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.

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.

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.

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.

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.

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.

Polymyxin B prevents increased sympathetic activity and alveolar macrophage tumor necrosis factor release in parenterally fed rats.

OBJECTIVE: To determine the effects of polymyxin B sulfate in rats fed by total parenteral nutrition on norepinephrine excretion, macrophage tumor necrosis factor production, and bacterial translocation. DESIGN: Randomized animal study. SETTING: A university teaching hospital in Seattle, Wash. MATERIALS AND METHODS: Three groups of rats were studied: chow plus intravenous saline, total parenteral nutrition, or total parenteral nutrition supplemented with polymyxin B sulfate. After 5 days, urinary excretion of norepinephrine and epinephrine was calculated, peritoneal and alveolar macrophages were cultured, and their spontaneous and lipopolysaccharide-stimulated tumor necrosis factor production was measured. Mesenteric lymph nodes were cultured for bacteria. RESULTS: Rats fed by total parenteral nutrition had increased urine norepinephrine excretion (33%) and alveolar macrophage tumor necrosis factor production (80%) and trends for increased epinephrine excretion and bacterial translocation compared with rats fed chow. Alveolar but not peritoneal macrophage tumor necrosis factor production was significantly related to norepinephrine excretion (r = .5, P < .01). The addition of polymyxin B to total parenteral nutrition decreased weight gain (P < .05), urinary norepinephrine excretion (P < .01), and alveolar macrophage tumor necrosis factor production (P < .05) compared with rats fed by total parenteral nutrition. Polymyxin B also tended to decrease the magnitude of bacterial translocation. CONCLUSIONS: Alveolar macrophage tumor necrosis factor production appears to be influenced by sympathetic nervous activity. Total parenteral nutrition-induced endotoxemia may indirectly alter macrophage function by stimulating sympathetic nervous activity.

TPN-induced sympathetic activation is related to diet, bacterial translocation, and an intravenous line.

OBJECTIVE: To investigate the effects of an intravenous line and the administration of a total parenteral nutrition (TPN) formula by the parenteral and oral routes on bacterial translocation and urinary catecholamine excretion in rodents. METHODS: Rats were fed chow with or without an intravenous line and a fat-free TPN solution either orally or intravenously for 5 consecutive days. Urine was collected on the first, third, and fifth days of feeding and quantitatively analyzed for norepinephrine and epinephrine excretion. Mesenteric lymph nodes were cultured for bacteria at the end of the study (day 5). RESULTS: Oral and intravenous TPN diets significantly increased norepinephrine excretion over time (P < .0001) compared with excretion in rats fed chow. Oral TPN diets increased epinephrine secretion after 5 days of feeding. The route of feeding TPN solution had no effect on norepinephrine or epinephrine excretion. Chow-fed rats with intravenous lines tended to have increased norepinephrine excretion over 5 days of feeding compared with chow-fed rats without intravenous lines (55% vs 13%, P = .08). Rats with bacterial translocation had greater norepinephrine excretion (mean +/- SEM, 136 +/- 23 pmol/mumol of creatinine) than rats without bacterial translocation (64 +/- 14 pmol/mumol of creatinine) (P < .05). CONCLUSIONS: Intravenous and oral fat-free, hypertonic glucose diets increase sympathetic nervous activity. This diet-induced sympathetic activity may be related to the presence of an intravenous line, bacterial translocation, the thermic effects of hypertonic glucose, and/or the absence of orally ingested food substances in rodent chow. In this model of rodent feeding, increased sympathetic activity may account for alterations in intestinal and immunologic defenses.

Morphine inhibits TRH-induced intestinal transit increases.

The current study examined the effects of intraperitoneal (IP) and intracisternal (IC) administration of the opiate agonist, morphine, and an opioid, central beta-endorphin, on thyrotropin releasing hormone (TRH)-induced small intestinal transit increases. Anesthetized rats, 14-day and older, were studied to determine age-related differences. Results showed that in all age groups IP morphine (2 mg/kg) blocked TRH (15 micrograms)-induced increases in transit of a charcoal bolus. Morphine 1 microgram and beta-endorphin 1 microgram administered IC in 0.6 microliter failed to block TRH (10 microgram)-induced increases in intestinal transit in 14-day-old rats. However both morphine and beta-endorphin 1 micrograms IC blocked TRH-induced increases in adult rats. Dose-response studies demonstrated that higher doses (greater than 1 microgram) of morphine IC were required to block TRH-induced increases in preweaning rats.

Thyrotropin-releasing hormone stimulates intestinal transit in young rats.

The effect of intracisternal injection of thyrotropin-releasing hormone (TRH) on small intestinal transit of a charcoal bolus was investigated in 14-, 21-, 28- and 35-day-old and adult rats. Intracisternal TRH (15 micrograms in 2 microliters) was administered, and transit (distance traveled by the charcoal) was measured 120 min later. In all age groups, intracisternal TRH increased charcoal transit significantly (P less than 0.05) as compared to saline-treated controls. This increase in transit was not mimicked by intravascular TRH, and it was blocked in all age groups by prior intraperitoneal injection of atropine (2 micrograms/g body weight). Vagotomy blocked TRH-induced increases in small intestine transit in rats of 28 days and older. Prior intraperitoneal injection of the antiserotonin compound, cyproheptadine (1 microgram/g body weight) reduced TRH-induced increases in small intestine transit in all age groups. These results demonstrate that centrally administered TRH stimulates small intestine transit through both cholinergic and serotonergic mechanisms in rats as early as 14 days of age.

Morphine inhibits TRH-induced gastric contractile activity.

This study investigated the effect of centrally and peripherally administered thyrotropin releasing hormone (TRH) on gastric contractile activity of rats 14, 21, 28 and adult (greater than or equal to 50) days (D) of age, and the effect of morphine pretreatment on that response. Rats were anesthetized with urethane, then a tension transducer was implanted on the anterior gastric corpus. Following baseline recording, rats were pretreated with intraperitoneal morphine (2 mg/kg). TRH (5 micrograms) in saline or saline alone (0.6 microliters) was then injected into the cisternum magnum. Additionally, dose response to TRH was examined in 14- and 50-day-old rats. Intracisternal TRH induced a dose-related increase in gastric contractile activity in both 14- and 50-day-old rats. Higher doses of TRH (10 and 30 micrograms) prolonged the response as compared to low doses. Peripheral morphine pretreatment blocked the TRH-induced increase in gastric contractile activity in all age groups although a higher morphine dose (10 mg/kg) was needed to block the effect in 28D rats. Intravenous TRH (5, 10, 30 micrograms) produced an increase in gastric contractile activity in 14D rats which was blocked by vagotomy.

Mediation of thyrotropin-releasing hormone induced gastric motility increases in developing rats.

Centrally administered thyrotropin-releasing hormone (TRH) induces vagally mediated gastrointestinal effects which may be cholinergic, serotonergic or a combination. This study investigated mediation of TRH-stimulated gastric motility in developing rats. A serotonin (5-HT) antagonist (5-HT2, ketanserin or xylamidine; 5-HT3, MDL 72222) or an acetylcholine receptor blocker (atropine) was administered intraperitoneally 30 min prior to intracisternal TRH (5-10 micrograms). The 5-HT-depleting para-chlorophenylalanine (p-CPA) was administered 48 or 72 h prior to TRH. Gastric motility, monitored via extraluminal strain gauge, was not increased with TRH in atropine-pretreated rats. MDL 72222 had a significant age-related effect on TRH-induced gastric motility increases while 5-HT2 antagonists and p-CPA treatment did not. Thus, acetylcholine receptor blockade inhibits TRH-stimulated gastric motility in young and adult rats while 5-HT3 antagonism eliminates the motility response in young (7 and 10 days) rats.

Morningness-eveningness and early-morning salivary cortisol levels.

The purposes of this exploratory study were: (1) to describe a 2-h segment of the early-morning salivary cortisol levels of morning (M) and evening (E) types of healthy, day-active adults on one morning; and (2) to compare selected demographic and sleep characteristics. The sample consisted of 20 subjects, aged 23-39 years, 10 of each type. Measures included: morningness-eveningness questionnaire score, demographic information, self-report sleep characteristics, and self-report of well-being. Beginning with time of arising, seven salivary samples were collected at approximately 20-min intervals. Among the sleep variables, bedtime (p = 0.005), time of mid-sleep (p = 0.002), and arising time (p = 0.043) were later in the E group as compared to the M group. Six M and one E subject awoke spontaneously on the morning of sampling without an awakening aid (p = 0.018). Even though total hours of sleep were comparable between groups, E subjects reported feeling less rested in the morning (p = 0.019). Although mean M group salivary cortisol levels were greater than mean E group levels for each sampling time, there were no significant group differences. Eight M subjects reached a sampling period salivary cortisol peak by 50 min after arising, contrasted with six E subjects who reached their peak at that time. These preliminary findings suggest that E types demonstrate lower morning arousal and a delay in their early-morning peak of salivary cortisol relative to M types. Further study is needed to explore the relationship between M and E types, their sleep-wake patterns, and cortisol secretion patterns.

Gastric relaxation prior to enteral feeding.

The purpose of this investigation was to determine whether the observed gastric relaxation associated with the intragastric infusion of a liquid meal could be conditioned to the temporarily associated auditory cues to enteral feeding and thus produce decreased intragastric pressures under "sham" feeding conditions. Eight normal volunteers received either enteral feedings or sham feedings followed by enteral feedings on 72 separate trial days. The feedings were administered at a constant rate via a Harvard infusion pump. Intragastric pressure changes were monitored by an open tipped pressure cannula which was attached to the feeding tube. A sham feeding consisted of carrying out all preparatory procedures including activation of the feeding pump which was visually screened from the patient. Without the subjects' knowledge the liquid diet was diverted to another reservoir instead of through the nasogastric tube. This sham type infusion produced a gastric response similar to the response to a normal diet infusion as evidenced by a decrease in intragastric pressure and a suppression of irregular high amplitude contractions that are associated with hunger. This anticipatory response to enteral feeding indicative of prospective relaxation of the stomach may enhance the subsequent accommodation to a volume of diet. Additional studies are needed to investigate the importance of visual and auditory cues on patient tolerance of enteral feedings.

Rate and volume of intermittent enteral feeding.

The purpose of this investigation was to determine the effects of the volume of enteral feedings and the rate at which they were administered on subject tolerance and gastric pressure changes. Fourteen normal volunteers received enteral feedings on 9 or 10 separate days. These feedings (Ensure) were administered in combinations of 3 volumes (250, 350, and 500 ml) and of 2 rates (30 and 85 ml/min). The effect on gastric motility was monitored by an open-tipped catheter. Nine of the subjects also received 750 ml administered at 30 ml/min. Six of the 14 subjects experienced nausea and/or discomfort during the first feeding trial (250 ml at 30 ml/min); however, subsequent feedings were tolerated without this discomfort. The rate at which feedings were administered had little effect on the time following feeding until the return of regular motility or on the mean motility index when 250 ml were administered; however, when larger volumes were administered at the faster rate, longer time was taken for the return of regular motility. Feedings administered at the faster rate were associated with a greater number of subjective complaints of abdominal discomfort, nausea, fullness, and cramping. The volume of a feeding has a significant effect on both the time required for regular motility to return following feeding and on the mean motility index, with the larger feeding volumes suppressing activity progressively longer. The volume of feeding (up to 750) ml) had little effect upon symptomatic tolerance of subjects when these feedings were administered at 30 ml/min. There was no significant interaction effect of rate and volume on the time required for motility to return following feedings. The results of this study indicate that normal subjects can tolerate bolus feedings of (250-750 ml) administered at 30 ml/min without distress. Additional studies are needed to compare bolus and continuous feedings in relation to patient tolerance, gastric emptying, and nutritional outcome.