The national prevalence of disorders of gut brain interaction in the United Kingdom in comparison to their worldwide prevalence: Results from the Rome foundation global epidemiology study

There are minimal epidemiological data comparing the burden of disorders of gut brain interaction (DGBI) in the UK with other countries. We compared the prevalence of DGBI in the UK with other countries that participated in the Rome Foundation Global Epidemiology Study (RFGES) online.


| INTRODUC TI ON
The Rome Foundation Global Epidemiological Study (RFGES) spanning six continents provided the most comprehensive worldwide data on the prevalence of all 22 Rome IV disorders of gut-brain interaction (DGBI). 1 The global prevalence of these disorders was found to be high, with 40.3% of participants meeting criteria for at least one DGBI. 1 Aside from the overall global prevalence of DGBI and their interactions and overlap, the original study has, importantly, captured data on the burden and impact of these conditions with data on healthcare utilization and impact on quality-of-life worldwide. These data have not only been important in raising awareness of just how prevalent DGBI are on a worldwide scale but have also provided unique opportunities to understand how the prevalence of DGBI may vary amongst countries, and examining sociodemographic factors that may contribute to epidemiological differences, including dietary practices. The first country-level analysis of the RFGES dataset provided detailed national prevalence data for all 22 DGBIs in Israel, and compared the prevalence, healthcare utilization, and quality-of-life data with the other 25 countries that completed the questionnaire using the same Internet-based methodology. 2 However, to our knowledge, no studies have previously compared the epidemiology of DGBI in the UK with their epidemiology worldwide.
In the UK, despite DGBI accounting for a significant proportion of gastroenterology outpatient workload, 3 and substantial direct financial costs estimated to be between £1.3 and £2 billion for irritable bowel syndrome (IBS) alone, 4 these chronic disorders are given low priority in the gastroenterology training curriculum, [5][6][7] are of limited priority for research funding, 8 and there are only a few specialized centers nationally that offer integrated multidisciplinary care for DGBI, despite this being recognized increasingly as the standard of care. 9 Recently updated evidence-based national DGBI guidelines from the British Society of Gastroenterology on IBS and functional dyspepsia (FD) have emphasized the role of making positive diagnoses, and use of sequential first-, second-, and third-line therapies, IV DGBI, including irritable bowel syndrome (4.3%) and functional dyspepsia (6.8%), was similar to the other countries. Fecal incontinence, opioid-induced constipation, chronic nausea and vomiting, and cannabinoid hyperemesis (p < 0.05) were more prevalent in the UK. Cyclic vomiting, functional constipation, unspecified functional bowel disorder, and proctalgia fugax (p < 0.05) were more prevalent in the other 25 countries. Diet in the UK population consisted of higher consumption of meat and milk (p < 0.001), and lower consumption of rice, fruit, eggs, tofu, pasta, vegetables/ legumes, and fish (p < 0.001).

Conclusions and Inferences:
The prevalence and burden of DGBI is consistently high in the UK and in the rest of the world. Opioid prescribing, cultural, dietary, and lifestyle factors may contribute to differences in the prevalence of some DGBI between the UK and other countries. with an emphasis on developing multidisciplinary services, including trained dietitians and behavioral gut-brain therapists. 10,11 Although recent data from Australia suggest that the development of integrated multidisciplinary services is likely to be more cost-effective and efficacious compared with gastroenterologistonly care, 12,13 there are a lack of detailed national epidemiological data on DGBI in the UK in comparison with other countries. Such data would improve the understanding of the national epidemiology and impact of DGBI in the UK in comparison with other countries, and to understand population-specific factors that may influence prevalence, treatments, and outcomes. Detailed UK epidemiological data would therefore be of importance in planning future service development, including resource allocation on a national level to provide the standards of care recommended in the recently published national guidelines.
The aims of this study, therefore, were to compare the burden and prevalence of DGBI in the UK with that in the other 25 countries that participated in the online part of the RFGES. We also aimed to compare factors that may influence DGBI prevalence between the UK and other countries, including dietary intake, socioeconomic, sociodemographic, and demographic factors.

| Data collection
The UK was one of the 26 countries in the RFGES where data were collected by an anonymous Internet survey. The methodology for the RFGES has been described in depth elsewhere. 1

| Study populations
The participants from all 26 countries were selected based exclusively on demographic characteristics as defined in the prespecified study parameters, which included at least 2000 participants, 50% female participants and 50% male participants, with 40% aged 18-39 years, 40% aged 40-64 years, and 20% aged 65+ years, with a representative national geographic distribution. The survey had multiple built-in quality-assurance measures to exclude poor-quality responders and minimize the risk of missing data or incorrect values. The electronic questionnaire included electronic informed consent. Ethical review was completed for all countries taking part in the RFGES, and formal ethical approval was waived for the UK and for the other Internet countries by the internal review board of the University of North Carolina at Chapel Hill, the United States, where the data collection was coordinated, as the data collected were totally anonymous to investigators with no means of identification in the present or future.

| Study questionnaire
The study questionnaire included the entire Rome IV Adult Diagnostic Questionnaire, 14 18 In terms of dietary intake, participants from all 26 countries were asked on their frequency of intake of 10 food types (rice, milk, eggs, bread, pasta, meat, fruits, tofu, vegetables/legumes, and fish).
Intake of each of these types of food was assessed in terms of average days per week of consumption. For the purposes of further analyses, food consumption was categorized into three categories based on frequency of intake of these food types: "don't eat" (participants that do not consume this food type at all), "eat some" (those that consumed the food type 1-3 days per week), and "eat often" (those that consume the food type ≥4 days per week).

| Adjusting for possible organic disease
Consistent with the approach taken in the previously published RFGES papers, 1,2 individuals with known organic gastrointestinal disease were excluded from meeting the criteria for a DGBI in this study. To reduce the chances of overestimation of the prevalence of DGBI, participants were asked whether they had ever been diagnosed by a doctor with any of a list of organic gastrointestinal diseases or had undergone bowel resection. Respondents with celiac disease, gastrointestinal cancer, or inflammatory bowel disease (Crohn's disease or ulcerative colitis) were excluded from all Rome IV DGBI diagnoses. Patients with peptic ulcer disease were excluded from esophageal, gastroduodenal, and biliary diagnoses. Finally, subjects with a history of diverticulitis or bowel resection were excluded from diagnosis of bowel and anorectal disorders. 1 Those who were disqualified for a DGBI were kept in the study analyses as participants who did not meet diagnostic criteria for DGBI. The proportion of participants excluded from DGBI eligibility due to having a known organic GI condition was similar (2.6% in the UK cohort vs. 2.9% in the other 25 countries).

| Statistical methods
Descriptive statistics and a z-test for the prevalence of each of the 22 DGBI and "any DGBI" were reported. Prevalence rates were pooled across the other 25 countries using the Yang's meta-prevalence method. 19

| RE SULTS
Some of the data in this paper have already been reported in previous RFGES papers. 1,2 This is inevitable since the original paper included a broad range of descriptive statistics for all countries (N = 33) and all DGBI (N = 22). 1 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. Overall, the number of participants in the UK was 2027 and 52,100 in the other 25 countries, with almost identical gender distributions in both groups (Table S1).

| Sociodemographic factors
There were some sociodemographic differences between the UK survey sample and the other 25 countries surveyed, which are likely to be representative of UK national sociodemographic. The UK sample included more participants in the older age bracket, with fewer 18-to 39-year-olds compared with the other 25 countries pooled (Table S1). There were also population-specific differences in religious beliefs, marital status, type of area lived in, and education status in the UK population, compared with the 25 countries pooled together (Table S1).

| Overall DGBI prevalence for the UK and the other 25 countries pooled together
The prevalence rate of having any DGBI and each of the 22 DGBI in the UK, compared with the pooled prevalence in the other 25 countries, is presented in Table 1 and Figure 1. The overall prevalence rate of having a DGBI in the other 25 countries pooled was higher at 41.2% (95% CI 40.8%-41.6%) compared with 37.6% (95% CI 35.5%-39.7%) in the UK (p = 0.001). Prevalence rates for having at least one DGBI were similar across all geographical regions within the UK ranging from 31.9% in Southeast England to 42.1% in the Midlands ( Figure 2).
In the UK, 64.4% of those with a DGBI met diagnostic criteria for only one DGBI, while 35.6% met diagnostic criteria for a DGBI in two, three, or four anatomic GI regions ( Figure 3A). Similarly, in the other 25 countries, 66.9% met diagnostic criteria for only one DGBI, while 33.1% met diagnostic criteria for DGBI in two, three, or four anatomic regions ( Figure 3B).

| DGBI with similar prevalence in the UK compared with the other 25 countries pooled together
The prevalence of 14 of the 22 DGBI was similar between the UK and the other 25 countries pooled together ( Table 1). Disorders of gut brain interaction with similar prevalence included IBS, which had a UK prevalence of 4.3% (95% CI 3.4-5.2%) compared with 4.5% (95% CI 4.3%-4.7%) in the other 25 countries pooled ( Figure 4A).
There were very few cases of either centrally mediated abdominal pain or functional biliary disorders in all 26 countries, with no differences in prevalence between the UK and the 25 countries pooled (Table 1).

| DGBI with different prevalence in the UK compared with the other 25 countries pooled together
Chronic nausea and vomiting, cannabinoid hyperemesis, opioidinduced constipation, and fecal incontinence were more prevalent in the UK compared with the 25 countries pooled (Table 1). By contrast, cyclic vomiting, functional constipation, unspecified functional bowel disorder, and proctalgia fugax had a higher prevalence in the 25 countries pooled (Table 1).

| DGBI prevalence rates in the UK and the other 25 countries pooled together by anatomical region
In the UK and the 25 countries pooled, bowel disorders were the most prevalent DGBI, followed by gastroduodenal disorders, anorectal disorders, and then esophageal disorders (Table 1). Overall, esophageal DGBI were more prevalent in the UK, whereas bowel DGBI had a higher pooled prevalence in the other 25 countries (Table 1 and Figures S1 and S2). However, the UK prevalence of gastroduodenal and anorectal disorders did not differ (Table 1).

| Distribution of IBS and FD subtypes in the UK and the other 25 countries pooled together
Overall IBS and FD prevalence and subtype prevalence rates were similar between the UK and the 25 countries pooled (

| Comparison of IBS severity between the UK and the other 25 countries pooled together
Irritable bowel syndrome severity in the UK tended to be higher than most other countries surveyed and was ranked third highest amongst the 26 countries surveyed in terms of severity, only be-

| Dietary intake in the UK compared with the other 25 countries pooled together
Food pattern and frequency varied between the UK and the 25 countries pooled for all 10 food groups that were surveyed (summarized in Table S2 and Table 3). Frequent milk and meat consumption was higher amongst UK participants. Whilst frequent rice, eggs, tofu, and pasta intake were more common dietary constituents in the other 25 countries (Table 3). A higher proportion of UK participants reported not eating vegetables, legumes, and fruits at all; meanwhile, moderate vegetable, legumes, and fruit consumption was higher amongst participants from the other 25 countries (Table 3). Fish consumption frequency is also different in the UK, with a higher proportion of UK participants reporting that they "never" eat fish, and a lower proportion in the UK reporting that they eat fish ≥4 days per week.

| The burden of DGBI in the UK and the other 25 countries pooled together
Meeting diagnostic criteria for any DGBI in the UK was associated  (Table 4).

| DISCUSS ION
This study has provided the most comprehensive evaluation of the   26 The current data are also consistent with another study, which has shown that Rome IV opioid-induced constipation prevalence is higher in the UK compared with the USA and Canada. 27 Taken together these data, therefore, highlight the need to raise awareness of the hazards and lack of benefit for opioids for the treatment of chronic noncancer pain. The findings also support an increasing body of evidence within gastroenterology that opioids can be detrimental for chronic pain resulting in hyperalgesia and adverse outcomes. 28 Chronic nausea and vomiting, in addition to their association with cannabis use disorder, are also known gastrointestinal symptoms related to opioid use. These current data will therefore be valuable in raising awareness of opioid-induced bowel dysfunction, which is more common in the UK than the rest of the world. Fortunately, there are several peripherally acting mu-opioid antagonists now available, and recent international evidence-based clinical practice recommendations. 29 Therefore, with early recognition and intervention, leading to a safe reduction and replacement of opioids, effective symptomatic treatment can be achieved for these patients.
Although the exact reasons why four other DGBI including fecal incontinence and proctalgia fugax had a different prevalence in the UK compared with the other 25 countries are unclear, there are several sociodemographic factors identified in this study that may have influenced this variance and will, therefore, be discussed in detail.

TA B L E 4 (Continued)
Notably, the UK population surveyed, consisted of a slightly higher proportion of patients in the older age group categories compared with the other 25 countries, which may have contributed to the increased prevalence rate of fecal incontinence, and the lower prevalence of bowel DGBI, which tend to be more prevalent in younger individuals. Interestingly, two "non-IBS" bowel DGBI, namely functional constipation and unspecified functional bowel disorder, were amongst the disorders that were more prevalent in the other 25 countries pooled, when compared with the UK. The clinical importance of these less specific bowel disorders is debatable, and it has recently been suggested that these disorders are part of a less severe spectrum of IBS. 30 One important factor that may account for some of the variance in bowel disorder prevalence is dietary intake. To the authors' knowledge, this is the first DGBI epidemiology study that has compared food intake between the UK and other countries. The role of dietary intake in contributing to gastrointestinal symptoms is being appreciated increasingly in DGBI. 31 It is therefore interesting that there were differences in food intake of all 10 food groups surveyed between the UK and the rest of the world. British diets consisted of lower rice intake, more regular milk and meat consumption, less frequent pasta consumption, and differences in the frequency of egg,  Figure 2) build a strong case for the development of cost-effective models of multidisciplinary integrated care throughout the UK, with access to specialist medical, dietetic, and gut-brain behavioral therapies as per the British Society of Gastroenterology guidelines. 10,11 The reasons for higher IBS severity amongst men in the UK compared with the rest of the world are unclear and merit further study. It has been hypothesized that there are sex-specific differences in the presentation of IBS, but very few studies have assessed this. 45,46 Despite IBS being considered a benign condition, a recent UK study has shown that men with IBS are willing to accept a median 5% risk of death in return for a chance of a permanent cure. 47 The median accepted risk of death was higher in men, those with more severe IBS symptoms, depression, and a poorer IBS-related quality of life. 47 Put into context, although our study confirms that the prevalence of IBS in males in the UK is almost three times lower than the prevalence in females, IBS is still common in males, accounting for As in the original RFGES study, 2 although efforts were made to adjust for organic gastrointestinal diagnoses, participants in the 26 countries were not seen by clinicians or providers prior to inclusion.
Hence, undiagnosed organic DGBI mimics may not have been excluded, although their prevalence will be lower than most DGBI, and therefore, the RFGES provides a close approximation of the true prevalence of DGBI in the community. There were several other limitations. First, we have described differences between the UK and the other 25 Internet countries, which follows the approach of Sperber et al. 2 This enables easier comparison with previous work.
However, an alternative approach would have been to consider characteristics by country as was undertaken for the forest plots of DGBI using multilevel modeling. The emphasis here, however, is the contrast between the UK and other countries. Second, a similar number of participants from each participating nation were re- is protective against experiencing symptoms of DGBI. Finally, despite the age-matched inclusion criteria in the protocol, UK participants were slightly older than participants in the other 25 countries, and although this may be reflective of the national demographic, we cannot exclude the possibility that this may have influenced the findings.
In conclusion, this study has provided the most detailed epidemiological data on all 22 Rome IV DGBI in the UK, to date, and compared them with pooled data from 25 other countries worldwide.
Disorders of gut brain interaction are highly prevalent throughout the UK and are associated with a high burden of healthcare utiliza-

AUTH O R CO NTR I B UTI O N S
HJ reviewed the literature, performed statistical analysis, data interpretation, and drafted the manuscript. LAH was involved with conceptualization, study design, data interpretation, and reviewed the manuscript. RMW was involved with the study design, statistical analysis and interpretation, and reviewed the manuscript. AA, IA, CJB, MC, ME, PAP, and ACF were involved with conceptualization, study design, and revised the manuscript. FS reviewed the statistical analysis and helped with data presentation and creation of graphical display of DGBI prevalence between countries. PJW, SB, OSP, and ADS were involved with the original data collection for the RFGES, reviewed and approved the study design, and revised the manuscript. DHV was involved with conceptualization, study design, interpretation, helped write and revise the manuscript, and is the guarantor.

ACK N OWLED G M ENTS
HJ was supported by the Saudi Arabian Cultural Bureau in London.

CO N FLI C T O F I NTER E S T S TATEM ENT
None of the authors have any financial disclosures to declare that are relevant to this work.