study.

Methods:

Using Epic Cosmos, a large deidentified U.S. electronic health record platform, we identified individuals with Crohn’s disease (CD) or ulcerative colitis (UC) and a concomitant MS diagnosis between August 2010 and August 2025.

Results:

Among 1,027,704 CD and 1,294,362 UC patients, 8,098 (0.79%; 95%CI:0.77%–0.81%) and 9,564 (0.74%; 95%CI:0.73%–0.76%) had MS, respectively. In contrast, among vedolizumab-treated patients, only 125 with CD (0.22%; 95%CI:0.18%–0.26%) and 109 with UC (0.17%; 95%CI:0.14%–0.20%) developed MS within five years of treatment.

Conclusion:

While causality cannot be inferred, our findings highlight an opportunity to further explore whether vedolizumab-associated differences in MS prevalence may relate to gut-associated immune processes.

Plain language summary

How the gut-targeted drug vedolizumab may influence the immune system in multiple sclerosis

Multiple sclerosis (MS) is a disease in which the body’s own immune system attacks the brain and spinal cord. Scientists are still learning what triggers this immune attack, but there is growing evidence that the gut—often called the “second brain”—may play an important role. Immune cells known as T cells can become activated, or “licensed,” in the gut before traveling through the bloodstream to other parts of the body, including the brain. In this study, we asked whether blocking immune cell movement from the gut might reduce the risk of developing MS. We focused on a drug called vedolizumab, which is approved for treating inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. Vedolizumab works by preventing certain immune cells from leaving the gut and entering circulation. Using a large, nationwide U.S. database of electronic health records (Epic Cosmos), we analyzed data from more than 2.3 million people with IBD between 2010 and 2025. We found that approximately 0.7–0.8% of patients with Crohn’s disease or ulcerative colitis also had a diagnosis of MS. However, a smaller proportion of patients treated with vedolizumab—about 0.17–0.22%—had an MS diagnosis recorded within five years after starting the drug. Because this was an observational study using health records, it cannot determine whether vedolizumab causes a lower risk of MS. The observed differences may be influenced by other factors, such as treatment selection or differences in healthcare use. However, these findings suggest a potential association between gut-targeted immune therapy and MS that warrants further study. They also support growing interest in the connection between the gut and the brain through the immune system, often referred to as the gut–brain axis. Future research, including prospective and mechanistic studies, will be needed to better understand these relationships and their implications.

Keywords

electronic health records (EHR)gut–brain axis immune cell migration inflammatory bowel disease (IBD)integrin α4β7 multiple sclerosis (MS)neuroimmunology real-world evidence T-cell trafficking vedolizumab

Introduction

Multiple lines of evidence from both human studies and animal models demonstrate that autoreactive T cells, including those specific for central nervous system (CNS) antigens, can undergo activation and differentiation, also referred to as “licensing,” within gut-associated lymphoid tissue or the intestinal lamina propria, often in response to microbiota-derived antigens or metabolites. This licensing is characterized by upregulation of pro-inflammatory pathways, such as Th17 differentiation, and is dependent on interactions with local antigen-presenting cells and MHC class II molecules.^1–3 Following licensing in the gut, these T cells can acquire migratory properties that enable them to cross the blood–brain barrier and initiate neuroinflammation. Disruption of gut homing or activation, for example, by blocking the α4β7 integrin, or by knocking out its ligand mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), can reduce the encephalitogenic potential of these T cells and attenuate CNS disease severity in experimental models.^4,5

Natalizumab is a therapeutic monoclonal antibody approved for the treatment of persons with multiple sclerosis (MS) and Crohn’s disease (CD) that antagonizes α4 integrin and its binding to vascular cell adhesion molecule-1 (VCAM-1) on the blood–brain barrier (BBB) and MAdCAM-1 on the intestinal endothelium.⁶ It is currently incompletely understood to what extent natalizumab’s beneficial effects are mediated through inhibiting leukocyte migration across the BBB, or T cell licensing in the gut.

In this context, the role of vedolizumab, a humanized monoclonal antibody that selectively targets α4β7 integrin to prevent T cell trafficking to the gut, warrants attention. Vedolizumab is FDA-approved for the treatment of moderate to severe CD and ulcerative colitis (UC), where it has demonstrated efficacy and safety in reducing intestinal inflammation.⁷ Unlike natalizumab, which blocks both α4β1 and α4β7 integrins and prevents CNS trafficking of lymphocytes but carries a risk of progressive multifocal leukoencephalopathy,⁶ vedolizumab is gut-selective and spares CNS immune surveillance. While vedolizumab is widely used for inflammatory bowel disease (IBD) as a first-line therapy, its potential implications in MS are poorly understood. If gut activation is indeed a prerequisite for encephalitogenic T cell licensing, then targeting α4β7-mediated trafficking might hold therapeutic potential for MS. In this study, we investigated whether vedolizumab exposure is associated with MS prevalence by comparing patients with IBD overall with those treated with vedolizumab.

Methods

We leveraged Epic Cosmos, a large-scale, deidentified electronic health record data platform that aggregates clinical information from hundreds of healthcare organizations across the United States and encompasses data on approximately 300 million patients.⁸ We identified individuals with a diagnosis of CD (ICD-10 code K50.*) or UC (ICD-10 code: K51.*) and a concomitant diagnosis of MS (ICD-10 code G35) between August 21, 2010, and August 20, 2025. We then identified vedolizumab-treated patients with IBD, excluding those with a prevedolizumab diagnosis of MS, and determined the percentage with a diagnosis of MS within 5 years of vedolizumab exposure. The 5-year post-exposure window was chosen to capture potential longer-term effects of vedolizumab and to account for delays in MS diagnosis.

Prevalence estimates with 95% confidence intervals (CIs) were calculated, and chi-square tests were used to compare prevalence rates between groups. pp Values < 0.05 were considered statistically significant.

This manuscript did not involve human participants or animal experiments. Accordingly, it does not constitute human subject research; institutional review board or ethics committee approval and written informed consent were not required. The manuscript includes no images, videos, or other potentially identifiable personal information. This work is not a clinical trial; therefore, trial registration and a protocol/statistical analysis plan are not applicable.

Results

At the time of the study query in January 2026, there were a total of 300,284,589 patients in Epic Cosmos. Demographic characteristics of CD and UC cohorts, stratified by MS status and vedolizumab exposure, are shown in Supplemental Table 1.

Among 1,027,704 patients with a recorded diagnosis of CD between August 21, 2010, and August 20, 2025, 8098 patients (0.79%, 95% CI: 0.77%–0.81%) had coexisting MS. During the same period, among patients with CD treated with vedolizumab (excluding those with a prevedolizumab diagnosis of MS), 125 (0.22%, 95% CI: 0.18%–0.26%) were diagnosed with MS within 5 years of vedolizumab treatment (Figure 1). This represented a statistically significant difference compared with the prevalence of MS in all patients with CD (0.22% vs 0.79%, χ² = 228.8, p < 0.001).

Figure 1.

Prevalence of multiple sclerosis in inflammatory bowel disease versus vedolizumab-treated inflammatory bowel disease.

Among 1,294,362 patients with a diagnosis of UC, 9564 (0.74%, 95% CI: 0.73%–0.76%) had coexisting MS. In patients with UC treated with vedolizumab (excluding those with a prevedolizumab diagnosis of MS), 109 (0.17%, 95% CI 0.14%–0.20%) were diagnosed with MS within 5 years of vedolizumab treatment (Figure 1). This also represented a statistically significant difference compared with the prevalence of MS in all patients with UC (0.17% vs 0.74%, χ² = 274.6, p < 0.001).

Discussion

In this study, we found a discrepancy in the prevalence of MS between patients with IBD and those with IBD treated with vedolizumab, with the latter prevalence being significantly lower. This discrepancy is noteworthy and highlights an opportunity to further investigate whether the observed differences in MS prevalence among vedolizumab-treated patients may be associated with gut-related immune processes.

Building on this observation, the lower prevalence of MS among vedolizumab-treated patients with IBD is consistent with the hypothesis that selective blockade of gut-homing pathways may be associated with immune dynamics relevant to CNS autoimmunity. From a biological plausibility standpoint, vedolizumab’s inhibition of α4β7–MAdCAM-1 interactions restricts lymphocyte trafficking into intestinal tissue,⁹ potentially limiting the gut-dependent licensing of autoreactive T cells that has been described in both experimental models and human studies.^1–3 In this way, vedolizumab provides a unique clinical context in which to explore the hypothesis regarding the role of gut immune activation in encephalitogenic T cell priming (Figure 2).

Figure 2.

Mechanism of action of vedolizumab and hypothesized reduction in the occurrence of multiple sclerosis (MS).

Importantly, our observations do not establish that vedolizumab is protective against MS, and the proposed biological pathways should be viewed as hypothesis-generating. The reduced prevalence could be explained by several alternative factors, including prescribing patterns, confounding by indication, or differences in healthcare utilization. Moreover, MS and IBD case identification in this study relied on ICD-10 diagnostic codes within a large, deidentified EHR dataset. As with all administrative and EHR-based analyses, diagnostic misclassification is possible, including potential miscoding or incomplete capture of diagnoses. Taken together, the large scale of the dataset (approximately 300 million patients) and the consistency of findings across both IBD subtypes support the internal consistency of our observation, while not eliminating the possibility of residual bias. Confounding by indication is an important limitation. Patients treated with vedolizumab likely represent a selected subgroup with distinct disease severity, treatment history, and healthcare utilization, which may influence MS ascertainment independently of any biological effect. Our analysis was descriptive only and did not adjust for potential confounders such as age, sex, race/ethnicity, calendar year, disease duration, prior or concomitant biologic exposure, treatment sequencing, or healthcare utilization. As a result, the observed differences in MS prevalence should be interpreted descriptively and as hypothesis-generating, rather than as evidence of an independent association. Also, given the large sample size, statistically significant differences may reflect small absolute differences and should not be interpreted as supporting causal inference. Temporal uncertainty is an additional limitation of this study. Although patients with a diagnosis of MS prior to vedolizumab exposure were excluded and a defined 5-year post-exposure window was applied, the temporal relationships among IBD onset, immune dysregulation, vedolizumab exposure, and MS development cannot be definitely established in this observational design. Reverse causation and delayed MS diagnosis, therefore, remain plausible explanations. Future studies employing case–control or longitudinal designs will be needed to more rigorously assess temporality and confounding in this context.

A recent case report described a patient with coexisting CD and MS who was successfully treated with dual biologic therapy using ocrelizumab for MS and vedolizumab for CD without adverse outcomes.¹⁰ While anecdotal, this highlights the feasibility and tolerability of such an approach and raises questions about potential immunologic synergies or redundancies.

Whether gut activation is necessary for encephalitogenic T cell priming, and whether gut-specific blockade via vedolizumab could influence MS disease activity, remain open questions. Future studies are needed to clarify these associations. Large-scale, prospective observational studies could help determine whether vedolizumab use truly alters the incidence of MS, while mechanistic clinical trials could interrogate its impact on gut–CNS immune crosstalk, T cell phenotypes, and CNS biomarkers. Parallel microbiome and immunophenotyping studies would also be valuable to establish whether gut-specific blockade shifts immune composition in ways that reduce encephalitogenic potential.

In conclusion, our findings underscore the importance of the gut–CNS axis in MS and provide a rationale for further exploration of vedolizumab as a potential therapeutic modulator in MS.

Supplemental Material

sj-docx-1-tan-10.1177_17562864261423751 – Supplemental material for Vedolizumab and the gut–CNS axis in multiple sclerosis: considering T cell licensing pathways

Supplemental material, sj-docx-1-tan-10.1177_17562864261423751 for Vedolizumab and the gut–CNS axis in multiple sclerosis: considering T cell licensing pathways by Afsaneh Shirani and Olaf Stuve in Therapeutic Advances in Neurological Disorders

Footnotes

Acknowledgements

Data used in this study came from Epic Cosmos, a dataset created in collaboration with a community of health systems using Epic, representing approximately 300 million patient records from over 1883 hospitals and 42,400 clinics as of January 2026. The community represents patients from all 50 states, D.C., Canada, Lebanon, and Saudi Arabia.

The authors would like to thank the Clinical Scholars Program at Saint Luke’s Marion Bloch Neuroscience Institute for its support

Declarations

ORCID iDs

Afsaneh Shirani

Olaf Stuve

Supplemental material

Supplemental material for this article is available online.

References

Bauer

Fang

Lämmle

, et al. Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two-photon imaging. Proc Natl Acad Sci USA 2023; 120(30): e2302697120.

Kawakami

Wekerle

Life history of a brain autoreactive T cell: from thymus through intestine to blood–brain barrier and brain lesion. Neurotherapeutics 2024; 21(6): e00442.

White

Cabrera

Mei

, et al. Gut inflammation promotes microbiota-specific CD4 T cell– mediated neuroinflammation. Nature 2025; 643(8071): 509–518.

Duc

Vigne

Bernier-Latmani

, et al. Disrupting myelin-specific Th17 cell gut homing confers protection in an adoptive transfer experimental autoimmune encephalomyelitis. Cell Rep 2019; 29(2): 378–390.e4.

Kuhbandner

Hammer

Haase

, et al. MAdCAM-1-mediated intestinal lymphocyte homing is critical for the development of active experimental autoimmune encephalomyelitis. Front Immunol 2019; 10: 903.

Shirani

Stüve

Natalizumab: perspectives from the bench to bedside. Cold Spring Harb Perspect Med 2018; 8(12): a029066.

Baumgart

Le Berre

Newer biologic and small-molecule therapies for inflammatory bowel disease. N Engl J Med 2021; 385(14): 1302–1315.

Epic Systems Corporation. Epic Cosmos. Available at: https://cosmos.epic.com/ (accessed 4 September 2025).

Wyant

Fedyk

Abhyankar

An overview of the mechanism of action of the monoclonal antibody vedolizumab. J Crohns Colitis 2016; 10(12): 1437–1444.

10.

Mitrev

Leong

, et al. Dual biologic therapy with ocrelizumab for multiple sclerosis and vedolizumab for Crohn’s disease: a case report and review of literature. World J Clin Cases 2022; 10(8): 2569–2576.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB