Gut microbiome and symptoms in females with irritable bowel syndrome: a cross-sectional analysis.

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is associated with abdominal pain and stool frequency/character alterations that are linked to changes in microbiome composition. We tested whether taxa differentially abundant between females with IBS vs healthy control females (HC) are associated with daily gastrointestinal and psychological symptom severity. Participants (age 18-50 year) completed a 3-day food record and collected a stool sample during the follicular phase. They also completed a 28-day diary rating symptom intensity; analysis focused on the three days after the stool sample collection. 16S rRNA gene sequencing was used for bacterial identification. Taxon abundance was compared between IBS and HC using zero-inflated quantile analysis (ZINQ). We found that females with IBS (n = 67) had greater Bacteroides abundance (q = 0.003) and lower odds of Bifidobacterium presence (q = 0.036) compared to HC (n = 46) after adjusting for age, race, body mass index, fibre intake, and hormonal contraception use. Intestimonas, Oscillibacter, and Phascolarctobacterium were more often present and Christensenellaceae R-7 group, Collinsella, Coprococcus 2, Moryella, Prevotella 9, Ruminococcaceae UCG-002, Ruminococcaceae UCG-005, and Ruminococcaceae UCG-014 were less commonly present in IBS compared to HC. Despite multiple taxon differences in IBS vs HC, we found no significant associations between taxon presence or abundance and average daily symptom severity within the IBS group. This may indicate the need to account for interactions between microbiome, dietary intake, metabolites, and host factors.

Genetic Variations in TrkB.T1 Isoform and Their Association with Somatic and Psychological Symptoms in Individuals with IBS.

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. Thus, we investigated the association of 10 single nucleotide polymorphisms (SNPs) in the regulatory 3' untranslated region (UTR) of NTRK2 (TrkB) kinase domain-deficient truncated isoform (TrkB.T1) and the BDNF Val66Met SNP with somatic and psychological symptoms and quality of life in a U.S. cohort (IBS n=464; healthy controls n=156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level and overall quality of life. Validation using U.K. BioBank (UKBB) data confirmed the association of rs2013566 with increased likelihood of headache. Several SNPs (rs1627784, rs1624327, rs1147198) showed significant associations with muscle pain in our U.S. cohort. Notably, these SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Together, our findings suggest that genetic variation within the 3'UTR region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms that may influence their quality of life. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications.

Stool and urine trefoil factor 3 levels: associations with symptoms, intestinal permeability, and microbial diversity in irritable bowel syndrome.

Previously we showed that urine trefoil factor 3 (TFF3) levels were higher in females with irritable bowel syndrome (IBS) compared to non-IBS females. To assess if TFF3 is associated with symptoms and/or reflect alterations in gastrointestinal permeability and gut microbiota in an IBS population, we correlated stool and urine TFF3 levels with IBS symptoms, intestinal permeability, stool microbial diversity and relative abundance of predominant bacterial families and genera. We also tested the relationship of stool TFF3 to urine TFF3, and compared results based on hormone contraception use. Samples were obtained from 93 females meeting Rome III IBS criteria and completing 4-week symptom diaries. TFF3 levels were measured by ELISA. Permeability was assessed with the urine lactulose/mannitol (L/M) ratio. Stool microbiota was assessed using 16S rRNA. Stool TFF3, but not urine TFF3, was associated positively with diarrhoea and loose stool consistency. Higher stool TFF3 was also associated with lower L/M ratio and microbial diversity. Of the 20 most abundant bacterial families Mogibacteriaceae and Christensenellaceae were inversely related to stool TFF3, with only Christensenellaceae remaining significant after multiple comparison adjustment. There were no significant relationships between stool or urine TFF3 levels and other symptoms, nor between stool and urine levels. In premenopausal females, urine TFF3 levels were higher in those reporting hormone contraception. Collectively these results suggest that higher stool TFF3 levels are associated with IBS symptoms (loose/diarrhoeal stools), lower gut permeability, and altered stool bacteria composition (decreased diversity and decreased Christensenellaceae), which further suggests that TFF3 may be an important marker of host-bacteria interaction.

The feasibility, usability, and clinical utility of traditional paper food and symptom journals for patients with irritable bowel syndrome.

BACKGROUND: Paper food and gastrointestinal (GI) symptom journals are used to help irritable bowel syndrome (IBS) patients determine potential trigger foods. The primary aim of this study was to evaluate the feasibility, usability, and clinical utility of such journals as a data collection tool. A secondary aim was to explore a method for analyzing journal data to describe patterns of diet and symptoms. METHODS: Participants (N=17) were asked to log three sets of 3-day food and symptom journals over a 15-day period. Feasibility was evaluated by journal completion rates, symptom logging compliance, and logging fatigability. The feasibility, usability, and clinical utility of journaling were also assessed by a customized evaluation and exit interview. For each journal, regression analyses were conducted to examine relationships between key meal nutrients and subsequent symptoms. KEY RESULTS: Most participants were young (mean age 35±12) Caucasian (N=13) women (N=14). Journal completion rates were 100% for all participants with no logging fatigability. Over half perceived paper journaling of food and symptoms as feasible, usable, and clinically useful. Thirteen participants demonstrated a strong association with at least one symptom and meal nutrient. Patterns of associations differed among participants. CONCLUSIONS AND INFERENCES: Paper journaling of food and GI symptoms for 9 days over a 15-day period appeared to be a feasible and usable data collection tool for IBS patients. Over half perceived journaling as at least somewhat clinically useful. Findings from this study support the anecdote that food trigger(s) and associated symptom(s) vary for each individual.

Sleep disturbances in irritable bowel syndrome: a systematic review.

BACKGROUND: Sleep disturbances are well-documented among persons with irritable bowel syndrome (IBS). Difficulty in falling asleep, shorter sleep time, frequent arousal and awakenings, or non-restorative sleep are the most common manifestations. Sleep disturbances are also related to a higher risk of having IBS. Some researchers have provided evidence of a positive association between poorer subjective sleep quality and increased severity and frequency in gastrointestinal (GI) symptoms in those with IBS. However, findings from studies using objective sleep and activity measures, such as polysomnography and actigraphy, are inconclusive. PURPOSE: This systematic review of the literature between 1990 and 2015 evaluates the evidence of sleep disturbances in adults with IBS and their relationship with GI symptoms.

Relationships of abdominal pain, reports to visceral and temperature pain sensitivity, conditioned pain modulation, and heart rate variability in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a heterogeneous condition with a number of pathophysiological mechanisms that appear to contribute to symptom chronicity. One of these is altered pain sensitivity. METHODS: Women between ages 18-45 were recruited the community. Of those enrolled, 56 had IBS and 36 were healthy control (HC) women. Participants completed questionnaires, kept a 4-week symptom diary and had a 12-h Holter placed to assess nighttime heart rate variability including high frequency power (HF), low frequency power (LF), and total power (TP). At mid-follicular phase approximately 80% of women completed a thermal pain sensitivity test with conditioned pain modulation and visceral pain sensitivity using a water load symptom provocation (WLSP) test. KEY RESULTS: As expected, daily abdominal pain was significantly higher in the IBS compared to HC group. There were no differences between the bowel pattern subgroups (IBS-diarrhea [IBS-D], IBS-constipation plus mixed [IBS-CM]). Thermal pain sensitivity did not differ between the IBS and the HC groups, but was significantly higher in the IBS-CM group than the IBS-D group. In the WLSP test, the IBS group experienced significantly more symptom distress than HCs and the IBS-CM group was higher than the IBS-D group. Heart rate variability indicators did not differ between the groups or IBS subgroups. Daily abdominal pain was positively correlated with LF and TP in the IBS group. CONCLUSIONS & INFERENCES: Despite similar levels of abdominal pain in IBS, the IBS-CM group demonstrated greater sensitivity to both thermal and visceral testing procedures.

Anticipation of public speaking and sleep and the hypothalamic-pituitary-adrenal axis in women with irritable bowel syndrome.

BACKGROUND: Evidence suggests that subgroups of patients with irritable bowel syndrome (IBS) are hyper-responsive to a variety of laboratory stress conditions. METHODS: This study compared sleep quality and night time plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in response to anticipation of public speaking between 43 women with IBS and 24 healthy control women. In addition, comparisons were made between subgroups within the IBS sample based on predominant stool patterns, 22 IBS-constipation and 21 IBS-diarrhea. Subjects slept three nights in a sleep laboratory, and on the third night serial blood samples were drawn every 20 min from 08:00 PM until awakening. As the subjects had different sleep onsets, each subject's results were synchronized to the first onset of stage 2 sleep. KEY RESULTS: Compared the healthy control group, women with IBS had significantly worse sleep efficiency, and higher cortisol but not ACTH levels over the night. However, there were no IBS bowel pattern subgroup differences. Among IBS subjects, cortisol levels early in the night were higher than found in our previous study with a similar protocol but without the threat of public speaking. These results suggest that a social stressor, such as public speaking prior to bedtime, increases cortisol but not ACTH levels suggesting HPA dysregulation in women with IBS. CONCLUSIONS & INFERENCES: This response to a social stressor contributes to our understanding of the relationship of stress to symptom expression in IBS.

Pro-inflammatory chemokine C-C motif ligand 16 (CCL-16) dysregulation in irritable bowel syndrome (IBS): a pilot study.

BACKGROUND: Irritable bowel syndrome (IBS) is a serious health problem that affects an estimated 10-15% of people worldwide and has economic consequences in the United States of over $30 billion annually. In the US, IBS affects all races and both sexes, with more females than males (2:1) reporting symptoms consistent with IBS. Although the etiology of this functional gastrointestinal disorder is unknown, literature suggests that a subclinical inflammatory component has a role in the etiologic mechanisms underlying IBS. The aim of this study was to evaluate the gene expression of inflammatory biomarkers in patients with and without IBS and among different IBS phenotypes. METHODS: Irritable bowel syndrome patients (n=12) that met Rome III Criteria for IBS longer than 6months were compared with healthy matched controls (n=12). Peripheral whole blood from fasting participants was collected and RNA was extracted. The expression of 96 inflammatory genes was then analyzed using a custom quantitative real-time PCR array. KEY RESULTS: CCL-16 gene expression was upregulated by 7.46-fold in IBS patients when compared with controls. CCL-16 was overexpressed by over 130-fold in IBS-constipation patients when compared with both controls and IBS-diarrhea patients. CONCLUSIONS & INFERENCES: These results further suggest a subclinical inflammatory component underlying IBS. To better understand the phenotypic differences in IBS it is important to broaden the study of these inflammatory and other biomarkers.

Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome.

BACKGROUND: Alterations in serotonin (5-HT) are suspected in the pathophysiology of irritable bowel syndrome (IBS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin and has two isoforms: TPH1 and TPH2. Genetic variants in both genes have been studied in various disorders related to serotonin dysregulation. The aim of this study was to examine whether TPH gene variants were associated with IBS and IBS-related gastrointestinal (GI) symptoms. METHODS: Five single nucleotide polymorphisms (SNPs) from the TPH1 and one SNP from the TPH2 were genotyped in 199 IBS patients and 79 healthy controls. All subjects were Caucasian women of European origin. Irritable bowel syndrome patients filled in a daily diary with five GI symptoms and stool characteristics for 28 days. KEY RESULTS: The TPH1 SNPs showed no association with the diagnosis of IBS. However, among IBS patients, all five TPH1 SNPs showed some association with diarrhea and loose type of stool consistency, with P-values rating from 0.01 to 0.20. The TPH2 SNP showed a trend towards a reduced risk of IBS and possible associations with stool characteristics, both hard and loose stools. However, no P-values were less than the conservative multiple-comparison-adjusted threshold of 0.001 and hence these results must be interpreted cautiously. CONCLUSIONS & INFERENCES: This study is the first to assess associations of TPH gene variants with IBS-related GI symptoms and stool characteristics. The possible association of TPH gene variants with diarrhea needs to be verified in an independent sample.

Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome.

Evidence suggests that patients with irritable bowel syndrome (IBS) are hyper-responsive to environmental, physical and visceral stimuli. IBS patients also frequently report poor sleep quality. This study compared serum cortisol and plasma catecholamine levels during sleep between women with IBS (n = 30) and healthy controls (n = 31), and among subgroups within the IBS sample based on predominant stool patterns, IBS-diarrhoea (n = 14), IBS-constipation (n = 7) and IBS-alternators (n = 9). Cortisol was measured from serial blood samples drawn every 20 min, and catecholamines every hour, in a sleep laboratory from 8 pm until awakening. Because of the varied sleep schedules of the individual participants, each subject's hormone series time base was referenced with respect to their onset of Stage 2 sleep. Overall, there were no significant differences in cortisol or catecholamine patterns between women with IBS and controls, nor were there any group by time interactions. However, women with constipation-predominant IBS demonstrated significantly increased noradrenaline, adrenaline and cortisol levels throughout the sleep interval, and women with diarrhoea-predominant IBS were significantly lower on noradrenaline and cortisol. These results suggest that differences in neuroendocrine levels during sleep among IBS predominant bowel pattern subgroups may be greater than differences between IBS women and controls. Neuroendocrine profiles during sleep may contribute to our understanding of symptom expression in IBS.

Heart rate variability is related to pain severity and predominant bowel pattern in women with irritable bowel syndrome.

This study examined heart rate variability (HRV) in women with irritable bowel syndrome (IBS) to determine its association with gut pain and predominant bowel pattern. Women with IBS (constipation predominant n = 45, diarrhoea predominant n = 64, alternating n = 56) and healthy controls (n = 50) were recruited from the community. Severity of gut pain was measured retrospectively. The HRV (24 h) was summarized as high-frequency (HF) power and the ratio of low-frequency (LF) power to HF power. Among those women with IBS who have severe gut pain, the 15 constipation-predominant women had lower (P = 0.01) HF power and higher (P = 0.003) LF/HF ratio (geometric means 70 and 7.5, respectively) than the 21 women with diarrhoea-predominant IBS (286 and 3.1) and controls (224 and 3.9). In contrast, among women without severe pain, there is a smaller and not quite significant difference in the opposite direction. Using a broader definition of pain severity based on several questions nearly doubles the number of subjects in the severe pain group and shows even more significant results. The relationship of predominant bowel pattern to HRV is qualitatively different in the subgroup of patients with more severe pain than in the subgroup with less severe pain.

Subjective and objective sleep indices in women with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) commonly report sleep disturbances. This study examined self-report (Pittsburgh Sleep Quality Inventory) sleep quality and polysomnography (PSG) sleep variables in 18 women with mild-to-moderate IBS, 18 with severe IBS and 38 with age- and gender-matched controls. All women were studied on two consecutive nights in a sleep research laboratory where PSG data were collected. Retrospective and daily measures were obtained of self-reported sleep quality, psychological distress and gastrointestinal symptoms across one menstrual cycle. Self-report measures of psychological distress and sleep quality were significantly worse in the IBS-severe (IBS-S) group compared with controls. Rapid eye movement (REM) latency was higher in the two IBS groups on Night 1 than the control group (P = 0.06). Percentage time in REM was highest in the IBS-S on Night 2. All groups demonstrated greater sleep disruption on Night 1 (adaptation) when compared with Night 2. These results highlight the importance of considering the 'first-night effect' in those with IBS and the lack of concordance between self-report and objective indices of sleep in women with IBS.

Effects of age, feeding regimen, and glucocorticoids on catecholamine and cortisol excretion in preterm infants.

BACKGROUND: The sympathoadrenal system is important in maintaining normal physiologic functioning in infants and increased output also can reflect stress. We sought to determine the effects of age, feeding regimen, and glucocorticoids on catecholamine and cortisol excretion in preterm infants and to assess whether a particular strategy of feeding enhanced sympathoadrenal development or was stressful. METHODS: Preterm infants (26-30 wk gestation; n = 171) were assigned randomly to begin trophic feedings from day 4 through 14 (trophic group) or to start feedings at day 15 (standard group) with feedings administered either by bolus every 3 hours (bolus) or continuously over 24 hours (continuous). At 10, 28, 40, 50, and 60 days of age, urine was collected continuously for 6 hours for measurement of catecholamines (norepinephrine, epinephrine, dopamine), cortisol, and creatinine. Data were available for 98 infants. RESULTS: Norepinephrine excretion increased with postnatal age. The increase with age was significantly greater in the trophic group compared with that in the standard group. Epinephrine excretion did not change with age, and there were no differences between trophic and standard groups. Dopamine excretion increased with age but was similar between trophic and standard groups (borderline significantly greater in the trophic group). Cortisol excretion increased with age and also was similar between trophic and standard groups. There was no effect on catecholamine or cortisol excretion of bolus vs continuous feedings, antenatal or postnatal corticosteroids, gestational age at birth, age at which full feedings were attained, or use of human milk compared with preterm formula. CONCLUSIONS: The greatest determinant of catecholamine and cortisol excretion is postnatal age. Feeding method, type of feeding, and glucocorticoid administration in the amounts customarily used have little significant effect on catecholamine or cortisol excretion. The apparent link between early feeding and norepinephrine (and possibly dopamine) excretion warrants further investigation.

Autonomic nervous system function in women with irritable bowel syndrome.

Autonomic nervous system (ANS) balance was assessed in women with and without irritable bowel syndrome (IBS) using laboratory tests of function (ie, expiratory/inspiratory ratio, Valsalva, posture changes, and cold pressor) and spectral and nonspectral measures of heart rate variability (HRV). Women with (N = 103) and without IBS (N = 49) were recruited, interviewed, then completed a laboratory assessment and wore a 24-hr Holter monitor Analysis using the entire sample showed little difference between IBS and control women and between subgroups with IBS on either laboratory measures or 24-hr HRV measures. However, analysis restricted to those women with severe IBS symptoms showed quite pronounced differences between two IBS subgroups on 24-hr HRV measures. Parasympathetic tone was significantly lower and ANS balance was significantly higher in the constipation-predominant compared to the diarrhea-predominant group. Subgroups of women with IBS do differ in ANS function as measured by 24-hr HRV; however, these differences are only apparent among women with severe symptoms. These findings point out the importance of considering symptom severity when interpreting studies of IBS.

Circadian rhythmicity of cortisol and body temperature: morningness-eveningness effects.

The purpose of this study was to describe and compare the circadian rhythm of body temperature and cortisol, as well as self-reported clock times of sleep onset and offset on weekdays and weekends in 19 healthy adult "larks" (morning chronotypes) and "owls" (evening chronotypes), defined by the Home and Ostberg questionnaire. Day-active subjects entered the General Clinical Research Center, where blood was sampled every 2 h over 38 h for later analysis for cortisol concentration by enzyme immunoassay. Rectal body temperature was measured continuously. Lights were turned off at 22:30 for sleep and turned on at 06:00, when subjects were awakened. The acrophases (peak times) of the cortisol and temperature rhythms occurred 55 minutes (P < or = .05) and 68 minutes (P < .01), respectively, earlier in the morningness group. The amplitude of the cortisol rhythm was lower in the eveningness than in the morningness group (P = n.s.). Subject groups differed on all indices of habitual and preferred timing of sleep and work weekdays and weekends (P = .05-.001).