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Keywords:

  • barostat;
  • hypersensitivity;
  • irritable bowel syndrome;
  • meal;
  • visceroperception

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References

Background  Visceral hypersensitivity is frequently observed in irritable bowel syndrome (IBS). Previous studies have shown that administration of a meal can aggravate symptoms or increase visceroperception in IBS patients. We investigated whether meal ingestion could increase the sensitivity of the barostat procedure for the detection of visceral hypersensitivity in IBS patients.

Methods  Seventy-one IBS patients and 30 healthy controls (HC) were included in the study. All subjects underwent a barostat procedure under fasted and postprandial conditions to measure visceroperception. Urge, discomfort, and pain were scored on a visual analog scale. Furthermore, percentages of hypersensitive IBS patients and HC were calculated and dynamic rectal compliance was assessed.

Key Results  In IBS patients, urge, discomfort, and pain scores were significantly increased postprandially vs the fasted state. The HC showed increased scores for urge and pain only. Rectal dynamic compliance remained unaltered in both groups. Postprandial hypersensitivity percentages did not significantly differ vs the fasted state in IBS patients, nor in HC.

Conclusions & Inferences  Postprandial barostat measurement enhances visceroperception in IBS but has no added value to detect visceral hypersensitivity in individual IBS patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References

Irritable bowel syndrome (IBS) is a frequently occurring functional gastrointestinal disorder, characterized by abdominal discomfort or pain associated with changes in bowel habits.1,2 In the Western world, IBS affects up to 20% of the population and is more frequent in women than men.1 One of the mechanisms involved in symptom generation and in the pathophysiology of IBS is visceral hypersensitivity.3,4 In 1973, Ritchie et al. were the first to demonstrate increased pain responses to rectal balloon distensions in IBS patients compared to healthy individuals.5 Since then, several studies have confirmed that perception of pain, but also of urge and discomfort in response to rectal distension, is increased in IBS compared to healthy controls (HC).5–10 This is referred to as visceral hypersensitivity and is associated with symptoms.3,11–14 Studies have reported different results with respect to the prevalence of visceral hypersensitivity in IBS patients, with rates varying between 33% and 90%.3,9–12,15

In IBS, meal ingestion often provokes or aggravates symptoms.16–20 In several studies, the effect of nutrients on visceral perception in IBS has been assessed.23–29 As fat-rich food in particular is reported to induce abdominal complaints in IBS,17,21,22 most investigators have used food with a high-fat content to modulate visceral perception.23–28 These studies found that pain perception in the fasted state was increased in IBS patients vs HC. Additionally, they showed a postprandial increase in visceral perception compared to the fasted state in IBS patients but not in controls. These observations indicate that nutrients and fat in particular, have an important role in the modulation of visceral perception in IBS. However, when analyzing these studies in more detail, it is obvious that calorie-density varied markedly among studies and also that lipids or fat were often administered intraduodenally,23–25,28 which is not a physiologic route.

As food triggers IBS symptoms and visceroperception is a potential biomarker for IBS, we hypothesize that oral ingestion of an ‘average size’ meal will increase sensitivity of the visceroperception test in IBS patients compared to measurement in the fasted state. We also postulate that ingestion of a meal will increase hypersensitivity in IBS patients and thereby potentially enhance the discriminative capacity between IBS and HC.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References

Participants

A total of 71 IBS patients diagnosed according to the Rome III criteria, were included via routine clinical care for barostat measurement, at the outpatient clinic of the division Gastroenterology–Hepatology of the Maastricht University Medical Center+. Thirty healthy volunteers were recruited via local advertisements. Before participation, a brief medical history was taken to exclude the presence of gastrointestinal disorders. Informed consent was obtained prior to their participation. The study protocol had been approved by the Ethics Committee of the Maastricht University Medical Center+ and was executed according to the Declaration of Helsinki (59th general assembly of the WMA, Seoul, South Korea, October 2008). The study has been registered in the US National Library of Medicine (http://www.clinicaltrials.gov, NCT00775060).

Sample size was determined using OpenEpi Sample Size Calculator (Emory University, Atlanta, GA, USA). The primary aim was to assess the effect of a meal on visceral perception in IBS patients. Based on data from Simrén,23 it was estimated that 36 subjects would provide a power of 80% to detect an 8 mmHg pressure change of the pain threshold before and after the meal, assuming a variance of 12 and a two-sided significance level of 0.05. Assuming that 50% of IBS patients are hypersensitive, we aimed to include 72 patients with IBS. As secondary aim, we studied the effect of a meal in HC and compared these findings with those in IBS patients.

Protocol

All patients and HC underwent two barostat measurements interspaced with a 15 min break that was followed by ingestion of a standard liquid meal before the second barostat measurement. The barostat protocol for the assessment of rectal sensitivity and dynamic compliance was performed as described previously by Vanhoutvin et al.30

Meal

The liquid meal consisted of 200 mL of Nutridrink® (Nutricia Nederland B.V.; Zoetermeer, the Netherlands), enriched with 15 mL Calogen® (50 g fat per 100 mL) (Nutricia Nederland B.V.). Total energy density of the drink was 368 kcal, and included 12.0 g proteins, 36.8 g carbohydrates, and 19.1 g fat.

Barostat

Participants arrived in the hospital after an overnight fast. They self-administered a rectal enema containing 60 mL of tap water to clean the rectum and were instructed to void rectal contents 5 min thereafter.

Rectal perception and compliance were measured with an electronic barostat (Distender II; G&J Electronics, Toronto, ON, Canada, part: C7-CB-R). During the rectal barostat investigation, a commercially available barostat balloon of non-compliant material (Mui Scientific, Missisauga, ON, Canada, part: C7-2CB-R) was lubricated with KY-gel (Johnsson & Joshnsson, Longhorne, PA, USA) and inserted into the rectum, 4 cm proximal to the anal sphincter. Balloon distensions were controlled using a standard software package (Version 6.7; G&J Electronics).

The barostat protocol consisted of four subsequent procedures (Fig. 1) for the assessment of visceral perception and rectal compliance, respectively. In both patients and controls, only subpart 3 and 4 of the barostat protocol were repeated during the second, postprandial measurement.

image

Figure 1.  Barostat protocol with (1) sensitization; (2) measurement of MDP; (3) assessment of visceroperception, and (4) measurement of rectal dynamic compliance.

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1. Balloon unfolding  The first part of the protocol consisted of a single distension at an absolute pressure of 25 mmHg to sensitize the rectum and to ensure that the balloon was not leaky and placed correctly.

2. Minimal distension pressure measurement  Subsequently, to measure minimal distension pressure (MDP), a staircase distension protocol was applied with increasing pressure steps of 1 mmHg for 30 s each, ranging from 0 to 20 mmHg. The minimal balloon pressure needed to overcome the intra-abdominal pressure (MDP), was detected via interference of the respiratory curves with the balloon volume curve. The obtained MDP-value was used to standardize the perception protocol (see section 3).

3. Measurement of visceral perception  A semi-random staircase protocol was applied, consisting of 17 pressure steps between 0 and 50 mmHg above MDP, with increments of 3 mmHg. Duration of each pressure step was 1 min, interspaced with a 30 s interval at MDP. Thirty seconds after initiation of each pressure step urge, discomfort, and pain were scored, using a visual analog scale (VAS) with a range between 0 and 100 mm.

4. Compliance  After finishing the visceral perception measurement, MDP was set to zero. Rectal compliance was then measured using a staircase distension protocol with pressure steps of 5 mmHg each (range 0–50 mmHg) and a duration of 30 s. Rectal dynamic compliance was assessed by calculating the maximum volume increase between two pressure steps over the compliance protocol, divided by the pressure difference of the two steps.

Visceral hypersensitivity

Fasting and postprandial visceral hypersensitivity were calculated according to the definition used by van der Veek et al. for each time point, i.e., the mean pain threshold in HC minus 2SD.15 Using the data of this study, the fasted mean pain threshold in HC was 11 mmHg above MDP, whereas the postprandial mean pain threshold in HC was 8 mmHg above MDP. A VAS-score >10 mm for pain at or before this threshold indicated hypersensitivity. According to this cut-off, percentages IBS patients and HC classified as hypersensitive in the fasted and postprandial state were compared.

Statistical analyses

Urge, discomfort, pain, and compliance curves were analyzed using a Gaussian non-linear regression, including a random effect and an autocorrelation.30 The effect of a meal on urge, discomfort, and pain and on rectal dynamic compliance was considered significant if the 90% confidence intervals (CIs) did not overlap.31 Furthermore, differences of area under curves (AUCs) between IBS patients and HC were calculated in the fasted vs the postprandial state to assess and quantitate the effect of meal ingestion between groups. A Wilcoxon signed rank test was used to compare thresholds for urge, discomfort, and pain in the fasting vs the postprandial state. Dichotomous variables were compared with a McNemar cross-tabulation within groups and using a chi-square test between groups (spss 16.0 for Macintosh, Chicago IL, USA). A Mann–Whithey U-test was used to compare age between IBS patients and controls. A two-sided P-value below 0.05 was considered to be statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References

Baseline characteristics

Mean age (±SEM) did not differ between IBS patients and HC (38.4 ± 1.7 years and 36.6 ± 3.1 years, respectively; P = 0.59). Of the IBS patients, 70% was female compared to 63% in the HC. In the IBS patients, bowel habits for diarrhea (IBS-D), constipation (IBS-C), and mixed stool pattern (IBS-M) were 49%, 31%, and 20%, respectively.

Effect of a meal within groups

Figs 1–3 show the non-linear regression curves (with their corresponding CI’s) of visceral perception, i.e., urge, discomfort, and pain, in IBS patients and HC. CI’s were very small in all cases.

image

Figure 2.  Urge scores in IBS patients and healthy controls under fasted and postprandial conditions.

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image

Figure 3.  Discomfort scores in IBS patients and healthy controls under fasted and postprandial conditions.

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Urge  According to the CIs, scores for urge were significantly higher during the postprandial measurement compared to the fasted state in IBS patients. The increase was observed within the pressure range 5–50 mmHg. The HC also showed a significant increase of urge, over the whole pressure range of the protocol in the postprandial vs the fasted state, which is between 0 and 50 mmHg (Fig. 2).

Discomfort  Scores for discomfort were significantly increased in IBS patients over the pressure range (5–47 mmHg), during the postprandial measurement vs fasting. Discomfort scores in HC did not differ significantly between the fasted vs postprandial measurements (Fig. 3).

Pain  Within IBS patients, as well as in HC, postprandial scores for pain were significantly increased over the whole pressure range, compared to the fasted state (Fig. 4).

image

Figure 4.  Pain scores in IBS patients and healthy controls under fasted and postprandial conditions.

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Thresholds  In Fig. 5, the thresholds for urge, discomfort, and pain are shown. A significant increase of postprandial vs fasting median thresholds was found for urge [20 (0–44) mmHg vs 17 (0–37) mmHg] and discomfort [18.5 (0–53) mmHg vs 17 (0–53) mmHg] in HC and for discomfort in IBS patients [14 (0–50) mmHg vs 11 (0–50) mmHg]. A significant postprandial decrease was found for pain in IBS patients [14 (0–53) mmHg vs 17 (0–53) mmHg], while no differences were found for pain in HC, nor for urge in IBS patients.

image

Figure 5.  A–C Thresholds for urge (A), discomfort (B), and pain (C) in IBS patients and healthy controls, under fasted vs postprandial conditions. *< 0.05; **< 0.01.

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Visceral hypersensitivity Fig. 6 shows that the percentages of IBS patients and HC with hypersensitivity in the fasted vs postprandial state were not significantly different: for IBS patients 40.9% (29 of 71) vs 39.4% (28 of 71) and for HC 6.7% (2 of 30) vs 3.3% (1 of 30), based on previously defined criteria.15 Postprandially, four normosensitive IBS patients became hypersensitive, whereas five hypersensitive patients became normosensitive. With respect to IBS subgroups, no significant changes were observed in the percentage patients with hypersensitivity before compared to after meal intake: 34.3%vs 40.0% in IBS-D (= 0.73); 45.5%vs 31.8% in IBS-C (= 0.38) and 50.0%vs 50.0% in IBS-M (= 1.00).

image

Figure 6.  Fasted and postprandial hypersensitivity percentages in IBS patients and healthy controls.

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Rectal dynamic compliance  As shown in Fig. 7, rectal dynamic compliance remained unaltered in the postprandial state, compared to the fasted state in both groups.

image

Figure 7.  Rectal dynamic compliance in IBS patients and healthy controls under fasted and postprandial conditions.

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Effect of meal between groups

Urge, discomfort, pain, and rectal dynamic compliance  The difference in perception scores for urge and pain between IBS patients and HC was significantly larger in the postprandial state compared to the fasted state. No such difference was found for discomfort (Table 1). Furthermore, according to the confidence intervals, no differences between IBS patients and HC were found for rectal dynamic compliance in the fasted, nor in the postprandial state.

Table 1.   Differences of visceral perception between IBS patients and HC in the fasted vs the postprandial state for urge, discomfort, and pain
Perception parameterDelta AUC of IBS patients – HC [90% CI]
  1. The asterisks indicate significant differences between the deltas of the area under curve (AUC) of irritable bowel syndrome (IBS) patients minus healthy controls (HC) in the fasted vs the postprandial state.

Urge*
 Fasted367.13 [307.89–426.84]
 Postprandial535.97 [475.01–597.50]
Discomfort
 Fasted377.99 [306.64–450.48]
 Postprandial371.91 [296.49–488.06]
Pain*
 Fasted1497.02 [1452.90–1540.61]
 Postprandial1655.57 [1604.922–1705.75]

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References

The primary aim of this study was to investigate whether a liquid meal increased the sensitivity of the barostat procedure. We found an increased visceral perception in IBS patients for urge, discomfort, and pain after meal ingestion, and for urge and pain in HC. Despite the increase in visceroperception postprandially, the overall percentage of IBS patients with visceral hypersensitivity did not increase. Rectal compliance remained unaltered after meal intake.

Findings from this study confirm previous literature data with respect to an increase in visceral sensitivity in IBS patients vs healthy subjects.5–10 Several mechanisms have been postulated to be responsible for this altered perception, mainly aiming at increased perception and processing of pain by IBS patients.32–34 In addition, there is growing evidence suggesting that peripheral immune mechanisms and disturbed neuro-immune communication may play a role in the hypersensitivity observed in IBS patients.36

Our data confirm that a high-fat meal may augment visceral sensory responses of IBS patients as was previously shown after intraduodenal fat administration.23–25,28 Only two other studies have assessed the effect of meal intake on visceroperception via the physiologic route, i.e., after oral ingestion.26,27 Van der Veek et al. assessed the effect of a fat-rich liquid meal with a caloric load of 600 kcal [39 energy (EN)% fat, i.e., 234 kcal), on visceral perception in 26 IBS patients and 13 HC. They found that postprandial but not fasting pain scores were significantly elevated in IBS patients compared to HC.27 Simrén et al. studied 11 IBS patients and 13 healthy subjects in the fasted state and after a meal with a high caloric load (i.e., 800 kcal) and low in fat (20 EN% fat, i.e., 160 kcal) or high in fat (60 EN% fat, i.e., 480 kcal). In IBS patients only, rectal sensitivity increased significantly (i.e., lower thresholds for discomfort and pain and higher perceived pain intensity by VAS) at 30 and 60 min postprandially after the high-fat meal, but not after the low-fat meal.

These studies suggest that the fat load per se is a stronger stimulus than the caloric load, which justifies the composition of the meal used in this study, with a caloric load comparable to an average meal but high in fat. Whereas the numbers of patients and controls were relatively small in both above mentioned studies, this study included a higher number of patients, representing a non-selected general IBS population. In addition, measurements were performed as part of routine clinical care, which allowed us to show that increased meal-induced visceroperception is present in the general IBS population.

Although the IBS subtypes did not show any significant differences in their reaction to the liquid meal with regards to hypersensitivity, this remains inconclusive as this study was not powered to show differences between IBS subtypes.

We cannot exclude that the order of the repeated barostat measurements has affected viscerosensation, explaining the increased postprandial visceroperception observed in both the IBS patients and HC. However, previous studies that assessed the effect of a meal on postprandial perception, either used a similar design24,25,27 or performed measurements on separate days,23,26 and even used a conditioning distension26 to account for repeated measurements.35 Despite methodological issues, in all these studies it was found that visceral perception increased postprandially,23–28 meaning that the order of measurements has little effect on meal-induced increased visceroperception.

At group level, both fasted and postprandial perception scores to rectal distensions were increased in IBS patients, compared to HC. The shifts that we observed in the pain threshold of IBS patients are in line with the above mentioned observations, although this could not be found for urge and discomfort. Nonetheless, one has to keep in mind that the data from the thresholds are based on a single pressure level, whereas the perception curves include the full pressure range between 0 and 50 mmHg.

Although we demonstrated that postprandial perception of urge, discomfort, and pain increased in IBS patients, no postprandial effect could be detected on the percentage of IBS patients that were classified as hypersensitive. In total, 86% of IBS patients being hypersensitive in the postprandial state were also hypersensitive under fasting conditions. The postprandial increase in visceroperception as indicated by the perception curves is therefore likely to the result of an increased perception of patients that were already hypersensitive. The net effect is an overall increase of visceral perception of urge, discomfort, and pain on a group level, but not on the presence of visceral hypersensitivity as assessed on an individual level.

With respect to characteristics of the nine patients in whom the ‘sensitivity status’ changed between the fasting and postprandial state, eight were females. The age of the five hypersensitive patients who became normosensitive appeared to be lower compared to the four normosensitive patients who became hypersensitive (29.8 vs 46.3 years). In more detail, under fasting conditions, six of the nine patients had VAS-scores just above or below the threshold level. Therefore, a minor shift in the VAS did result in the change in their sensitivity status.

Oral administration of a meal increases overall visceral perception, and decreases rectal compliance in IBS patients compared to HC. However, the sensitivity of the barostat procedure is not increased as the discriminative capacity between IBS patients and HC based on visceral hypersensitivity remained unaltered. It is important to note that definitions for hypersensitivity differ between studies. The present findings implicate that a well-defined measure for visceral hypersensitivity is warranted, especially for clinical applications.

A possible limitation of our study included the short 15 min recovery time between two measurements. Data from the studies by Simrén et al. and van der Veek et al. provided substantial evidence that even a short recovery time of 5–15 min was found to be sufficient to show an effect of meal ingestion on visceroperception.26,27 Furthermore, this recovery time limited the burden for patients and HC by combining the fasted and postprandial barostat measurements with a fixed order of experiments (i.e., first fasted, then postprandial). This allowed us to test a large group of patients.

Currently, barostat examinations are not used ubiquitously as routine procedures in the work-up of patients with IBS to determine visceroperception. Visceral hypersensitivity, however, is considered a biomarker for at least a substantial subgroup of IBS patients but the postprandial condition does not facilitate higher discrimination between IBS patients and HC.

In conclusion, the results obtained by this study indicate that ingestion of a liquid meal modulates visceral perception in IBS. Meal ingestion prior to a barostat measurement induces different responses in IBS patients compared to healthy subjects. However, it does not increase the diagnostic yield of the barostat measurement to detect visceral hypersensitivity in the individual IBS patient. The majority of the IBS patients with postprandial hypersensitivity have shown to be already hypersensitive under fasting conditions.

When searching for biomarkers for IBS and diagnostic tools to detect altered visceroperception in IBS in clinical practice, it is important to be able to detect hypersensitivity by a short lasting, standardized, accurate, and preferably physiologic test procedure. Future research should focus on optimizing a test for the assessment of visceral hypersensitivity.

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References

SL performed measurements, analyzed data, and wrote manuscript; JMC recruited patients and wrote manuscript; DK analyzed data; CJK performed measurements; SAV performed measurements; PJL was responsible for statistical modeling; AML wrote protocol and performed measurements; JWK recruited patients; DMJ supervised data analyses and wrote manuscript; AAM was the initiator of the trial, supervision of protocol and writing manuscript and Head of research collaboration.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Competing Interests
  9. References
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