The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of this study is to investigate if circadian malalignment (unusual sleeping patterns), such as night shifts (sleeping during the day and being awake during the night time), worsens the inflammation of the gut. We hope to look at patients with Ulcerative Colitis and Healthy Controls.

Official Title
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The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Behavioral: 7-day sleep lab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: UC patients: M/F, 18-50 y/o Inactive Disease (Mayo Score ≤ 2) Stable medications with no disease flares for the > 3 months Left-sided UC (Montreal E1 or E2) Normal psychological evaluation and negative drug screen (See Below) Healthy Controls: M/F, 18-50 y/o, age ± 3y sex, race, and BMI match with UC subject No clinical evidence of any medical illness Normal psychological evaluation and negative drug screen (See Below) Exclusion Criteria: UC patients: Patients with other forms of colitis such as Crohn's disease (CD) or indeterminate colitis Patient with active UC (Mayo > 2) Pancolonic UC (colitis past the splenic flexure, Montreal E3)) Use of biologic or immunomodulatory medications (i.e. Infliximab, Adalimumab, azathioprine, Vedolizumab, methotrexate, etc.) Gastrointestinal surgery Other GI diseases or systemic diseases (cardiac, renal failure, cirrhosis) Shift work in the last 6 months Antibiotic use within last 12 weeks Patients who have used anti-diarrheal agents such as Lomotil or Imodium within 3 days of the study Prednisone use the last 30 days Significant Depression (score ≥ 14 BDI) Significant Anxiety (score ≥ 40 STAI) Use of probiotic supplement in last 4 weeks except yogurt. Intentional change in diet. Chronic use of NSAIDS. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Low dose aspirin is allowed. Chronic Alcohol use. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Have children under 6 months Healthy Controls: History of drug abuse, gastrointestinal (GI) surgery, GI diseases, or systemic diseases such as renal (creatinine>1.2 mg/dl), liver, cardiac, or diabetes (Hgb-A1c>8%) Antibiotic use within last 12 weeks Shift work in the last 6 months Use of probiotic supplement except yogurt in last 4 weeks. Atypical American diet with daily fiber ≥ 16 grams or daily saturated fat ≤ 11 grams by Food Frequency Questionnaire Chronic use of NSAIDS. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Chronic Alcohol use. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Significant Depression (score ≥ 14 BDI) Significant Anxiety (score ≥ 40 STAI) Regular use of medications that affect intestinal permeability, intestinal motility and/or endogenous melatonin including metoclopramide, NSAIDs, antibiotics, beta blocker, psychotropic medication, hypnotics and exogenous melatonin products during 4 weeks prior to the study People who crossed more than 2 time zones in the previous month Inability to sign an informed consent form. Have children under 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: 40 human subjects will be recruited into this proposed study: 20 Healthy Controls and 20 UC subjects with left sided inactive disease. Patients will be matched with Health Controls. Patients will have two study visits: the first is the initial in-clinic screening and the second is the 7-day sleep lab intervention. There will be no follow-up after the lab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sleep Lab<br> | Behavioral: 7-day sleep lab<br>* Patients will stay in 7-day sleep lab where light exposure, diet, and activity will be closely monitored. They will have two unprepped flexible sigmoidoscopies with rectal biopsy collection and stool collection. Cycles will be shifted by 12h once on Day 3 of sleep lab and be discharged after an 8 hour sleep session on Day 7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Phase Angle of Entrainment from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Phase angle of entrainment is the amount of time between dim light melatonin onset to sleep onset. Melatonin concentration in blood serum is measured by ELISA (enzyme-linked immunosorbent assay). | Blood drawn hourly for eight hours at baseline circadian rhythm (eight draws) and blood drawn hourly for twelve hours at circadian misalignment (12 draws). | 
| Change in Intestinal Permeability from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Intestinal permeability is assessed through spectrophotometric measurements of sucralose, sucrose, maltose and lactulose concentrations in urine following ingestion of a sugar cocktail. | 24 hour urine collection beginning at baseline and 24 hour urine collection at circadian misalignment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24 hour Urinary Melatonin Concentrations from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Spectrophotometry | 24 hour urine collection at baseline and 24 hour urine collection at circadian misalignment circadian | 
| Change in Mayo Score from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Within the endoscopic component of the Mayo Score, a score of 0 is given for normal mucosa or inactive UC, while a score of 1 is given for mild disease with evidence of mild friability, reduced vascular pattern, and mucosal erythema. | 30 minute flexible sigmoidoscopy at Baseline and 30 minute flexible sigmoidoscopy at Circadian Misalignment | 
| Change in Stool Calprotectin from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Calprotectin is a sensitive marker for inflammation in the gastrointestinal tract. Measured through enzyme linked immunosorbent assay for calprotectin in stool extract. | 10 minute stool collection conducted at baseline circadian rhythm and at circadian misalignment. | 
| Change in Concentration of Serum Cytokine Markers of Inflammation from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Enzyme linked immunosorbent assay | Blood is drawn every two hours over a 24 hour period at baseline (12 draws), and blood is drawn every two hours over a 24 hour period at circadian misalignment | 
| Changes in Clock Gene Expression in Peripheral Blood Mononuclear Cells from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | RNA Sequencing | Blood is drawn every two hours over a 24 hour period at baseline (12 draws), and blood is drawn every two hours over a 24 hour period at circadian misalignment | 
| Changes in Gene Expression of Colonic Tissue Biopsies from Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Tissue biopsies collected during flexible sigmoidoscopy conducted at Baseline Circadian Rhythm and at Circadian Misalignment. Assessed through histology and RNA Sequencing | 30 minute flexible sigmoidoscopy at Baseline and 30 minute flexible sigmoidoscopy at Circadian Misalignment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Circadian Rhythms