Circadian Misalignment in Inflammatory Bowel Disease
Condition: Inflammatory Bowel Diseases; Crohn Disease; Ulcerative Colitis
MeSH terms: Crohn Disease; Intestinal Diseases; Inflammatory Bowel Diseases
Study type: Observational

Summary: 
      This study is to explore the role the sleep/wake cycle (Circadian Rhythm) has on Inflammatory
      Bowel Disease. Participants will be asked to attend two clinic visits 14 days apart.
      Participants will complete a packet of questionnaires regarding their health and sleep
      habits. Over the 14 days between visits participants will be asked to wear a wrist actigraphy
      device that will measure their sleep-wake activity along with filling in a sleep diary.
      During the visits, participants will have a physical exam on visit 1 and on visit 2
      participants will be asked to give blood, stool, and urine samples. Additionally,
      participants may also give sigmoid tissue samples during an optional unprepped limited
      flexible sigmoidoscopy procedure.
    

Detailed description: 
      The long term goal of this Research proposal is to establish that circadian misalignment is a
      factor for disease flare in inflammatory bowel disease (IBD). In order to achieve this goal
      this project will focus on two aspects that are critical to address in the management of IBD
      - disease course and subclinical inflammation. One of the most challenging aspects of IBD
      medical care is that IBD has a very heterogeneous disease course. Some patients will quickly
      progress to surgery despite aggressive medical therapy while others have no disease flares on
      any medications. In order to address these factors, the investigator will access multiple
      factors about each IBD patient to determine what their previous disease course has been
      (history), known factors of their disease that are associated with disease course (location,
      age of diagnosis, etc), and markers of subclinical inflammation that are established
      predictors of disease flare. Our overall hypothesis is that circadian misalignment is an
      important factor in the disease course in IBD. To test this hypothesis, the investigator will
      conduct a series of experiments in humans to elucidate the role of circadian rhythms in IBD.
      In Aim 1, the investigator will test the hypothesis that circadian misalignment is present in
      IBD with an aggressive disease course by analyzing circadian rhythms by wrist actigraphy,
      urinary melatonin, and chronotype questionnaires. In Aim 2, the investigator will assess
      markers of subclinical inflammation in the same subjects from Aim1, and analyze established
      predictors of disease flare such as CRP, intestinal permeability, fecal calprotectin, and
      mucosal inflammation markers. The goal of this research proposal is to identify whether
      circadian misalignment is a factor in disease course in IBD. It is not to determine if IBD
      patients have increased circadian misalignment compared to healthy controls, therefore
      healthy controls are not used as a comparison group. However, Dr. Burgess and Dr. Levi's labs
      do have a large historical cohort of over 100 healthy controls that have completed wrist
      actigraphy measurements and chronotype questionnaires that can be used as a comparison if our
      hypothesis is proven incorrect.

      Experimental Design: Subjects with biopsy proven IBD (N=68) will be recruited, 24 CD (Crohn's
      Disease) and 24 UC (Ulcerative Colitis). All subjects will be between 18-70 years old.
      Subjects will be recruited from the Rush University GI Clinic. All subjects will complete
      questionnaires including IBD demographic history, an IBD quality of life, food timing, sleep
      questionnaires - PROMIS and RUSATED, and chronotype questionnaires - Owl and Lark and Munich.
      Each subject will be accessed by the PI for exclusion criteria including: 1) Active IBD (HBI
      ≥ 5 or Modified HBI ≥5); 2) Major depression (score ≥ 15 or any endorsement of suicidal
      intent on the Beck Depression; 3) Sleep apnea (score high risk ≥ 2 or more categories on the
      Berlin Questionnaire)(43); 4) Restless leg syndrome (score ≥ 15 on the IRLS Study Group
      Rating Scale(44)); 5) Regular use of medications that affect intestinal permeability, and/or
      endogenous melatonin including metoclopramide, NSAIDs, beta blocker, psychotropic medication,
      hypnotics and exogenous melatonin products during 4 weeks prior to the study; 6) People who
      have worked night shifts or crossed more than 2 time zones in the previous month; 7) Any
      major organ disease - renal impairment (creatinine>1.2 mg/dL - previous EMR labs must be
      within the past 12 months), diabetes (Hgb-A1c > 6.5% - no history of any form of diabetes);
      liver disease (LFTs > 1.5x nl - previous EMR labs must be within the past 12 months), or
      significant cardiac problems; 8) Inability to sign an informed consent.

      Subjects that meet these inclusion/exclusion criteria will be assessed by the PI, who will
      perform a physical exam, take a history, and review prior medical testing. Subjects will
      matched 1:1 during recruitment so N=12 in both CD and UC with aggressive disease and N=12 in
      both CD and UC with nonaggressive disease (See Experimental Design). All subjects will then
      have their sleep patterns recorded by wrist actigraphy (30 sec epochs, Actiwatch Spectrum,
      Phillips Inc.) for 14 days (±3 days). Wrist actigraphy is a reliable standard means of
      assessing sleep-wake activity,(45) and will be used to calculate circadian rhythm by
      dichotomy index and r24. During the 14days (±3 days) subjects will also keep a detailed
      consensus sleep diary which is a standardized prospective sleep measure.(46) At the end of
      the 14 days (±3 days), and a day prior to their visit, all subjects will complete an online
      self-administered 24 hour food recall (ASA24) and 24 h urine collection for urinary melatonin
      which is also a marker of central circadian rhythm.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Adults diagnosed with Ulcerative Colitis or Crohn's Disease.