Ulcerative Colitis
Conditions
Keywords
Circadian Rhythms
Brief summary
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.
Interventions
BEHAVIORAL7-day sleep lab
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.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Rush University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Dim Light Melatonin Onset (DLMO) From Baseline (Aligned) to Circadian Misalignment Misalignment | Blood is drawn every hour over 8 hours to measure plasma melatonin in dim light < 5 lux in Aligned Circadian Rhythms, and blood is drawn every hour for 12 hours under dim light in Misaligned Circadian rhythms. | Amount of time between dim light melatonin onset (DLMO) to sleep onset. The hours reported for this outcome measure equates the time of the day the participant fell asleep |
| Change in Intestinal Permeability From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 24 hour urine collection beginning at baseline and 24 hour urine collection at circadian misalignment, an average of 3 days from baseline 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mayo Score From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 30 minute flexible sigmoidoscopy at Baseline and 30 minute flexible sigmoidoscopy at 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. |
| Change in 24 Hour Urinary Melatonin Concentrations From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 24 hour urine collection at baseline and 24 hour urine collection at circadian misalignment circadian | Spectrophotometry |
| Change in Stool Calprotectin From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 10 minute stool collection conducted at baseline circadian rhythm and at circadian misalignment. | Calprotectin is a sensitive marker for inflammation in the gastrointestinal tract. Measured through enzyme linked immunosorbent assay for calprotectin in stool extract. |
| Change in Concentration of Serum Cytokine Markers of Inflammation From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 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 | Enzyme linked immunosorbent assay |
| Changes in Clock Gene Expression in Peripheral Blood Mononuclear Cells From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 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 | RNA Sequencing |
| Changes in Gene Expression of Colonic Tissue Biopsies From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | 30 minute flexible sigmoidoscopy at Baseline and 30 minute flexible sigmoidoscopy at Circadian Misalignment | Tissue biopsies collected during flexible sigmoidoscopy conducted at Baseline Circadian Rhythm and at Circadian Misalignment. Assessed through histology and RNA Sequencing |
Other
| Measure | Time frame | Description |
|---|---|---|
| Beck Depression Inventory | 3 Weeks prior to circadian lab assessments | The Beck Depression Inventory (BDI, BDI-II), created by Dr. Aaron T. Beck, is a 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depression. |
| Pittsburgh Sleep Quality Index | 3 Weeks prior to circadian lab assessments | The following questions relate to your usual sleep habits during the past month only. |
| Single Day Food Recall | Once before sleep lab | Automated Self-Administered 24-Hour Recall (ASA24) Dietary Assessment. Total nutrients from all supplements reported in a given day. |
| Diet | Once before sleep lab | Vioscreen Food Frequency Questionnaire (FFQ). Total of 19 measured food components. Vioscreen captures comprehensive dietary behaviors in just 30 minutes. It is a unique dietary questionnaire, management and analysis system that efficiently gathers and manages data that immediately identifies dietary habits and counsel for lifestyle changes. |
| Chronotype | Screening | The Munich ChronoType Questionnaire (MCTQ) uses a self-rated scale to assess individual phase of entrainment on work and work-free days; it is a tool to collect primary sleep times, such as bed- and rise-times, plus the clock time of becoming fully awake as well as sleep latency and inertia, in addition to other time points. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Control 7-day sleep lab: Healthy Control participants (no ulcerative colitis) will stay in 7-day sleep lab where light exposure, diet, and activity will be closely monitored. Participants at baseline will not have a misaligned circadian rhythm. They will have two unprepped flexible sigmoidoscopies with rectal biopsy collection and stool collection at baseline and after misalignment. 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. | 7 |
| Ulcerative Colitis 7-day sleep lab: Participants with ulcerative colitis will stay in 7-day sleep lab where light exposure, diet, and activity will be closely monitored. Participants at baseline will not have a misaligned circadian rhythm. They will have two unprepped flexible sigmoidoscopies with rectal biopsy collection and stool collection at baseline and after misalignment. 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. | 10 |
| Total | 17 |
Baseline characteristics
| Characteristic | Total | Healthy Control | Ulcerative Colitis |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 7 Participants | 10 Participants |
| Age, Continuous | 24 years | 32 years | 23.5 years |
| Race/Ethnicity, Customized African | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized African American | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 6 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 17 Participants | 7 Participants | 10 Participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 10 |
| other Total, other adverse events | 0 / 7 | 0 / 10 |
| serious Total, serious adverse events | 0 / 7 | 0 / 10 |
Outcome results
Primary
Change in Dim Light Melatonin Onset (DLMO) From Baseline (Aligned) to Circadian Misalignment Misalignment
Amount of time between dim light melatonin onset (DLMO) to sleep onset. The hours reported for this outcome measure equates the time of the day the participant fell asleep
Time frame: Blood is drawn every hour over 8 hours to measure plasma melatonin in dim light < 5 lux in Aligned Circadian Rhythms, and blood is drawn every hour for 12 hours under dim light in Misaligned Circadian rhythms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Control | Change in Dim Light Melatonin Onset (DLMO) From Baseline (Aligned) to Circadian Misalignment Misalignment | Baseline Aligned Circadian Rhythm | 20.72 hours | Standard Deviation 0.52 |
| Healthy Control | Change in Dim Light Melatonin Onset (DLMO) From Baseline (Aligned) to Circadian Misalignment Misalignment | Misaligned Circadian Rhythm | 23.05 hours | Standard Deviation 0.48 |
| Ulcerative Colitis | Change in Dim Light Melatonin Onset (DLMO) From Baseline (Aligned) to Circadian Misalignment Misalignment | Baseline Aligned Circadian Rhythm | 20.45 hours | Standard Deviation 1.08 |
| Ulcerative Colitis | Change in Dim Light Melatonin Onset (DLMO) From Baseline (Aligned) to Circadian Misalignment Misalignment | Misaligned Circadian Rhythm | 22.65 hours | Standard Deviation 1.88 |
Primary
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.
Time frame: 24 hour urine collection beginning at baseline and 24 hour urine collection at circadian misalignment, an average of 3 days from baseline to circadian misalignment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Control | Change in Intestinal Permeability From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Misaligned Circadian Rhythm | 0.088 % excretion of oral dose 12-24 hr urinar | Standard Deviation 0.053 |
| Healthy Control | Change in Intestinal Permeability From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Baseline Aligned Circadian Rhythm | 0.053 % excretion of oral dose 12-24 hr urinar | Standard Deviation 0.04 |
| Ulcerative Colitis | Change in Intestinal Permeability From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Misaligned Circadian Rhythm | 0.184 % excretion of oral dose 12-24 hr urinar | Standard Deviation 0.111 |
| Ulcerative Colitis | Change in Intestinal Permeability From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment | Baseline Aligned Circadian Rhythm | 0.141 % excretion of oral dose 12-24 hr urinar | Standard Deviation 0.065 |
Secondary
Change in 24 Hour Urinary Melatonin Concentrations From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment
Spectrophotometry
Time frame: 24 hour urine collection at baseline and 24 hour urine collection at circadian misalignment circadian
Secondary
Change in Concentration of Serum Cytokine Markers of Inflammation From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment
Enzyme linked immunosorbent assay
Time frame: 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
Secondary
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.
Time frame: 30 minute flexible sigmoidoscopy at Baseline and 30 minute flexible sigmoidoscopy at Circadian Misalignment
Secondary
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.
Time frame: 10 minute stool collection conducted at baseline circadian rhythm and at circadian misalignment.
Secondary
Changes in Clock Gene Expression in Peripheral Blood Mononuclear Cells From Baseline (Aligned Circadian Rhythms) to Circadian Misalignment
RNA Sequencing
Time frame: 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
Secondary
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
Time frame: 30 minute flexible sigmoidoscopy at Baseline and 30 minute flexible sigmoidoscopy at Circadian Misalignment
Other Pre-specified
Beck Depression Inventory
The Beck Depression Inventory (BDI, BDI-II), created by Dr. Aaron T. Beck, is a 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depression.
Time frame: 3 Weeks prior to circadian lab assessments
Other Pre-specified
Chronotype
The Munich ChronoType Questionnaire (MCTQ) uses a self-rated scale to assess individual phase of entrainment on work and work-free days; it is a tool to collect primary sleep times, such as bed- and rise-times, plus the clock time of becoming fully awake as well as sleep latency and inertia, in addition to other time points.
Time frame: Screening
Other Pre-specified
Diet
Vioscreen Food Frequency Questionnaire (FFQ). Total of 19 measured food components. Vioscreen captures comprehensive dietary behaviors in just 30 minutes. It is a unique dietary questionnaire, management and analysis system that efficiently gathers and manages data that immediately identifies dietary habits and counsel for lifestyle changes.
Time frame: Once before sleep lab
Other Pre-specified
Pittsburgh Sleep Quality Index
The following questions relate to your usual sleep habits during the past month only.
Time frame: 3 Weeks prior to circadian lab assessments
Other Pre-specified
Single Day Food Recall
Automated Self-Administered 24-Hour Recall (ASA24) Dietary Assessment. Total nutrients from all supplements reported in a given day.
Time frame: Once before sleep lab