Characteristics of disorders of gut– brain interaction in the Japanese population in the Rome Foundation Global Epidemiological Study

Background: The aims were to use Japanese data from the Rome Foundation Global Epidemiological Study (RFGES) to test the hypotheses that severity of gastrointestinal (GI) symptoms and psychosocial disturbance are ordered as Rome IV irritable bowel syndrome (IBS) > Rome III IBS > DGBI, not IBS > others. Methods: Subjects were 2504 Japanese in the RFGES. We assessed DGBI/IBS diagnoses with Rome IV/III, IBS Symptom Severity Scale (IBS- SSS), Patient Health Questionnaire (PHQ) for anxiety/depression and non- GI somatic symptoms, PROMIS- 10 for quality of life (QOL), Work Productivity and Activity Impairment (WPAI) Questionnaire, parts of Self- reported IBS Questionnaire (SIBSQ) for meal effect and stress effect, Food Frequency Questionnaire, and medication questions. Key Results: The prevalence of Rome IV DGBI was as follows; IBS- C 0.5%, IBS- D 0.8%, IBS- M 0.8%, IBS- U 0.1%, unspecified functional bowel disorder 10.7%, postprandial distress syndrome 2.2%, and epigastric


| INTRODUC TI ON
Irritable bowel syndrome (IBS) is one of the representative disorders of gut-brain interaction (DGBI) 1 with a high societal burden. 2 At the present, IBS is defined by the Rome IV diagnostic criteria, which require persistent or recurrent abdominal pain associated with two or more of the following: symptomatic changes by defecation, changes in frequency of defecation, and/or changes in stool form. 3 4 IBS places a significant financial burden on employers and society due to increased direct and indirect costs compared with the control population. 5 Moreover, as a prevalent and common disorder, IBS is highly researched. 4 The Rome Foundation Global Epidemiological Study (RFGES) is the most reliable epidemiological study on DGBI to date because it is a multinational study, conducted simultaneously with identical methodology using the latest iteration of the diagnostic criteria (Rome IV). 6,7 The results of the RFGES indicated that the world prevalence of IBS is 4.1% with Rome IV criteria and 10.1% with Rome III criteria. 6 Important changes in the Rome IV criteria 3 from the Rome III criteria 8 are that abdominal pain (rather than abdominal pain or discomfort) must be present for a diagnosis of IBS and that abdominal pain must occur at least once per week. By contrast, patients with abdominal discomfort only or with abdominal pain three times per month can be diagnosed as IBS using the Rome III criteria. 8 Cases that would have met Rome III criteria for IBS but do not meet Rome IV criteria are now frequently classified as unspecified functional bowel disorder (FBD), functional constipation or functional diarrhea. 9 The impact and merit of these changes in diagnostic criteria from Rome III to Rome IV has not been studied in depth.
In Japan, we previously reported that surrogate Rome IV IBS-C subjects felt a significantly higher degree of anxiety in their daily lives compared with Rome III IBS-C subjects. 10 A group of 20-to 49-year-old female surrogate Rome IV IBS-C subjects felt a higher degree of anxiety in their daily lives than their Rome III IBS-C counterparts. 10 However, there were many limitations in the previous study. The survey was based on the Rome III Diagnostic Questionnaire. Data were limited to IBS-C only and the anxiety questionnaire was not validated. The Japanese sample in the RFGES database is ideal to rectify the methodological problems in the previous report. In the first RFGES paper published, only partial Japanese DGBI data were shown including Rome IV prevalence rates of 2.2% for IBS, 16.6% for functional constipation, 5.2% for functional diarrhea, 1.2% for functional bloating/distention, 2.4% for functional dyspepsia, and 39.4% for having any DGBI, as well as a prevalence of IBS of 9.3% with Rome III criteria. 6 The Japanese IBS prevalence rate was lower compared to that of most other countries in the RFGES. Further analyses of Japanese DGBI data were not reported. Therefore, a more detailed report of IBS and other DGBI in Japan is invaluable.
The aim of this study was to conduct a precise assessment of DGBI in Japan using the Japanese subset of the RFGES database and to verify the following novel hypotheses: (1) severity of gastrointestinal (GI) symptoms and psychosocial disturbance are ordered as Rome IV IBS > Rome III IBS > other DGBI > all others; (2) Rome IV IBS has a strong association with psychosocial disturbance, and (3) the prevalence of DGBI is geographically homogenous in Japan.

| Study population
The study population was the subset of Japanese participants in the RFGES from which global data were previously published. 6,7 In brief, the minimum sample size from the Japanese general population was estimated as 2500 to better balance the sex ratios within age groups.
The pre-defined demographic parameters were 50% females and 50% males, and an age distribution of 40% for 18- • The data provide support for Rome IV IBS as a typical gut-brain disorder, but compared to Rome III-IBS the Rome-IV IBS diagnostic criteria may exclude clinically important cases.

| Survey
Details of the survey methods have already been published. 6,7 In brief, an internet survey was performed using survey participants recruited by a professional company (Qualtrics, LLC.) in November and December 2017. The survey was anonymous, nationwide, and had built-in quality-assurance measures to exclude poor-quality responders, including two attention-check questions, a completionspeed check, and repeated questions to detect inconsistent responders. The software ensured that there were no missing answers to compulsory questions, and had automated skip patterns, resulting in complete and accurate symptom pattern information. In the present analyses, the items in Table 1 were used. 11-20

| Evaluation of DGBI phenotypes and IBS characteristics
All individuals in the survey sample were diagnosed as having or not having DGBI based on the Rome IV criteria, 3,11 with those reporting a history of organic diagnoses excluded from DGBI diagnoses based on the same procedure as used in previous reports. 6,7 Rome III IBS 8,12 and its subtypes were identified independently. The remaining subjects were with organic diagnoses and/or history and without suprathreshold GI symptoms (all others). The four groups for verifying Hypothesis 1 were set after the exclusion of subjects with organic diagnoses and/or history as follows: Rome IV IBS, Rome III IBS without overlapping diagnosis of Rome IV, other DGBI without IBS, and all others. The severity of IBS was assessed with IBS-SSS. 14,15

| Statistical analyses
Data were analyzed with the Statistical Package for Social Science (SPSS) version 27.0 (IBM Japan) and SAS 9.4 (SAS). Data were summarized with actual numbers, prevalence, 95% confidence interval (CI). The four groups were compared with one way analysis of variance (ANOVA) with the post hoc test, Kruskal-Wallis test, χ 2 -test, or Fisher's exact test, as appropriate. Japanese regional differences in IBS/DGBI diagnoses were analyzed by cross- was performed to examine IBS-SSS and associated risk factors. A p-value less than 0.05 was regarded as significant.

| RE SULTS
Some of the data in this paper have already been reported in previous RFGES papers. 6,7 This is inevitable since the original paper included a broad range of descriptive statistics for all countries (n = 33) and all DGBI (n = 22). Other papers, including the present one, which use the same database, are reporting in-depth analyses for countries, disorders, and methods, and these include a brief overview of some specific data previously reported.

| Rome IV DGBI other than IBS
The prevalence rates of the other DGBI appear in Table 3. Among the Rome IV diagnoses other than IBS, there was significant female predominance in functional constipation (p < 0.001), unspecified functional bowel disorder (p = 0.028), postprandial distress syndrome (p = 0.027), and functional dysphagia (p = 0.014). Conversely, significant male dominance was seen in functional diarrhea (p < 0.001). The prevalence rates were significantly higher in younger subjects for functional constipation (p < 0.001), functional dyspepsia (p < 0.001), functional chest pain (p = 0.023), and reflux hypersensitivity (p = 0.033).

| Geographic distribution of IBS and other DGBI
There was no difference in the prevalence of Rome IV or III IBS, including subtypes, among the seven regions in Japan (Hokkaido, Tohoku, Kanto, Chubu, Kinki, Chushikoku, and Kyushu) ( Figure 1).

| Difference among Rome IV IBS, Rome III IBS, other GI symptoms, and controls
We identified 54 subjects with Rome IV IBS and 233 subjects with Rome III IBS ( Figure 2 Table 4).

| DISCUSS ION
This is the first country-specific report on the prevalence of IBS and other DGBI by Rome IV criteria in Japan, based on the database of the RFGES. Although many previous reports have been published on the epidemiology of IBS in Japan, including from our group, 16,[21][22][23][24][25][26][27] only a few reports were community-based. Sperber et al. 28 31 and this rate was also high for Rome III-IBS. The differences between men and women were less pronounced in the other Asian countries. 32 We showed previously that many features of IBS in Japan are different from those in other Asian countries. 33   small, this may be due to a type II error. Japan is relatively homogenous in terms of the characteristics of DGBI.

R
The strengths of this study are its highly reliable epidemiological design, 6 the multinational, global database which enables more extensive comparisons and replication of data, and multiple domain measurements. 7 The results support the rationale for the change from Rome III 8 to Rome IV 3 diagnostic criteria, especially for research. Second, the relatively low prevalence rate for Rome IV IBS in Japan could imply that the diagnostic criteria are too restrictive for use in regular GI practice.
There are some limitations to this study. First, it is an internet survey in which there could be selection bias even though the participants were randomly selected. Second, the findings were limited to Japan. It would be of great interest to test these same hypotheses using data from the other countries. In conclusion, the results of the study support the first, second, and third hypotheses. Data from Japan, a culturally homogenous country, suggest that the Rome IV diagnostic criteria for IBS select individuals who have greater disease severity, and hence, more gutbrain psychobehavioral involvement than those meeting the diagnostic criteria for Rome III IBS.

D I SCLOS U R E S
All authors declare no conflict of interest on this study.