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Prevalence of sleep disorder in irritable bowel syndrome: A systematic review with meta‑analysis Systematic Review/Meta-analysis

according to Background/Aims: We conducted this meta-analysis to evaluate the prevalence of sleep disorder in irritable bowel syndrome (IBS) patients and study the association between IBS and sleep disorder. Materials and Methods: A systematic search was conducted by searching PubMed, Embase, and Cochrane library databases using the following search terms: “functional gastrointestinal disorders,” “Sleep disturbance,” “Sleep disorder,” “insomnia,” “Dysomnias,” “irritable bowel syndrome,” and “IBS.” Studies evaluating the association between IBS and sleep disorder were identified. Data analysis was conducted using meta-analysis software Comprehensive Meta-Analysis (CMA) 2.0. Heterogeneity across studies was evaluated by χ 2 and I 2 statistics. Publication bias was evaluated by funnel plot, Begg’s test, and Egger’s test. Sensitivity analysis was also performed by removing each single study separately. Results: The bibliographical search yielded a total of 2866 studies. Finally, 36 studies including 63620 participants were identified. The prevalence of sleep disorder in IBS was 37.6% (95% CI: 31.4% to 44.3%) based on this meta-analysis. The pooled odds ratio was 2.618 (95% CI: 2.052% to 3.341). Publication bias was not determined. Regarding the sensitivity analysis, the outcome was stable regardless of which study was removed. Conclusions: The prevalence of sleep disorder was higher in IBS compared to healthy controls and may be associated with the pathogenesis of IBS. The prevalence of sleep disorder in IBS may differ according to different areas, age, gender, occupation, and IBS diagnostic criteria. Further studies are needed to investigate any possible causal relationship between sleep disorder and IBS. Abstract

geographical location and was higher among women than men. [8] The etiology of IBS remains unclear. Genetics and environmental factors, visceral hypersensitivity, gut microbiota, disorder of the gut brain axis, and psychological factors were thought to be involved. [9] Some studies have reported that sleep disorders were common in IBS patients. To our knowledge, the prevalence of sleep disorders among IBS varies from 7.1% to 73.9%. Moreover, sleep disorders may be associated with greater gastrointestinal symptom severity. [10] The global prevalence of sleep disorders among IBS has not been investigated. The aim of this meta-analysis was to identify the pooled coexistence rates of sleep disorder and IBS and to explore the association between IBS and sleep disorder.

Study selection
The inclusion criteria included: (1) articles reporting prevalence of sleep disorder in IBS patients and (2) available information on sleep disorder prevalence and sample size.

Data extraction
Two independent investigators extracted the data using standardized data extraction forms. Any discrepancies were resolved by consensus. The data collected included year of publication, geographic region, study design, methods for assessing sleep disorder, diagnostic criteria for IBS, prevalence of sleep disorder, mean age, occupation, and proportion of female and male participants.

Summary measures
The data analysis was performed using the Comprehensive Meta-Analysis software, Version 2 (Biosta, Inc. USA). The proportion of individuals with sleep disorder in each trial was combined to achieve a pooled prevalence of sleep disorder. Moreover, pooled odds ratios (ORs) were calculated to evaluate the association between sleep disorder and IBS. All results are presented with 95% confidence intervals.

SYNTHESIS OF RESULTS
The degree of heterogeneity of the studies was evaluated using the χ 2 test (with a value less than 0.1 considered significant) and the I 2 test (25, 50, and 75% representing low, moderate, and high heterogeneity, respectively). If significant heterogeneity (P < 0.1 or I 2 > 50%) was achieved, we used the random effect model to combine the effect sizes in these groups. Subgroup analyses were also performed to assess the effect of geographic region, gender, occupation, age, diagnostic criteria for IBS, and publication year. To assess the stability of the results, sensitivity analysis was also performed by excluding every single study respectively. Publication bias was assessed by egger's test and funnel plots.

Selection of studies
A total of 2866 studies were identified, of which 2581 studies were removed according to titles and abstracts. Then, 96 duplicate studies were excluded, leaving 189 records to be examined. On reviewing full-text articles, 67 unrelated studies, 34 reviews, 3 studies including participants with complications, and 49 studies with insufficient data were excluded. Finally, 36  studies including 63620 participants were identified [ Figure 1 and Table 1].
The sample size of these studies ranged between 23 and 23445. Of the 36 studies, 34 studies were cross-sectional studies, 1 study was a case-control study, and 1 study was a cohort study. Furthermore, 26 studies investigated the prevalence of sleep disorder among IBS patients and evaluated the association between IBS and sleep disorder; the other 10 studies only explored the prevalence of sleep disorder among IBS patients. All these studies used subjective sleep measures to assess sleep quality.

Sleep disorders and irritable bowel syndrome
The pooled prevalence of sleep disorders among IBS was 37.6% (95% CI: 31.4% to 44.3%) [ Figure 2]. A significant association was also identified between sleep disorders and IBS. The summary odds ratio was 2.618 (95% CI: 2.052% to 3.341) [ Figure 3]. The results were stable no matter which study was excluded according to sensitivity analysis [ Figure 4].

Publication bias
No significant publication bias was identified by funnel plot [ Figure 5]. Egger's regression test (P = 0.34) and Begg's test (P = 0.69) also did not show significant bias [ Table 2].

Sleep disorders and irritable bowel syndrome based on areas
Twenty-one studies were conducted in Asia (

Sleep disorders and irritable bowel syndrome based on publication year
Five studies were published before 2000, 9 were published The reason why sleep disorders are associated with IBS remains unclear. The gut-brain axis plays an important role in the pathogenesis of IBS. Central nervous system (CNS), autonomic nervous system (ANS), enteric nervous system (ENS), and hypothalamic pituitary adrenal (HPA) axis are thought to be involved. [47] Several studies found that sleep deprivation led to modification of the ANS activity indicating that sleep disorder may be associated with autonomic dysregulation. [48,49] The HPA axis has been reported to be inhibited by sleep and sleep disorder may result in a 24 hour increased secretion of ACTH and cortisol. [50] Moreover, the symptoms of IBS, such as abdominal pain, may activate sympathetic nervous system and reduce sleep efficiency. [51] The impact of altered microbiota on the development of IBS has been considered more seriously. Similar mechanism may exist between sleep and gut microbiota. Gut microbes may affect sleep status via degradation products such as muramyl peptides (MPs), lipopolysaccharide (LPS), [52] and melatonin. [53] These degradation products could activate immune cells leading to the release of cytokines, which could affect sleep. A recent study found short chain fat acids and microbiota metabolites might have a potential impact on central and hepatic circadian rhythm. [54] In return, circadian disorganization has been reported to alter the composition of gut microbiota under high-fat, high-sugar diet conditions in mice. [55] Chronic sleep disruption can also cause reversible changes in gut microbiota. [56] Sleep quality assessed by Pittsburgh sleep quality index was also found to be related to the composition of the gut microbiome in healthy older adults. [57] However, the results were controversial. A study reported the overall composition of gut microbiota maintained after several consecutive days of sleep restriction. [58] Overall, although the reason for sleep disorders seen commonly among IBS patients is obscure, gut-brain-microbiota axis disorder may underlie this association.
According to subgroup analysis, the prevalence of sleep disorders among IBS varied slightly in different geographical locations. We also found that the prevalence of sleep disorders among female IBS patients was higher than male IBS patients, however, the difference was not significant. Higher risk of sleep disorder and IBS in females compared with males has been reported by many studies. Sex hormones, [59] difference in visceral and somatic pain sensitivity, central processing of visceral stimuli, genetics, and immunologic/microbiome [60] may be causal factors.
Occupation subgroup analysis showed that nurses with IBS might have a higher risk of suffering from sleep disorders. Part of the reason may be the demanding, stressful working conditions. Age subgroup analysis revealed that the prevalence of sleep disorders among children and adolescents with IBS was higher than that among adults, but with no statistically significant difference. Academic stress may be an explanatory factor for this observation. Different IBS diagnostic criteria may lead to differences in prevalence based on subgroup analysis. The prevalence of sleep disorders among IBS seemed to be declining on the basis of publication year subgroup analysis, however, these differences were not statistically significant. There are some limitations of our meta-analyses. First, significant heterogeneity was found when data were pooled. Reasons for this heterogeneity may be different characteristics among identified studies. The random-effects model was used to provide a more conservative result. We hope our meta-analyses could show an epidemiologic and global perspective of the prevalence of sleep disorders among IBS patients. Second, most identified studies (34 of 36) in this meta-analysis were cross-sectional studies. We could only describe the association between sleep disorders and IBS but could not determine the cause. More case-control and cohort studies are needed to investigate the substantial causal relationship. Third, all included studies assessed sleep disorders using a subjective questionnaire. Objective measures may be more convincing.
In conclusion, this meta-analysis demonstrated a global prevalence of sleep disorders among IBS and identified an underlying association between them. Different geographical locations, age, gender, occupations, and IBS diagnostic criteria may affect the prevalence of sleep disorders in IBS. Further case-control and cohort studies are needed to elucidate a substantial causal relationship.

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Conflicts of interest
There are no conflicts of interest.