Circadian Misalignment in Inflammatory Bowel Disease

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.