Introduction
Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract, primarily characterized by abdominal pain and constipation in the absence of an organic disease. 1 Prevalence is reportedly 5–11% in most developed countries. 2 Epidemiological research on IBS in Japan has found the disease to be most common in men and women in their 20s (14% and 22%, respectively). 3 Notably, its incidence dramatically increases in Japanese youths in their late teenage years; it has been reported to affect 21–26% of university students. 4-5 IBS negatively affects an individual's quality of life (QOL), and it has a substantial impact on healthcare costs. 6-7 Its pathology can be divided into three major categories: gastrointestinal dysmotility, 8-9 hypersensitivity to visceral sensations, 10-11 and abnormal psychology. 12-14 The third cate- gory refers specifically to anxiety-related symptoms due to Address correspondence: Susumu SHIRABE, Center for Health and Community Medicine, Nagasaki University, Nagasaki-shi, Bun- kyo-machi 1-14, Nagasaki 852-8521, Japan Tel.: +81-95-819-2214, Fax: +81-95-819-2215, Email: shirabe@nagasaki-u.ac.jp Received September 19, 2017; Accepted December 28, 2017
Participants
There were 1300 respondents in total. We focused on students begning first year at young university student be- tween 2012-2013. Study exclusion criteria were as follows: aged 26 years or older (N =17), (2) not having Japanese as their first language (N = 51), (3) incomplete or not responses at questionnaires (N = 76). This resulted in data from 1156 students (mean age 18.9 ± 0.9 years) being analyzed; of these, 237 (21%) met Rome III criteria for a diagnosis of IBS (male: N = 79, female: N = 158).
Measures
(Note: This study used the Japanese versions of all measures listed below.) Rome III Modular Questionnaire The Rome III modular questionnaire is a self-report as- sessment tool developed to screen patients for IBS according to Rome III criteria. 22 For a diagnosis of IBS, the Rome III criteria stipulate that a person must have (a) recurrent abdominal pain or discomfort for at least three days per month in the last three months, along with at least two of the following: (b) improvement of pain or discomfort with defecation, (c) symptom onset associated with change in defecation frequency, or (d) onset associated with change in stool form or appearance. The reliability and validity of this instrument has been verified. In the present study, participants whose questionnaire responses indicated they met Rome III criteria were treated as having IBS ("IBS-positive").
Visceral Sensitivity Index (VSI)
The VSI is a 15-item scale used to measure GSA. 18 Re- spondents rate the applicability of each item on a six-point scale, from 1 (strongly agree) to 6 (strongly disagree). All items are then reverse-scored (0–5 points) and summed: scores range from 0 points (no GI-specific anxiety) to 75 points (severe GI-specific anxiety).
IBS Severity Index (IBS-SI)
The IBS-SI is a self-report scale for assessing the severity of gastrointestinal symptoms associated with IBS. 23 It is a 5-item scale, and overall scores can range from 0 to 500 points. Symptom severity is classified as subclinical (0 to 74 points), mild (75 to 174), moderate (175 to 299), or severe (300 to 500). psychosocial stress experienced by IBS patients, which cause gastrointestinal symptoms to worsen. 15-16 This exacer- bation of gastrointestinal symptoms can be attributed to elevated gastrointestinal-specific anxiety (GSA), which can be measured using the visceral sensitivity index (VSI). 17-18 GSA is defined as "the cognitive, affective, and behavioral response to fear of gastrointestinal sensations, symptoms, and the context in which these visceral sensations and symp- toms occur." 17 GSA is associated with hyperactivity of the amygdala. 19-20 This brain region is activated via the insular cortex, the prefrontal cortex, and the anterior cingulate gyrus, leading to exacerbated gastrointestinal symptoms. 20 When individuals with IBS perform avoidance behaviors in response to situations that elicit GSA, they exhibit hyper- vigilance and attentional bias toward visceral sensations, and become sensitive to even low-level stimuli. 21 Research to date suggests that GSA contributes to both the onset and symptomatic exacerbation of IBS, but this rela- tionship has never been sufficiently investigated in university students, a population whose age puts members at particular risk for developing IBS. One instrument for measuring GSA is the VSI. This scale can measure psychological dysfunction in IBS patients, and can also provide an endpoint for assessing the efficacy of IBS treatment. The present study investigates whether GSA is a risk factor for developing IBS, and whether it is associated with IBS symptom severity in university students. This study explored the following two hypotheses: Hypothesis 1. GSA is a risk factor for IBS. Hypothesis 2. GSA is associated with more severe IBS symptoms. Our findings suggest the importance of GSA as both an intervention target and an endpoint when evaluating IBS- related therapies, making it relevant in terms of both IBS symptoms and QOL.
Materials and Methods
Procedure
Questionnaire surveys were administered to university students during lecture classes from May 15, 2012, to Nov. 22, 2013. Participation was voluntary, and participants were not randomly selected. Consent was obtained after the purpose of the study and ethical considerations were explained verbally. Students were also verbally informed that non-participation would not result in any academic or other disadvantage. Only responses from students who provided consent were included in analysis.
Hospital Anxiety and Depression Scale (HADS)
The HADS is a 14-item self-report scale developed to assess anxiety and depression severity in patients with phys- ical symptoms. 24 It consists of an anxiety and a depression subscale (HADS-A and HADS-D, respectively), containing seven items each. Respondents answer each item on a four- point scale ranging from 0 to 3. HADS-A and HADS-D subscale scores range from 0 to 21 points. The optimal cut-off points as 'caseness' was defined a score of 8 or greater on both HADS-A and HADS-D. 25
Ethics
This study was conducted with the approval of the Ethics Committee of the Nagasaki University Graduate School of Biomedical Sciences, the research institution of the principal investigator (approval number: 12053008).
Data analysis
Statistical analysis was performed using SPSS 20.0 for Windows. Basic statistics are presented as mean ± standard deviation (SD), median, and interquartile range (IQR). The normally distributed of VSI was rejected by the Shapiro- Wilk normality test ( p < 0.05). Therefore, Wilcoxon signed- rank test and chi-squared test were used to determine to significance for between IBS-positive and IBS-negative group differences. Wilcoxon signed-rank test and chi-squared test were applied for continuous and categorical variables, respectively. In addition, ROC analysis was performed to determine a cut-off score for the VSI, in order to ascertain the presence or absence of associations between GSA and IBS status. The optimal cut-off points of VSI determined that is calculated a maximum value of Youden index (sensi- tivity + (specifity-1)). 26 The Youden index, which maximizes the vertical distance from line of equality to the point on the receiver operating characteristic curve, was used to find the optimal threshold points. Next, several multiple logistic re- gression analyses were conducted using this cut-off value to examine whether students with VSI scores above the cut-off were at greater risk for having IBS or for having more severe IBS symptoms. Odds ratio (OR), 95% confidence intervals (CIs) and p value were calculated using logistic regression analysis. Statistical significance was defined as p < 0.05.
Results
Demographic data of participants are listed in Table 1. The mean age was not significance between IBS-positive and IBS-negative group ( z = -1.22, p = 0.219). The prevalence of IBS as defined by the Rome III questionnaire was 21%. Chi-squared test showed that the portion of female was higher than male in the IBS-positive group, while the portion of female was lower than male in the IBS-negative group (x 2 = 61.09, df = 1, p < 0.001). Wilcoxon signed-rank test showed that IBS-positive individuals had significantly higher mean scores on the VSI (z = 9.12, p < 0.001), IBS-SI (z = 12.69, p < 0.001), and HADS-A (z = 9.12, p = 0.014) than IBS-nega- tive participants. No significant difference was observed between the groups' mean HADS-D scores ( z = -0.86, p = 0.385). Figure 1 shows the results of ROC analysis. The probability of being classified as IBS-positive was associated with a score of 16 or greater on the VSI, with a corresponding sen- sitivity of 0.63, a false positive rate (i.e., 1 - specificity) of 0.33, and an AUC of 0.69. In addition, maximized Youden index (J = 0.296) showed that optimal cut-off was 16 on the VSI score. Multiple logistic regression analysis was conducted with GSA severity (i.e., VSI score above ("high GSA") or below ("low GSA") the cutoff value) as the independent variable, and provisional IBS diagnosis (as described in the Methods section) as the dependent variable. Results are shown in Table 2. The crude OR for being IBS-positive among par- ticipants in the high GSA group was 3.40 (95% CI: 2.37– 4.33) versus the low GSA group, which means that students with a VSI score above the cutoff value were at significantly greater risk for having IBS. The same analysis was then performed again, with age, sex, IBS-SI, HADS-A and HADS-D subscores as moderator variables. Results revealed that students with high GSA were at significantly greater risk of having IBS, with an adjusted OR of 2.64 (95% CI: 1.87– 3.71). Next, multiple logistic regression analysis was conducted with IBS symptom severity (i.e., subclinical, mild, moderate, or severe, based on IBS-SI score) as the independent vari- able, and GSA severity (i.e., high or low GSA, based on VSI score) as the dependent variable. Results are shown in Table 3.The crude OR for high GSA in the relation to each classi- fication of the IBS symptoms were as follows: 0.32 (95% CI: 0.24-0.41) for subclinical, 1.06 (0.90–1.46) for mild, 3.09 (2.28-4.21) for moderate, and 7.33 (3.00-17.91). The same analysis was then run again, this time introducing age, sex, IBS status, HADS-A and HADS-D subscores as moderator variables. The corresponding adjusted odds ratios for clas- sification of the IBS symptoms were 0.44 (95% CI: 0.33- 0.58) for subclinical, 1.15 (0.90–1.46) for mild status, 2.19 (1.57–3.07) for moderate status, and 5.63 (2.24–14.15) for severe status, indicating that a high VSI score is associated with more severe pathology in IBS symptoms.
Abbreviations: SD = standard deviation; IQR = interquartile range; IBS =irrtable bowel syndrome; VSI = visceral sensitivity index; IBS-SI = irritable bowel syndrome severity index; HADS-A and HADS-D = subscale of the hospital anxiety and depression scale. Sensitivit 140
gastrointestinal symptom-specific anxiety; High GSA (VSI score of ≥ 16 points); Low GSA (VSI score of ≤ 15 points); IBS-SI = irritable bowel syndrome severity
Note: *OR adjusted for age, sex, IBS status, HADS-A and HADS-D. Abbreviations: CI = confidence intervals; OR = odds ratio; IBS = irritable bowel syndrome; GSA = gastrointestinal symptom-specific anxiety; High GSA (VSI score of ≥ 16 points); Low GSA (VSI score of ≥ 15 points); IBS-SI = irritable bowel syndrome severity index; Subclinical, Mild, Moderate, and Severe = classification of IBS severity; HADS-A and HADS-D = subscale of the hospital anxiety and depression scale.
Discussion
We consider the hypotheses of the present study in turn. Hypothesis 1 was supported: students with a VSI score above the ROC cutoff value were more likely to have IBS than students with a score below it. Hypothesis 2 was also supported: students with a VSI score above the ROC cutoff value were at risk for symptomatic exacerbation of IBS symptoms. A discussion of the research findings supporting these two hypotheses follows. Previous studies have shown that IBS patients can experi- ence worsening gastrointestinal symptoms not only due to exogenous, psychosocial stress, but also due to endogenous stress triggered by GSA. 20 The present study demonstrated that GSA may act as a psychological stressor in university students, as well, resulting in exacerbation of gastrointestinal symptoms. This finding supports the hypothesis of a previous study, which focused on developing the VSI as an instrument capable of measuring GSA. 17 Moreover, our findings show that university students with VSI scores above the proposed cut-off value are more likely to have IBS than students with scores below this value. This trend was significant, and per- sisted even after controlling for anxiety and depression se- verity, as measured by the HADS. These findings indicate that the GSA may be a promising therapeutic marker when treating IBS in university students. In one human study, IBS patients exhibited stronger acti- vation of emotion-related brain regions associated with visceral sensations following colonic stimulation using a barostat than healthy adults. 11 , 27 - 28 In addition, when IBS patients perform avoidance behaviors in response to situa- tions that elicit GSA, they exhibit hypervigilance and atten- tional bias towards visceral sensations, and become sensitive to even low-level stimuli. 21 This creates a vicious cycle: the repeated appearance of gastrointestinal symptoms elicits anxiety, which in turn further exacerbates symptoms, and so on. We hope that the results of the present study will lead to GSA being included as a treatment endpoint in more inter- ventions, whether they involve pharmacological treatments or non-drug approaches, such as behavioral, psychological, and nutritional therapies. Notably, recent years have seen psychotherapy, specifically cognitive-behavioral therapy, conducted with the goal of reducing GSA. Reports on cogni- tive-behavioral therapy to date have confirmed the approach to be effective in reducing GSA and in improving gastroin- testinal symptom severity and QOL. 30-31 Three limitations of the present study should be noted. The first is that this study was conducted at a single institution, a university located in a medium-sized city in Kyushu, in western Japan. Generalizability of findings is thus limited. The second is that this was a questionnaire-based study. Because IBS diagnoses were not made or confirmed by phy- sicians, it is possible that the disease was over-diagnosed. The third limitation is that as a cross-sectional survey, cause- effect relationships cannot be inferred from our results. In conclusion, our findings indicate that people with elevated GSA—specifically, a score of 16 points or higher on the VSI—are more likely to have IBS, as well as more severe gastrointestinal symptoms.
Acknowledgments
We would like to express our gratitude to the participants of the present study. This study was supported by the Center for Health and Community Medicine at Nagasaki University and the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number 15K21234).
Disclosure Statement
All authors declare that they have no conflicts of interest.
Reference
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