Chronotype, Social Jet Lag, Sleep Debt and Food Timing in Inflammatory Bowel Disease

Abstract

The preference of the sleep/wake cycle can be grouped into categories or chronotypes. Inflammatory bowel disease (IBD) has been linked to poor sleep quality which correlates with disease severity. Social jet lag (SJL) is the difference between sleep timing on work and free days and is a marker for circadian misalignment which has been linked to increased inflammation. We investigated whether chronotype, SJL, sleep debt, and food timing were associated with an IBD specific complications and a lower quality of life. 191 subjects (115 IBD subjects and 76 healthy controls (HC)) completed the Pittsburgh Sleep Quality Index (PSQI), Morningness-Eveningness Questionnaire (MEQ), Munich ChronoType Questionnaire (MCTQ), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and a structured Food Timing Questionnaire. Later chronotype (by MEQ) was associated with a worse SIBDQ (r= −0.209; P<0.05). SJL was increased in IBD at 1.32 hr ± 1.03 vs. 1.05 hr ± 0.97 in HC, P< 0.05, when adjusted for age. SJL (>2 hrs) was present in 40% of severe/complicated Crohn’s patients (fistulizing or structuring Crohn’s or history of Crohn’s related surgery) compared to only 16% of uncomplicated Crohn’s patients (P<0.05). Sleep debt was increased in IBD subjects compared to HC at 21.90m ± 25.37 vs. 11.49m ± 13.58, P<0.05. IBD subjects with inconsistent breakfast or dinner times had lower SIBDQ scores (4.78± 1.28 vs. 5.49± 1.02, P<0.05; 4.95± 0.31 vs. 5.42± 0.32, P<0.05 respectively). In summary, later chronotype, and markers of circadian misalignment (social jet lag, sleep debt, and inconsistent meal timing) were associated with IBD disease specific complications and/or lower quality of life.

INTRODUCTION

Circadian rhythms orchestrate multiple biological processes over a 24 hour day including body temperature, metabolism,¹ mucosal, and systemic immunity.² It is therefore not surprising that circadian disruption has been associated with increased risk of metabolic dysfunction such as metabolic syndrome/diabetes and obesity,^3–6 as well as immune and inflammatory disorders.^2,7–9 Thus, maintaining circadian homeostasis through central and peripheral circadian clock is essential for a host healthy state. The timing of the central clock, or master clock, which is located in the suprachiasmatic nucleus (SCN), is synchronized mainly by light,¹⁰ which controls the timing of the peripheral clocks in almost every organ of the body. The peripheral clock of the intestinal tract is entrained mainly by the time of food consumption.¹¹ Chronotype refers to the circadian phase entrainment of an individual based on exogenous (i.e. light) and endogenous (age, sex, circadian genes) factors and reflects their propensity to be awake or asleep at a particular time of day. Individuals experience social jet lag (SJL) when there is a habitual discrepancy between their actual sleep times and their endogenous circadian rhythms due to social obligations while sleep debt (SD) is the difference between average sleep duration for the week and sleep duration during work days. Later chronotypes accumulate sleep debt on work days as individuals need to conform to work schedules, while early chronotypes accumulate sleep debt on free days as they stay awake later due to social obligations. SJL and SD are markers of circadian misalignment.¹² Circadian misalignment can occur through irregular sleep/wake schedule such as in shift workers, ^13,14 night light exposure and/or with irregular food timing ^15–17 and can lead to metabolic dysfunction and a pro-inflammatory state resulting in either a trigger for metabolic/inflammatory disorders and/or worsening of the disease course. For example, chronotype, social jet lag, and sleep debt have been associated with an increased risk for obesity and metabolic syndrome.³ In addition, shift workers have increased concentrations of serum lipopolysaccharide-binding protein (LBP) and serum interleukin-6 (IL-6), reflecting greater systemic inflammation.¹⁸ Shift work, which currently makes up ~ 3% of the US work force of which ~ 3% is night shift work,¹⁹ has been associated with a number of gastrointestinal diseases including colon cancer, peptic ulcer disease, and irritable bowel syndrome.^20,21

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immune-inflammatory disorder of the gastrointestinal tract (GIT). It has a waxing and waning course with periods of asymptomatic remission interrupted with episodes of disease ‘flare’ where patients can present with bloody stools, diarrhea, fever and abdominal pain.²² Periods of disease inactivity can last months or even years, with a cumulative probability ~ 90% of patients having an intermittently relapsing disease course.²³ It is estimated that up to 1.4 million people in the US and 2.2 million people in Europe suffer from IBD, with almost 100,000 to 110,000 new cases diagnosed annually.²⁴ IBD carries a significant health burden, primarily due to management of flares and associated complications like hospitalizations and surgeries accounting for $6.3 billion treatment costs in the US alone.²⁵ Thus, better understanding the factors that promote IBD flare ups and an aggressive disease course has potential to prevent or at least minimize the personal and societal burden of IBD.

The exact etiology of IBD remains unknown, but evidence suggests that it results from an inappropriate inflammatory immune response to intestinal microbiota, or bacterial products, in a genetically susceptible host.²⁶ This inappropriate immune response is likely the result of a complex interplay among demographic, genetic, behavioral, and environmental risk factors, including age, sex, race, BMI, socioeconomic status, cigarette smoking, and diet just to name a few. ^22,26 Most of these factors impact microbiota composition/function and/or intestinal barrier integrity and mucosal immunity.^27–29. Intestinal dysbiosis is present in IBD and is a possible risk factor for disease flare.³⁰ Thus, it appears that any factor(s) capable of modulating intestinal microbiota, intestinal barrier integrity, or mucosal immunity can impact IBD disease course and trigger IBD flares.

One potential factor that could influence the intestinal microbiota and regulation of intestinal barrier and mucosal immunity and thus could impact IBD disease course is ‘circadian misalignment’ and one of its consequences, sleep disturbance. Sleep disturbance is prevalent in IBD, and we ^31–33 and others ³⁴ have shown that IBD patients, even those asymptomatic patients in remission, have disrupted sleep which, in turn, is associated with poor quality of life ³⁵ and increased risk of future IBD flare up.³⁴ Most relevant to IBD, we showed that disruption of circadian rhythms by light/dark reversal, modeling shift work; significantly worsen dextran sulfate sodium (DSS) model of colitis.³⁶ In addition, human IBD subjects had suppressed clock gene expression in colonic mucosa and peripheral blood mononuclear cells (PBMCs).³⁷ Furthermore, intestinal barrier function ^1,18,38 and microbiota composition, ³⁹ factors that clearly play central role in disease course in IBD, are altered with circadian disruption.⁴⁰ Indeed, multiple studies in rodents ^41–44 have shown that both the systemic and mucosal immune systems are regulated by circadian machinery and that circadian misalignment is associated with pro-inflammatory changes in microbiota composition, such as low diversity and increased abundance of proteobacteria.⁴⁵ Furthermore, time of feeding in mice significantly impacted microbiota composition.⁴⁶

Thus, there is increasing evidence that circadian misalignment and disruption of circadian rhythms can lead to a pro-inflammatory state. Yet, there is no study evaluating a potential impact of circadian entrainment or chronotype in IBD. Accordingly, the goal of this study was to fill this gap in our knowledge by testing the hypotheses that: (1) chronotype (category of circadian entrainment), and social jet lag would be different in IBD compared to HC and (2) chronotype and/or circadian misalignment from social jet lag and resultant sleep debt would be associated with a worse IBD specific QOL, and more severe IBD phenotype (fistulizing or stricturing Crohn’s) and disease course (need for surgery).

METHODS

Study Design:

The study was designed as a retrospective cross-sectional study with naturally occurring groups of healthy subjects and IBD subjects. Some analyses are done only for IBD subjects as that group had the data available e.g. disease severity, quality of life and food timing.

Setting/Sample:

Subjects with IBD and healthy controls (HC) were recruited from a large Midwestern academic medical center ambulatory GI clinic and behavioral sciences research laboratory, respectively. All subjects gave written informed consent at the time of enrollment and prior to completing the questionnaires. The study and all procedures were approved by Rush University Medical Center Institutional Review Board. The IBD subjects had endoscopy and biopsy proven inflammatory bowel disease- either Crohn’s disease or ulcerative colitis. Subjects were excluded if they met any of the following exclusion criteria: 1) unable to give informed consent, 2) pre-existing organ failure or comorbidities such as a) liver disease (cirrhosis or persistently abnormal aspartate transaminase (AST) and alanine transaminase (ALT) that are 2X> normal); b) kidney disease (creatinine>2.0 mg/dL); c) clinically significant lung disease or heart failure; d) HIV infection 3) major depression (score ≥ 15 or endorsement of suicidal intent on the Beck Depression Inventory) 4) sleep apnea (score high risk ≥ 2 or more categories on the Berlin Questionnaire), 5) restless leg syndrome (using the International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria for restless leg syndrome), 6) currently taking sedatives and/or hypnotics. Healthy controls had no history of GI disease or symptoms.

Instruments:

All study instruments were administered either as paper and pencil tests or as an online survey using Survey Monkey during the study visit. The battery of instruments required approximately 30 minutes to complete.

Demographics and Medical History:

A structured questionnaire included items regarding demographics, past medical history, use of IBD specific medications, past surgical history, and social history.

Disease Activity:

Subjects with IBD answered questions related to CD or UC to assess disease severity and disease course. These included age of IBD diagnosis, ⁴⁷ current and past IBD medications, steroid dependence, history of IBD surgery and Crohn’s Disease Activity Index questionnaire ⁴⁸ (CD) or modified Harvey-Bradshaw questionnaire (UC) ⁴⁹ to assess disease activity at the time of enrollment. Subject’s responses and relevant available endoscopies were reviewed by a physician to determine disease location, phenotype, and Montreal classification.⁴⁷ Presence of perirectal disease, fistulas, strictures, and/or history of IBD related surgeries were considered as disease complications.^50,51 Subject’s responses were reviewed by a GI physician and crossed checked by review of their electronic medical record to ensure they were accurate.

Quality of Life (QOL):

The Short IBD Questionnaire (SIBDQ) was used to measure the health-related quality of life (HRQOL) in subjects with IBD. The SIBDQ is a validated questionnaire consisting of 10 questions ⁵² with high test- retest reliability (Pearson r>0.8) and validity.⁵³ It assesses four QOL domains: physical, social, emotional, and systemic and is scored on a 7-point Likert scale from 1 (severe problem) to 7 (no problems at all). The absolute score ranges from 10 (poor HRQOL) to 70 (optimum HRQOL).

Sleep quality:

The Pittsburgh Sleep Quality Index (PSQI) was used to assess the sleep quality in all subjects. The PSQI is a 19 item validated questionnaire consisting of 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping meds and daytime dysfunction.^54,55 PSQI items use varying response categories that include usual bed time, usual wake time, number of actual hours slept, and number of minutes to fall asleep, as well as forced-choice Likert-type responses. Overall scores range from 0 to 21 with lower scores indicating better sleep.

Chronotypes:

A. The Morningness-Eveningness questionnaire (MEQ) is a validated 19 question self-administered questionnaire to determine the morningness- eveningness type.^56–58 These questions ask people to consider their “feeling best” rhythms and indicate preferred clock time blocks for sleep and engagement in various hypothetical situations (e.g., physical exercise, tests, work), in addition to assessing morning alertness, morning appetite, evening tiredness, and alarm clock dependency.⁵⁹ Scores can range from 16 to 86 with higher scores indicating extreme morning type and lower scores indicating extreme evening type.

B. The Munich ChronoType Questionnaire (MCTQ) ⁶⁰ contains questions pertaining to sleep and activity times such as: bedtime, length of time to fall asleep, time of awakening, and use of alarm clock on workdays and work free days. All questions are asked separately for work and for work-free days. Chronotype is estimated as the midpoint of sleep on work-free days minus half of the difference between sleep duration on work-free days and average sleep duration of the week to control for sleep debt (Midpoint of Sleep on work-Free days, Sleep-Corrected, MSF_sc).⁵⁹ The classification of the MCTQ can be extreme early, normal or extreme late.⁶¹

The MCTQ was also used to calculate social jet lag and sleep debt.⁵⁹ Social jet lag (SJL) is the difference between the timing of the midpoint of sleep on work days and work-free days,⁶² and is considered significant if greater than two hours.³ Sleep debt is the difference between average sleep duration for the week and sleep duration during work days.⁶²

Food Timing:

The major zeitgeber or signal that entrains the rhythm of the intestinal circadian system is food timing ^10,63,64 compared to the central clock which is time of light exposure.¹⁰ A structured food demographics questionnaire was therefore developed to access food timing. The questionnaire consists of eight questions asking subjects’ eating habits on work days and non-work days. Questions include the time of the main meal during work and non-work days, time of last meal before bed, consistency of dinner within work and non-work days, and consistency of breakfast, lunch, and dinner between work and non-work days. The food timing questionnaire was administered only to the IBD subjects.

Statistics

Fisher Exact Test, ANOVA and independent T-tests were used to compare the subject groups. The relationship between MEQ scores and MCTQ scores in IBD and HC were analyzed by logistic regression or ANOVA with age as a covariate. SIBDQ was compared to MEQ and PSQI scores by linear regression. Social jet lag and sleep debt were compared in HC and IBD or in CD with or without complications by Mann-Whitney U test or Chi squared test, respectively. All statistical analysis were two tailed and statistical significance was determined by using a p-value of <0.05. Statistical analysis was performed with SPSS software, version 22.0 (SPSS Inc. Chicago).

RESULTS

Subject characteristics

191 subjects (115 IBD subjects and 76 healthy controls) agreed to participate and completed the questionnaires. All (n=76) of the healthy controls (HC) and 123 of the 190 (64.73%) IBD subjects, who had enrolled in the study, completed all the study questionnaires. The main reason for the drop out was lack of time to complete the questionnaires or voluntary withdrawal. After review of the electronic medical record, we excluded 8 IBD subjects from the analysis (7 who worked night shift and 1 who had colectomy with ileostomy). Thus, data from 115 IBD subjects and 76 healthy controls were analyzed. Characteristics of the study population are shown in Table 1.There were no significant differences in demographic characteristics between IBD and control group except for age with healthy controls being significantly younger (34.13 years ± 11.96) than the IBD group (40.94 years ± 14.73) (P<0.05). Anthropometric information was not obtained for the study.

Table 1.

Demographics and Health Behaviors of IBD Subjects and Healthy Controls

	IBD	HC	p-value
Number of Respondents	115	76
Mean Age	41.4 ± 14.81 (N=115)	34.13 ± 11.96 (N=76)	p < 0.01
Sex			p = 0.46
Male	44/115 (38%)	34/76 (45%)
Female	71/115 (62%)	42/76 (55%)
Race			p = 0.10
American Indian/Alaska Native	1/115 (1%)	1/69 (1%)
Asian	4/115 (3%)	6/69 (9%)
African American	16/115 (13%)	15/69 (22%)
Caucasian	93/115 (82%)	43/69 (62%)
Multiracial	1/115 (1%)	4/69 (6%)
Social History
Smoker	10/115 (9%)	2/76 (3%)	p = 0.14
Alcohol Use	70/115 (61%)	42/76 (55%)	p = 0.38
Illicit drug Use	4/115 (3%)	0/76 (0%)	p = 0.16

Morningness-Eveningness Questionnaire (MEQ)

There was not a significant differences in chronotype between healthy controls and IBD subjects when adjusted for age. (Table 2). IBD subjects had morning (40%), neutral (50%), or evening (7%) chronotypes compared with healthy controls, which had morning (32%), neutral (58%), or evening (11%) chronotypes. The mean MEQ score in IBD subjects was 56.53±9.80 vs. 53.46±8.78 in HC, which was not statistically different when adjusted for age (OR=1.28, CI 0.82–2.00, P=0.27).

Table 2.

Chronotypes of IBD and HC by MEQ scores

Chronotypes		IBD (N=112)	HC (N=76)
	Extreme morning type	12/112 (10%)	0/76 (0%)
	Moderately morning type	34/112(30%)	24/76 (32%)
	Neutral type	57/112 (50%)	44/76 (58%)
	Moderately evening type	9/112 (7%)	8/76 (11%)
	Extreme evening type	0/112 (0%)	0/76 (0%)

OR 1.28, CI 0.815–2.00, P=0.27

SIBDQ scores were lower in IBD subjects with lower MEQ scores, reflecting that a worse health related quality of life (HRQOL) was associated with evening chronotypes (Figure 1A, r= −0.209, P<0.05). When adjusted for age, this relation was still significant. There were no statistically significant relationships between MEQ and other IBD specific complications, such as steroid dependence, surgery, immunomodulator use, frequent disease flares, or perirectal disease in CD.

Figure 1.

Morningness- Eveningness Questionnaire (MEQ) scores and Munich ChronoType Questionnaire (MCTQ) in Inflammatory Bowel Disease (IBD). A Relationship between Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores and MEQ scores. B Corrected Midpoint of Sleep from MCTQ in IBD and Healthy Controls. C Social jet lag (Difference in midpoint of sleep in work days versus free days) in Healthy controls and IBD. D. Social jet lag (> 2 h) in Crohn’s disease patient with and without disease related complications ** denotes a significant P value < 0.05.

The Munich ChronoType Questionnaire (MCTQ)

MSF_sc significantly correlated with age (r=0.54, r²=0.27, p<0.01). Adjusted for age, MSF_sc was 3.56h ± 1.35 in IBD and 4.29h ± 1.10 in HC which was significantly earlier in those with an IBD diagnosis (OR 1.41, 95% CI 1.05–1.89, P < 0.05, Figure 1B).

Social Jet Lag (SJL) and Sleep Debt (SD)

Social jet lag (SJL) significantly correlated with age (r=0.41, r²=0.17, P<0.01). Adjusting for age, there was a significant difference in SJL between IBD and healthy controls. SJL in IBD subjects was 1.3hr ± 1.03 vs. 1.05hr ± 0.97 in controls, (OR 1.95, 95% CI 1.34–2.84 P<0.05, Figure 1C). SJL was associated with more severe (“aggressive”) disease phenotype (fistulizing or stricturing Crohn’s) and disease course (those who had Crohn’s related surgery) in Crohn’s patients. SJL > 2 hours was present in 19/47 (40%) of those with aggressive Crohn’s compared with only 4/25 (16%) of uncomplicated Crohn’s patients (Figure 1D).

Sleep debt (SD) did not significantly correlate with age. There was a significant difference in SD between IBD and healthy controls. SD in IBD patients was 21.90m ± 25.37 vs. 11.49m ± 13.58 in controls (OR 5.68, CI 1.89–17.12, P<0.05) (Figure 2A). IBD subjects with “aggressive” disease course had more sleep debt compared to those with non-aggressive disease. In CD subjects with fistulizing/structuring phenotypes or history of Crohn’s related surgery sleep debt was 26.92m ± 29.35 compared to 5.61 m ± 9.22 in those with uncomplicated Crohn’s (OR 48.98, CI 2.95–812.51, P<0.01) (Figure 2B). Time in bed before sleep (sleep latency) was increased in IBD subjects compared to HC on work and free days. On free days sleep latency was 19.21m ± 19.46 vs. 9.20m ± 6.46, P<0.01, and on work days was 20.59m ± 17.68 vs. 9.97m ± 7.04, P<0.01(Figures 2D & 2E).

Figure 2.

Sleep Debt in Inflammatory Bowel Disease (IBD) subjects and healthy controls (HC) based on Munich ChronoType Questionnaire. A Total sleep debt in IBD and HC. B Sleep Debt in Crohn’s Disease subjects with and without disease complications. C Sleep Duration on Free and Work Days in IBD subjects and HC. D Sleep Latency on Free Days in IBD and HC. E Sleep Latency on Work Days in IBD subjects and HC. ** denotes a significant P value < 0.05.

Food Timing

IBD subjects with inconsistent breakfast or dinner times had lower SIBDQ scores than the subjects with consistent timings of breakfast or dinner times at 4.78 ± 1.28 vs. 5.49 ± 1.02, (P<0.05), and 4.95 ± 0.31 vs 5.42 ± 0.32, (P<0.05), respectively (Figure 3).

Figure 3.

Dinner times and SIBDQ scores in Inflammatory Bowel Disease subjects with consistent and inconsistent dinner times. ** denotes a significant P value < 0.05.

Sleep Quality

IBD subjects had higher composite PSQI scores compared with healthy controls (6.23 ± 3.5 vs. 3.03 ± 1.75, P<0.05), indicating poorer sleep in the IBD population. IBD subjects reported poorer sleep parameters in all components of PSQI (Supplemental Table 1). As expected, IBD subjects with poorer PSQI scores had lower SIBDQ scores (Pearson’s r= −0.445, P< 0.05) (Supplemental Figure 1). With lower SIBDQ scores, subjects had worse subjective sleep quality (Pearson’s r= −0.503, P< 0.05), increased sleep onset latency (Pearson’s r= −0.285, P<0.05), increased sleep disturbances (Pearson’s r= −0.399, P< 0.05), and increased daytime dysfunction (Pearson’s r= −0.539, P< 0.05). There were no significant differences between PSQI scores for IBD subjects with or without IBD disease complications such as steroid dependence, immunomodulator use, frequent disease flares, or perirectal disease in CD. Chronotype (MSFsc) did note correlate with PSQI in our sample but there was a trend (P=0.56).

DISCUSSION

To our knowledge this is the second study to assess the relationship between chronotype and IBD⁶⁵ and the first to examine social jet lag, sleep debt, and food timing with disease characteristics in IBD. The main findings of the present study were that (I) later chronotype was associated with a decreased IBD health related quality of life; (II) social jet lag and sleep debt was increased in IBD subjects compared to healthy controls; (III) in CD, social jet lag and sleep debt were increased in those with more aggressive phenotypes (fistulizing or stricturing) that is well known to be associated with complications, such as surgery; and (IV) inconsistent meal time was associated with a worse IBD specific quality of life.

A late chronotype and social jet lag have also been reported as increasing symptoms in other chronic diseases like joint pain ⁶⁶ and inflammatory cardio metabolic disorders.^67,68 In addition, late chronotype and social jet lag have been shown to be associated with obesity, increased onset of diabetes, and poorer glycemic control.^3–6 There is emerging evidence suggesting that later chronotypes and circadian misalignment can impact multiple diseases including metabolic syndrome, ⁶⁸ cerebrovascular disease ⁶⁹ and neurodegenerative disorders like Parkinson’s disease. ^67,70 Specifically in the GI tract, circadian misalignment has also been associated with altered colonic motility, ^71,72 irritable bowel syndrome (IBS), ^72,73 peptic ulcer disease, ⁷⁴ and colon cancer.¹¹ In IBD, polymorphism of one of the core clock genes, PERIOD3, was associated with susceptibility to IBD and an aggressive phenotype in CD.⁷⁵

It is important to highlight our finding that social jet lag, and sleep debt are markers for circadian misalignment and were associated with disease complications (perirectal disease, fistulas, strictures, and/or surgery) in Crohn’s subjects. The overall difference in these markers between IBD and HC was small, but within Crohn’s disease with complications were of larger magnitude. Interestingly, MCTQ, a subjective report of sleep timing on work and free days, was significantly different between IBD and HC and in CD with and without complications in the present study while MEQ, which is a psychologic preference for activity, was not. Therefore, sleep timing not psychological preference may be a biologically more important measure of chronotype in IBD. However, the mechanisms underlying this negative impact of chronotype and social jet lag on IBD is not known and accessing the magnitude of this finding requires further study. Intestinal circadian machinery is entrained by time of eating⁶³ and thus irregular eating habits and/or “wrong time eating” could lead to intestinal circadian misalignment. ^64,72 “Wrong time eating” could impact gastrointestinal function, increase obesity and metabolic syndrome.⁷⁶ We assessed time of meals and regularity of meal time using a structured questionnaire and found that IBD subjects with inconsistent breakfast or inconsistent dinner times had lower SIBDQ scores compared to subjects with consistent meal times.

Recently, there has been an increased interest on the impact of sleep and sleep disturbances in IBD, with multiple studies, including this one, showing that subjects with IBD frequently have disrupted sleep ³² and that those with disrupted sleep are at increased risk for a disease flare.³⁴ Our findings by PSQI are consistent with prior studies that IBD subjects have disrupted sleep (Supplemental Table 1), ^31,32 and poor sleep quality in IBD subjects correlated with a poorer quality of life as measured by SIBDQ (Supplemental Figure 1) and chronotype by MSFsc.

There are a number of limitations to the present study. The study is retrospective and cross sectional and thus causal link cannot be ascertained. Furthermore, IBD disease activity and circadian rhythms were not objectively measured by endoscopy or dim light melatonin onset, respectively, but estimated by validated questionnaires. There were also significant age differences in the two groups; IBD subjects were significantly older than healthy subjects; however, we adjusted for age in the analyses to overcome this potential confounding factor. Of note, social jet lag is typically associated with later chronotypes and younger age, but we found increased social jet lag in IBD despite having a cohort with older age and earlier chronotype. Finally, a larger sample size would strengthen the power to find differences between the two groups and correlate other factors such as BMI or PSQI, which has been shown to be associated with social jet lag and chronotype. ^3,65 Future studies using a larger IBD cohort are required to validate our findings in the present study.

In summary, this is the first study to assess the association of chronotype, social jet lag, and sleep debt with IBD. Later chronotype was associated with a lower health related quality of life. In addition, social jet lag and sleep debt were increased in IBD subjects compared to healthy controls, and in CD social jet lag and sleep debt were associated with a more severe and aggressive fistulizing and stricturing Crohn’s disease phenotypes that frequently requires surgery. Finally, inconsistent meal timing was associated with a lower health related quality of life. Our findings suggest that optimizing circadian and sleep hygiene should be considered in management of IBD patients, and provide support for larger cross sectional studies to test if sleep and circadian treatments can improve patient quality of life and disease course.

Supplementary Material

12

Supplemental Figure 1 Relationship between Short Inflammatory Bowel Disease Questionnaire scores and Pittsburg Sleep Quality Index scores in Inflammatory Bowel Disease subjects.