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.

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.

This bar graph illustrates the prevalence of multiple sclerosis (MS) among patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, comparing the overall IBD population with patients treated with vedolizumab. Data were derived from Epic Cosmos between August 21, 2010, and August 20, 2025. Patients with a diagnosis of MS prior to vedolizumab initiation were excluded from the vedolizumab-treated cohort. Error bars denote 95% confidence intervals. Values above each bar show the prevalence with corresponding confidence intervals, and n/N indicates the number of MS cases (n) and the total number of patients in each cohort (N).

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.