Serum Tryptophan Metabolite Levels During Sleep in Patients With and Without Irritable Bowel Syndrome (IBS)

Biological Research for Nursing 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1099800415594251 brn.sagepub.com

Margaret M. Heitkemper, PhD, RN1, Claire Jungyoun Han, PhC, RN1, Monica E. Jarrett, PhD, RN1, Haiwei Gu, PhD2, Danijel Djukovic, PhD2, Robert J. Shulman, MD3, Daniel Raftery, PhD2,4, Wendy A. Henderson, PhD, RN5, and Kevin C. Cain, PhD6

Abstract Poor sleep and stress are more frequently reported by women with irritable bowel syndrome (IBS) than by healthy control (HC) women. The pathophysiology linking poor sleep and stress to gastrointestinal symptoms remains poorly understood. We used a metabolomic approach to determine whether tryptophan (TRP) metabolites differ between women with and without IBS and whether the levels are associated with sleep indices and serum cortisol levels. This study sample included 38 women with IBS and 21 HCs. The women were studied in a sleep laboratory for three consecutive nights. On the third night of the study, a social stressor was introduced, then blood samples were drawn every 20 min and sleep indices were measured. Metabolites were determined by targeted liquid chromatography tandem mass spectrometry in a sample collected 1 hr after the onset of sleep. The ratios of each metabolite to TRP were used for analyses. Correlations were controlled for age and oral contraceptive use. Melatonin/TRP levels were lower (p ¼ .005) in the IBS-diarrhea group versus the IBS-constipation and HC groups, and kynurenine/TRP ratios tended to be lower (p ¼ .067) in the total IBS and IBS-diarrhea groups compared to HCs. Associations within the HC group included melatonin/TRP with polysomnography-sleep efficiency (r ¼ .61, p ¼ .006) and weaker positive correlations with the other ratios for either sleep efficiency or percentage time in rapid eye movement sleep (r > .40, p ¼ .025–.091). This study suggests that reductions in early nighttime melatonin/TRP levels may be related to altered sleep quality in IBS, particularly those with diarrhea. Keywords metabolomics, irritable bowel syndrome, sleep, tryptophan, melatonin Irritable bowel syndrome (IBS) affects 10%–20% of adults worldwide, exerting a tremendous economic, social, and emotional toll. IBS is a heterogeneous condition in terms of both clinical presentation (diarrhea, constipation, and both) and pathophysiology. Patients with IBS report a number of comorbid conditions and symptoms including, but not limited to, musculoskeletal pain, headache, pelvic pain, and poor sleep (Lackner, Jaccard, & Baum, 2013). Poor sleep is one of the most common symptoms experienced by patients with IBS and is a predictor of gastrointestinal (GI) symptoms as well as psychological distress symptoms the next day (Jarrett, Heitkemper, Cain, Burr, & Hertig, 2000). In addition, we have demonstrated an elevation in early nighttime serum cortisol levels and decreased sleep efficiency in women with IBS when they are exposed to a social stressor prior to bedtime (Heitkemper et al., 2012). Tryptophan (TRP) is an essential amino acid involved in both central and peripheral functions. TRP and its metabolites such as serotonin (5-hydroxytryptophan [5-HT]), melatonin,

and kynurenine (KYN) have multiple effects impacting pain perception, mood, gut motility, and sleep/arousal (O’Mahony, Clarke, Borre, Dinan, & Cryan, 2015; Savitz et al., 2015). The 1

Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA, USA 2 Department of Anesthesiology and Pain Medicine, Northwest Metabolomics Research Center, University of Washington, Seattle, WA, USA 3 Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 4 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 5 Digestive Disorders Unit, Biobehavioral Branch, Division of Intramural Research, NINR, NIH, DHHS, Bethesda, MD, USA 6 Department of Biostatistics and Office of Nursing Research, University of Washington, Seattle, WA, USA Corresponding Author: Margaret M. Heitkemper, PhD, Department of Biobehavioral Nursing and Health Systems, University of Washington, Box 357266, Seattle, WA 98195, USA. Email: [email protected]

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Biological Research for Nursing The purpose of this pilot study was to use targeted liquid chromatography/mass spectrometry (LC-MS/MS) to analyze TRP metabolites in previously collected serum samples drawn 1 hr after the onset of sleep (Stage 2) as determined by polysomnography (PSG). We compared the IBS group to the healthy control (HC) group as well as IBS subgroups (IBSconstipation [IBS-C] vs. IBS-diarrhea [D]) for potential differences in the TRP metabolite ratios (5-HT/TRP, melatonin/ TRP, KYN/TRP, KYNA/TRP, 3-hydroxykynurenine/TRP, anthranilate/TRP, xanthurenate/TRP, and niacinamide/TRP). Next, we explored the potential relationships of serum cortisol, PSG variables (sleep efficiency, percentage time in rapid eye movement [REM] sleep) and self-reported sleep indicators to TRP metabolites.

Material and Method Participants: Recruitment and Eligibility Figure 1. Tryptophan (TRP) metabolism pathway. TRP is metabolized via two pathways: the kynurenine (KYN; most common) and the serotonin/melatonin.

predominant TRP catabolism pathway is via KYN, with approximately 95% of TRP converted through this route (Figure 1). The metabolites in this pathway have both neuroprotective and neurotoxic effects, and there is biologic flexibility in the route of TRP metabolism. For example, the KYN pathway is upregulated by proinflammatory activation as well as cortisol (Asp, Holtze, Powell, Karlsson, & Erhardt, 2010; Fukuda, 2014; O’Mahony et al., 2015). Cytokines such as interleukin-6 and tumor necrosis factor-a increase the enzymatic activity of indoleamine 2,3 dioxygenase (IDO; O’Mahony et al., 2015), which regulates the conversion of TRP to KYN. Cortisol has been shown to upregulate the activity of TRP 2,3-dioxygenase activity in rodent models (Badawy, 2013). Recently alterations in TRP metabolism have been the focus of research related to inflammation and stress models of IBS. In one study using a single morning blood sample of TRP and KYN, Clarke and colleagues (2009) found that men with IBS had higher levels of KYN, higher KYN/TRP ratios, and lower kynurenate (KYNA)/TRP ratios relative to a control group of men without IBS. The authors hypothesized that these findings reflected an overall increase in the KYN pathway as well as increased potential for greater production of neurotoxic metabolites. They did not measure other downstream metabolites. It may be hypothesized that if more TRP was shuttled to the KYN pathway, then less would be available for conversion to serotonin and melatonin, potentially affecting sleep adversely. In a recent small study (14 controls and 9 patients with IBS), Kennedy et al. (2014) found that acute TRP depletion and subsequent alterations in serum TRP and KYN levels influenced daytime hippocampal-mediated cognitive performance (e.g., memory) in the participants with IBS. Whether TRP alterations are associated with sleep architecture and/or symptoms in patients remains to be explored.

We drew the blood samples for this pilot study during a previously reported study of sleep, stress, and GI symptoms (Heitkemper et al., 2012). Participants included 38 women with IBS and 21 HC women whom we recruited through community advertisements and screened for eligibility by telephone. To be included in the IBS group, women had to be diagnosed by a primary care provider and meet Rome III criteria for IBS, as described in Drossman et al. (2006, p. 889). They also had to have either predominately constipation stools (lumpy or hard stools; IBS-C group) or predominately diarrhea stools (mushy or watery stools; IBS-D group). Members of the HC group could not have a history of functional GI disorders or other serious health problems. To control for variability in menstrual cycle, menstruating women (ages 18–45 years) were studied in the mid-luteal phase of their cycle. Women could be using contraceptives. Women were excluded if they (a) had a history of organic GI disease, cardiac arrhythmia, or renal or gynecological issues; (b) were taking medications for GI symptoms; (c) were taking any medications daily that would alter 5-HT; (d) had a body mass index (BMI) > 35 kg/m2; (e) worked during the late evening or night; (f) had a known sleep disorder; (g) had severe comorbid pain or psychiatric conditions; or (h) drank caffeine-containing beverages (>300 mg caffeine) in the afternoon/evening or 3 servings of alcohol/day. The University of Washington Human Subjects Review Committee approved the study, and we obtained informed consent from the participants. Based on a power analysis testing for mean differences among groups, the accrual goal for the parent study was 27 subjects in each of the three groups. The sample size available for the present report allowed for 84% power for detecting a mean difference of 0.8 standard deviation (SD) between the IBS and HC groups and 87% power for detecting a mean difference of 1.0 SD between any two of the three groups (HC, IBS-C, and IBS-D). There was 85% power for detecting a correlation of 0.60 in the HC group and 83% power for detecting a correlation of 0.45 in the IBS group.

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Measures and Protocol Sleep indices. For the PSG measures, we used standard scoring criteria with 30-s epochs (DelRosso, Chesson, & Hoque, 2014). The sleep indices we used have previously been shown to detect significant group differences (Heitkemper et al., 2012) in examining relationships of PSG sleep indices with TRP metabolites. These indices included sleep efficiency index (total sleep time/time in bed), sleep onset latency (minute from lights out to the onset of Stage 2 sleep), percentage time awake, and percentage time in REM sleep. The inter-rater agreement was greater than 90%. Because of the pilot nature of this study, we utilized samples from only 1 time point (1 hr post PSGdetermined sleep onset) for metabolite analyses. All participants refrained from eating a meal immediately prior to and during the sleep study. The morning after the PSG measures were taken, women completed the Morning Sleep Questionnaire, which includes 23 items such as time to fall asleep, time staying asleep and waking up time, aches and pains (e.g., legs) or distractions during the night (e.g., noise and light), overall sleep quality, whether their sleep was worse or better than at home, and medications taken in the last 24 hr. Cortisol. Blood for cortisol determination was collected peripherally via intravenous (IV) catheter 1 hr after sleep onset in silicone-coated tubes, centrifuged, and the serum layer removed. Cortisol levels were determined by chemiluminescence assay and processed in an automated Immulite Analyzer (Diagnostic Products Co.). The inter- and intra-assay variations are 5.4% and 2.7%, respectively (Heitkemper et al., 2012). Metabolites. Targeted LC-MS/MS based on an AB-Sciex 5500 QTrap Triple Quad MS was performed on the serum samples (Zhu et al., 2014). Overall, 156 metabolites were measured, reflecting approximately 25 metabolic pathways, however, we report here only metabolites of the TRP pathway. The three TRP metabolites of primary interest in this study were KYN, KYNA, and melatonin. Metabolites of secondary interest were anthranilate, 3-hydroxykynurenine, xanthurenate, niacinamide, and 5-HT (Figure 1). All metabolites are expressed as a ratio to TRP. The metabolite identities were confirmed by spiking a pooled serum sample with mixtures of standard compounds (each mixture contained five standard metabolites). The samples were run in two batches. Because the MS results are relative, not absolute, values from the two batches are not necessarily scaled the same, and thus standardization was done within each batch by dividing the spectral count of a given metabolite by the median across all samples in that batch of the spectral count of that metabolite. A pooled serum sample was run every 10 biological samples as a quality control to monitor instrument performance.

Procedure Women were studied for three nights (first night—adaptation, second night—baseline, and third night—stress and blood draw

night) in the mid-luteal menstrual phase at a university sleep laboratory. We interviewed women to gather demographic and baseline symptom data and provided a tour of the sleep laboratory. On each of these three nights, women arrived 2–3 hr before going to bed to have electrodes placed for PSG (electroencephalogram, electromyogram, and electrooculogram; Embla Recording System, Thornton, CO). On these days, they were asked to refrain from drinking caffeine-containing beverages. On the third night an IV line was inserted at approximately 8 p.m., and blood samples were collected every 20 min across the night. Prior to the initial blood draw, the women were reminded that they would need to perform a publicspeaking exercise in the morning, and that their presentation would be videotaped and attended by staff. The morning after each sleep night women completed the Morning Sleep Questionnaire to indicate their perceived sleep quality that night (Heitkemper et al., 2012). The women completed a symptom diary throughout their menstrual cycle (e.g., GI symptoms, sleep, and psychological distress) and after the onset of the next menstrual cycle. We provided monetary compensation for their participation and time.

Data Analysis Student’s t-test statistics and chi-square tests were used to compare demographic variables in the IBS versus the HC groups. We presented group differences in sleep indices and cortisol levels in a previous publication (Heitkemper et al., 2012). For each TRP metabolite, t-tests were used to evaluate mean differences between groups. The group comparisons were IBS versus HC, IBS-D versus HC, IBS-C versus HC, and IBS-D versus IBS-C. Partial correlations were used to test the association of metabolites with cortisol levels, PSG-sleep indices, and self-reported sleep quality, controlling for age, and oral contraceptive use. All statistical tests were two tailed and were performed using SPSS Statistics 17 for Windows. No formal adjustments were made for the multiple comparisons done in this pilot study, and results should be interpreted with caution.

Results Demographic Characteristics, Sleep Indices, and Cortisol Serum samples were available for 38 women with IBS and 21 HC women for the present study. The women averaged 28.6 years (SD ¼ 6) of age and were primarily Caucasian (IBS: 93%, HC: 79%). The average BMI was 23.6 kg/m2 (SD ¼ 3.7; Heitkemper et al., 2012). There were no IBS versus HC group differences in the demographic data. On the third night, women with IBS as compared to HC women had reduced PSGdetermined sleep efficiency (IBS: 76% vs. HC: 82%, p ¼ .04), total sleep time in minutes, Mean (SD), IBS: 361 (58) vs. HC: 393 (44), p ¼ .02, and percentage of time in REM sleep, IBS: 17.5 (5.6) vs. HC: 21.2 (5.2), p ¼ .003. Cortisol levels were higher in the women with IBS, 0.38 (0.20) mg/dl, as compared to the HC women, 0.24 (0.18) mg/dl, p ¼ .02. When separated by bowel pattern, women in both IBS subgroups had

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Table 1. Summary of Differences in Tryptophan Metabolite Ratios, Reported as Mean (SD), Between All Subjects With Irritable Bowel Syndrome (IBS) and Those in the IBS-Diarrhea (IBS-D) and IBS-Constipation (IBS-C) Groups as Compared to Healthy Controls (HCs). Metabolite TRP Serotonin/melatonin 5-HTP/TRP Melatonin/TRP KYN KYN/TRP KYNA/TRP KYNA/KYN 3-HKYN/TRP Anthranilate/TRP Xanthurenate/TRP Niacinamide/TRP

HC (n ¼ 21)

IBS (n ¼ 38)

p1

IBS-D (n ¼ 18)

p2

IBS-C (n ¼ 20)

p3

p4

1.01 (0.24)

1.08 (0.24)

ns

1.10 (0.24)

ns

1.06 (0.24)

ns

ns

1.00 (0.25) 1.04 (0.35)

0.98 (0.21) 0.88 (0.46)

ns .159

0.95 (0.21) 0.71 (0.33)

ns .005

0.99 (0.22) 1.03 (0.51)

ns ns

ns .031

0.98 (0.20) 1.23 (0.47) 1.27 (0.45) 1.00 (0.25) 1.02 (0.33) 1.00 (0.14) 0.92 (0.27)

0.89 1.18 1.36 0.97 1.09 0.98 1.01

.067 ns ns ns ns ns ns

0.87 1.10 1.27 0.94 1.01 0.97 0.93

.083 ns ns ns ns ns ns

0.91 (0.16) 1.26 (0.39) 1.44 (0.67) 1.00 (0.20) 1.16 (0.60) 0.99 (0.12) 1.08 (0.43)

.196 ns ns ns ns ns .172

ns ns ns ns ns ns ns

(0.17) (0.40) (0.58) (0.20) (0.49) (0.10) (0.35)

(0.17) (0.40) (0.47) (0.19) (0.35) (0.08) (0.22)

Note. p1 ¼ p value for the two-group comparison IBS versus HC; p2 ¼ p value for the comparison IBS-D versus HC; p3 ¼ p value for the comparison IBS-C versus HC; p4 ¼ p value for the comparison IBS-D versus IBS-C; ns (not significant) ¼ p > .20; SD ¼ standard deviation; TRP ¼ tryptophan; 5-HTP ¼ 5-hydroxytryptophan; KYN ¼ kynurenine; KYNA ¼ kynurenate; 3-HKYN ¼ 3-hydroxykynurenine.

Table 2. Correlation of Tryptophan Metabolites With Cortisol and Sleep Quality Indicators in Healthy Controls (HC; n ¼ 21) and Women With Irritable Bowel Syndrome (IBS; n ¼ 38). PSG Cortisol (μg/dl) Metabolite TRP Serotonin/melatonin 5-HTP/TRP Melatonin/TRP KYN KYN/TRP KYNA/TRP KYNA/KYN 3-HKYN/TRP Anthranilate/TRP Xanthurenate/TRP Niacinamide/TRP

Sleep efficiency (%)

HC

IBS

HC

.21

.12

.30

.14 .01

.09 .27

.40* .61**

.17 .18 .28 .29 .14 .21 .23

.01 .08 .07 .09 .11 .28* .02

.15 .44* .42* .15 .23 .16 .34

IBS .04 .03 .02 .17 .21 .22 .08 .00 .18 .15

Self-reported % Time in REM HC

HC

IBS

.11

.04

.20

.44* .41*

.07 .03

.13 .17

.08 .14

.35 .33 .14 .43* .15 .49** .51**

.12 .11 .08 .08 .00 .22 .17

.29 .24 .10 .13 .42* .19 .14

.37

IBS

Sleep quality

.19 .10 .08 .01 .20 .09 .05

Note. PSG ¼ polysomnography; REM ¼ rapid eye movement; TRP ¼ tryptophan; 5-HTP ¼ 5-hydroxytryptophan; KYN ¼ kynurenine; KYNA ¼ kynurenate; 3-HKYN ¼ 3-hydroxykynurenine. *.05 < p < .10. **p ≤ .05.

significantly higher cortisol levels, IBS-D: 0.40 (0.22) mg/dl; IBS-C: 0.36 (0.19) mg/dl; p ¼ .02, p ¼ .07, respectively, when compared to the HC group. There were no IBS versus HC group differences in hormonal contraceptive use.

TRP Metabolites: Group Comparisons Overall there were no differences between the IBS and HC groups in TRP levels measured 1 hr post-sleep onset. The melatonin/TRP ratio was significantly lower in the IBS-D group as compared to both the HC and IBS-C groups when controlling for covariates (Table 1). We also found a trend toward reduced KYN/TRP in the total IBS and the IBS-D groups when compared to the HC group.

Correlation of Cortisol With TRP Metabolites There were no statistically significant correlations between cortisol and TRP metabolites in either the IBS or HC group, though two correlations with cortisol trended toward significance in the IBS group: melatonin/TRP with r ¼ .27, p ¼ .113, and xanthurenate/TRP with r ¼ .28, p ¼ .097 (Table 2).

Correlation of PSG and Self-Reported Sleep Indices With TRP Metabolites Within the HC group, PSG-sleep efficiency was positively associated with melatonin/TRP (r ¼ .61, p ¼ .006). Most (six out of eight) of the other metabolite ratios to TRP showed a

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somewhat weaker positive correlation with at least one of the PSG sleep measures (e.g., sleep efficiency or percentage time in REM sleep; r > .40, p ¼ .025–.091). However, this pattern did not hold in the IBS group: all of the correlations between metabolites and PSG variables had r < .23. No metabolites were significantly correlated with self-reported sleep quality (Table 2).

Discussion This pilot study utilized a metabolomics approach to compare serum TRP metabolites in women with IBS (IBS-D and IBS-C) and HC women 1 hr after PSG-determined sleep onset, following the introduction of a social stressor. We also explored the relationships of cortisol, PSG and self-reported sleep indices with TRP metabolites. Based on the study by Clarke et al. (2009), who found higher levels of KYN/TRP and lower of KYNA/KYN in a morning sample from IBS patients as compared to an HC group, we expected to find similar group differences in our nighttime sample; however, we found the opposite. That is, nighttime serum KYN/TRP tended to be lower in our sample of women with IBS (p ¼ .067) when compared to HC women. In exploring relationships of KYN pathway metabolites with PSG and self-reported sleep indices, we found several significant and trending relationships, primarily in the HC group. Our finding of no group differences in TRP levels is similar to that of Fitzgerald et al. (2008) who found no group differences in a single morning sample of TRP between women with IBS and HC women. However, these investigators found that the women with IBS had significantly higher levels of KYN and a trend toward higher KYN/TRP, which is similar to the report of Clarke et al. (2009) who found higher morning KYN/TRP in men with IBS. There are several reasons that could account for the discrepancy between our findings and those of Clarke et al. First, Clarke et al. included only male IBS patients and HCs while our study included only women. The authors also provided limited demographic data (e.g., age) and phenotypic description (e.g., IBS-C and IBS-D) of the sample, thus making comparisons difficult. Second, in the Clarke study a percentage of IBS patients (20%) and controls (15%) smoked, whereas none of our subjects smoked. Third, the time of sampling in our study differed from both the Fitzgerald et al. and Clarke et al. studies. TRP and its metabolites, including melatonin, have shown a pattern of variability that is modified by light as well as food, and thus sampling time needs to be considered before comparisons across studies can be made. Our prior description of this cohort showed that the percentage time in REM sleep throughout the night, sleep efficiency, as well as self-reported sleep quality, were lower and serum cortisol levels were higher in those participants with IBS relative to HCs (Heitkemper et al., 2012). Here, we present findings that the IBS-D group also had reduced serum melatonin/ TRP levels at 1 hr post-sleep onset. However, unlike with the HC group, we found no significant relationships between melatonin/TRP levels and PSG sleep indices in the IBS group. This finding does not discount the possibility that reduced

melatonin, especially early in the night, may be linked to the pathophysiology of IBS through other mechanisms. Reduced melatonin production may contribute to the pathophysiology of IBS via a decrease in analgesia, altered motility, and/or increased intestinal secretion (Siah, Wong, & Ho, 2014) in those with IBS-D. Researchers have shown that melatonin has GI protective effects (Siah et al., 2014). For example, animal studies support the association of reduced melatonin levels and stress-induced ulcerations in the GI tract (Zhang et al., 2015). Whether a reduction in melatonin early in the night as well as a lack of correlation between melatonin and sleep indices are associated with functional GI measures such as increased permeability and/or increased visceral sensitivity in persons with IBS-D remains to be established. Although we failed to find marked differences in KYNpathway metabolites between women with IBS and HCs in the present study, 3-hydroxykynurenine/TRP, xanthurenate/TRP, and niacinamide/TRP did show positive correlations with percentage time in REM sleep in the HC group. In addition, anthralinate/TRP and KYNA/TRP were positively correlated with self-report sleep quality in the IBS group. Research in individuals with major psychiatric illnesses (e.g., depression) has suggested that elevations in KYN metabolites may influence the function and structure (volume) of the hippocampus and possibly the amygdala as evaluated by structural magnetic resonance imaging (Savitz et al., 2015). These areas have also been identified as areas important to abdominal pain–related fear learning and memory processes in IBS (Icenhour et al., 2015). To our knowledge, this is the first study to report TRP metabolite levels during sleep in patients with IBS. There are several important limitations to this preliminary study. The sample size is small and multiple comparisons were made. Only women of reproductive age were studied and data from only one time point were analyzed. As such, our findings need to be interpreted with caution and, more importantly, replicated. In summary, this pilot study provides preliminary evidence that reductions in early nighttime melatonin levels may be important in the pathophysiology of sleep disturbances in individuals with IBS-D. A next step is to further describe the pattern of metabolites across the night in sync with cortisol and sleep indices. Assessments of TRP metabolites with functional prospective assays (e.g., permeability and pain sensitivity) in a larger sample are warranted.

Nursing Implications Novel biomarkers hold potential for understanding physiological links among symptoms in patients with chronic health problems such as IBS. This study demonstrates the usefulness of a metabolomics approach to gain insights into the etiology of symptoms in IBS. Behavioral factors such as exposure to bright light through use of electronic devices at bedtime may suppress the secretion of melatonin early in the night and possibly influence GI function and symptoms the next day. Social stressors at bedtime result in the activation of the hypothalamic–pituitary– adrenal axis and lead to disturbed sleep, perhaps through

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alterations in TRP metabolism. Nursing scientists are well positioned to test whether sleep hygiene practices can positively influence the symptom burden of patients with IBS, particularly those with diarrhea. Acknowledgment The authors would like to thank the University of Washington Nutrition and Obesity Research Center (P30 DK035816) for support of the metabolomics analysis.

Author Contribution MMH contributed to conception and design contributed to acquisition, analysis, and interpretation of data; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. CJH contributed to conception contributed to analysis of data; drafted manuscript; critically revised manuscript. MEJ contributed to conception and design contributed to acquisition, analysis, and interpretation of data. HG contributed to conception contributed to analysis of data. DD contributed to design contributed to analysis of data. RJS contributed to conception contributed to interpretation of data. DR contributed to design contributed to analysis of data. WAH contributed to conception contributed to interpretation of data. KCC contributed to conception and design contributed to acquisition, analysis, and interpretation.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by the NINR, NIH (NR04101).

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