Clinical trial NCT04828031: Vitamin D Regulation of Gut Specific B Cells and Antibodies Targeting Gut Bacteria in Inflammatory Bowel Disease
Official title: Vitamin D Regulation of α4β7+ B Cell Immunophenotypes and Mucosal Antibody Response to Commensal Gut Bacteria in Patients With Inflammatory Bowel Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Inflammatory Bowel Diseases
Ulcerative Colitis
Crohn Disease
Keywords: Gut Microbiome, Vitamin D, Dysbiosis, Inflammation
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Doris Duke Charitable Foundation
First posted: 2021-04-01
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label prospective clinical trial with vitamin D 50,000 IU PO every week for 12 weeks in patients with inflammatory bowel disease (IBD) with 25(OH)D ≤ 25 ng/mL
Primary purpose: TREATMENT

Brief summary: Specific Aim 1: Characterize the effects of vitamin D treatment on expression of α4β7 on B cells in patients with inflammatory bowel disease (IBD).

Specific Aim 2: Determine the effects of vitamin D treatment on fecal immunoglobulins, percentage of Ig-coated gut bacteria, gut microbiome composition (global and bound by immunoglobulins) in patients with IBD and the association of these parameters with change in α4β7+ B cells .

Specific Aim 3: Compare BCR repertoire (BCR clonotypes, immunoglobulin heavy chain gene (IGHV), and isotype usage) between α4β7+ and α4β7- B cells in patients with IBD and identify α4β7+ BCR clonotypes associated with Ig-bound gut bacteria .


Eligibility criteria: Inclusion Criteria:

* Adult patients (18 years or older) with inflammatory bowel disease (ulcerative colitis or Crohn's disease)
* Low serum vitamin D (25(OH)D ≤ 25 ng/mL
* Not currently on high dose vitamin D supplementation
* No prior bowel resections
* No antibiotic use in past 3 months.

Exclusion Criteria:

* Patients less than 18 years old
* No diagnosis of IBD
* Serum 25(OH)D \> 25 ng/mL
* Patients already on vitamin D supplementation
* Prior history of bowel surgery (colectomy or small bowel resections)
* Recent antibiotic use in past 3 months
* Renal Dysfunction
* History of Hypercalcemia
* History of HIV
* History of IgA deficiency
* History of Common Variable Immunodeficiency (CVID)
* Active C. diff infection

Primary outcomes:
measure: Reduction in α4β7+ B cells by 20%
timeFrame: Week 12
measure: Reduction in immunoglobulin coating of commensal gut bacteria by 20%.
timeFrame: Week 12
Secondary outcomes:
measure: Increase in serum vitamin D (25(OH)D levels by 10 ng/mL
timeFrame: Week 12
measure: Decrease in disease activity index scores by 50%
timeFrame: Week 12
measure: Decrease cohort mean fecal calprotectin or C-reactive protein (CRP) by 50%.
timeFrame: Week 12
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: John Mark Gubatan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Souza HSP, Fiocchi C, Iliopoulos D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol. 2017 Dec;14(12):739-749. doi: 10.1038/nrgastro.2017.110. Epub 2017 Aug 23.
citation: Caruso R, Lo BC, Nunez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol. 2020 Jul;20(7):411-426. doi: 10.1038/s41577-019-0268-7. Epub 2020 Jan 31.
citation: Rengarajan S, Vivio EE, Parkes M, Peterson DA, Roberson EDO, Newberry RD, Ciorba MA, Hsieh CS. Dynamic immunoglobulin responses to gut bacteria during inflammatory bowel disease. Gut Microbes. 2020 May 3;11(3):405-420. doi: 10.1080/19490976.2019.1626683. Epub 2019 Jun 16.
citation: Castro-Dopico T, Dennison TW, Ferdinand JR, Mathews RJ, Fleming A, Clift D, Stewart BJ, Jing C, Strongili K, Labzin LI, Monk EJM, Saeb-Parsy K, Bryant CE, Clare S, Parkes M, Clatworthy MR. Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis. Immunity. 2019 Apr 16;50(4):1099-1114.e10. doi: 10.1016/j.immuni.2019.02.006. Epub 2019 Mar 12.
citation: Gubatan J, Chou ND, Nielsen OH, Moss AC. Systematic review with meta-analysis: association of vitamin D status with clinical outcomes in adult patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2019 Dec;50(11-12):1146-1158. doi: 10.1111/apt.15506. Epub 2019 Oct 24.
citation: Gubatan J, Mitsuhashi S, Zenlea T, Rosenberg L, Robson S, Moss AC. Low Serum Vitamin D During Remission Increases Risk of Clinical Relapse in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2017 Feb;15(2):240-246.e1. doi: 10.1016/j.cgh.2016.05.035. Epub 2016 Jun 4.
citation: Gubatan J, Moss AC. Vitamin D in inflammatory bowel disease: more than just a supplement. Curr Opin Gastroenterol. 2018 Jul;34(4):217-225. doi: 10.1097/MOG.0000000000000449.
citation: Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol. 2007 Mar;8(3):285-93. doi: 10.1038/ni1433. Epub 2007 Jan 28.
citation: Gubatan J, Rubin SJS, Bai L, Haileselassie Y, Levitte S, Balabanis T, Patel A, Sharma A, Sinha SR, Habtezion A. Vitamin D Is Associated with alpha4beta7+ Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease. J Crohns Colitis. 2021 Dec 18;15(12):1980-1990. doi: 10.1093/ecco-jcc/jjab114.