Vitamin D Is Associated with α4β7+ Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease
John Gubatan, Samuel J. S. Rubin, Lawrence Bai, Yeneneh Haileselassie, Steven Levitte, Tatiana Balabanis, Akshar Patel, Arpita Sharma, Sidhartha R. Sinha, Aida Habtezion
Abstract
BACKGROUND AND AIMS: Vitamin D downregulates the in vitro expression of the gut-tropic integrin α4β7 on immune cells. The clinical relevance of this finding in patients with inflammatory bowel disease [IBD] is unclear. We tested the hypothesis that vitamin D is associated with α4β7 immunophenotypes and risk of vedolizumab [anti-α4β7] failure in IBD. METHODS: We performed single-cell immunophenotyping of peripheral and intestinal immune cells using mass cytometry [CyTOF] in vedolizumab-naïve patients with IBD [N = 48]. We analysed whole-genome mucosal gene expression [GSE73661] from GEMINI I and GEMINI long-term safety [LTS] to determine the association between vitamin D receptor [VDR] and integrin alpha-4 [ITGA4] and beta-7 [ITGB7] genes. We estimated the odds of vedolizumab failure with low pre-treatment vitamin D in a combined retrospective and prospective IBD cohort [N = 252] with logistic regression. RESULTS: Immunophenotyping revealed that higher 25[OH]D was associated with decreased α4β7+ peripheral blood mononuclear cells [R = -0.400, p <0.01] and α4β7+ intestinal leukocytes [R = -0.538, p = 0.03]. Serum 25[OH]D was inversely associated with α4β7+ peripheral B cells and natural killer [NK] cells and α4β7+ intestinal B cells, NK cells, monocytes, and macrophages. Mucosal expression of VDR was inversely associated with ITGA4 and ITGB7 expression. In multivariate analysis, 25[OH]D <25 ng/mL was associated with increased vedolizumab primary non-response during induction (odds ratio [OR] 26.10, 95% confidence interval [CI] 14.30-48.90, p <0.001) and failure at 1-year follow-up [OR 6.10, 95% CI 3.06-12.17, p <0.001]. CONCLUSIONS: Low serum 25[OH]D is associated with α4β7+ immunophenotypes and predicts future vedolizumab failure in patients with IBD. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.