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DR NATASHA A KOLOSKI (Orcid ID : 0000-0002-8647-5933)

PROFESSOR MARJORIE M WALKER (Orcid ID : 0000-0002-7788-0056)

PROFESSOR G.J. HOLTMANN (Orcid ID : 0000-0002-0206-2358)

Article type : Original Scientific Paper

Submitted to: Alimentary Pharmacology & Therapeutics Date: 18 November 2018 -Revised 1

Population based study: Atopy and autoimmune diseases are associated with functional dyspepsia and irritable bowel syndrome, independent of psychological distress.

Running title: Atopy, autoimmune disorders, functional dyspepsia and IBS

Koloski Natasha,1-4 Jones Michael, 2,5 Walker Marjorie M,,1,2 Veysey Martin, 1 Zala Alkesh,6 Keely Simon, 1-2 Holtmann Gerald, 1,4 Talley Nicholas J 1,2, 6 1. Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia

2. Australian Gastrointestinal Research Alliance (AGIRA)

3. Department of Gastroenterology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia

4. School of Medicine, University of Queensland, St Lucia, QLD, Australia Author Manuscript 5. Macquarie University, Sydney, NSW, Australia.

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/apt.15120

Correspondence and Reprints:

Prof Nicholas Talley Faculty of Health & Medicine University of Newcastle Callaghan NSW 2305 Australia Email: [email protected]

Grant Support This study was supported by a grant from Prometheus laboratories

Specific author contributions: NAK was involved in study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content MJ was involved in study concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis MMW was involved in study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. MV was involved in acquisition of data and critical revision of the manuscript for important intellectual content AZ was involved in acquisition of data and critical revision of the manuscript for important intellectual content SK was involved in study concept and design; critical revision of the manuscript for important intellectual content; statistical analysis. GH was involved with analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. NJT was involved in study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision.

Author Manuscript

Disclosures:

MMW: Grant/Research Support: Prometheus Laboratories Inc [Irritable bowel syndrome (IBS Diagnostic), Commonwealth Diagnostics International (Biomarkers for FGIDs) MV: None to disclose AZ: None to disclose SK: Grant/Research Support: Cancer Institute NSW (Career Development Fellowship), National Health and Medical Research Council (Project Grant APP1128487) Commonwealth Diagnostics International (Biomarkers for FGIDs), Syntrix Biosystems (contract research - drug delivery). Consulting/Advisory Boards: Gossamer Bio, Aerpio Therapeutics

GH: Unrestricted educational support from Bayer Ptd, Ltd and the Falk Foundation. Research support was provided via the Princess Alexandra Hospital, Brisbane by GI Therapies Pty Limited, Takeda Development Center Asia, Pty Ltd, Eli Lilly Australia Pty Limited, F.Hoffmann-La Roche Limited, MedImmune Ltd Celgene Pty Limited, Celgene International II Sarl, Gilead Sciences Pty Limited, Quintiles Pty Limited, Vital Food Processors Ltd, Datapharm Australia Pty Ltd Commonwealth Laboratories, Pty Limited, Prometheus Laboratories, Falk GmbH and Co Kg, Nestle Pty Ltd, Mylan. Patent Holder: A biopsy device to take aseptic biopsies (US 20150320407 A1) NJT: Grant/Research Support: Rome Foundation; Abbott Pharmaceuticals; Datapharm; Pfizer; Salix [Irritable bowel syndrome]; Prometheus Laboratories Inc [Irritable bowel syndrome (IBS Diagnostic)]; Janssen [Constipation]. Consultant/Advisory Boards: Adelphi Values [Functional dyspepsia (patient-reported outcome measures)]; (Budesonide)]; GI therapies [Chronic constipation (Rhythm IC)]; Allergens PLC; Napo Pharmaceutical; Outpost Medicine; Samsung Bioepis; Yuhan [IBS]; Synergy [IBS]; Theravance [Gastroparesis]. Patent Holder: Biomarkers of irritable bowel syndrome [Irritable bowel syndrome] Licensing Questionnaires [Mayo Clinic Talley Bowel Disease Questionnaire - Mayo Dysphagia Questionnaire]; Nestec European Patent [Application No. 12735358.9]; Singapore ‘Provisional’ Patent [NTU Ref: TD/129/17 “Microbiota Modulation Of BDNF Tissue Repair Pathway].

Summary Background: The pathogenesis of functional GI disorders (FGIDs) is uncertain. However, underlying immune activation and psychological distress has been documented in irritable bowel syndrome (IBS)Author Manuscript and functional dyspepsia (FD). Epidemiological data from the UK suggest FGIDs are linked to atopy and certain autoimmune diseases but this has not been confirmed.

This article is protected by copyright. All rights reserved Aims: In a large population-based study we aimed to test if allergic or autoimmune diseases are independently associated with FGIDs, irrespective of psychological distress. Methods: A total of 3,542 people (mean age 57.9 years and 52.7% females) randomly selected from the Australian population, returned a mail survey (response rate = 43%). The survey asked about a physician diagnosis of autoimmune disease (scleroderma, psoriasis, rheumatoid arthritis and diabetes mellitus) or allergic conditions (asthma, food, pollen and/or animal allergy). The questionnaire assessed psychological distress and Rome III criteria for FD and IBS. Results: Asthma, food, pollen and animal allergies, psoriasis and rheumatoid arthritis were univariately significantly associated with IBS and FD. Food allergy (OR=1.66;95%CI 1.15- 2.40, P=0.007), psoriasis (OR=1.81;95%CI 1.19-2.74, P=0.006) and rheumatoid arthritis (OR=1.68;95%CI 1.15-2.4, P=0.007) were independent risk factors for IBS, controlling for age, sex and psychological distress. In FD, asthma (OR=1.32;95%CI 1.04-1.68, P=0.025) and food allergy (OR=1.78;95%CI 1.28-2.49, P=0.001) were independent predictors, controlling for age, sex and psychological distress. Conclusions: There is evidence that both atopic and autoimmune diseases are risk factors for FGIDs, independent of psychological distress, differing in IBS and FD. This provides evidence that different peripheral pathways may be involved in the pathogenesis of certain FGIDs. Keywords Functional gastrointestinal disorders; allergy; autoimmune disease; psychological distress

Introduction Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are the most common functional gastrointestinal disorders (FGIDs) affecting up to 20% of the general population.1 Treatment alleviates, but does not cure symptoms. 2 Recent research suggests that immune activation is likely a key player in the development of these disorders. 3-7 Evidence for innate immune activation in the mucosa in IBS and FD has been observed 6-7 but the prevalence of Author Manuscript immune activation in FGIDs is uncertain. An alternative approach examining the potential role of immune activation in FGIDs is to ascertain the prevalence of IBS and FD occurring alongside other conditions in the general population known to be associated with immune

A study from the UK, which evaluated 23,471 patients from the General Practice Research Database, found evidence for increased prevalence of immune and autoimmune disorders and IBS and functional dyspepsia. 8-9 It was found that there was an increased probability of a diagnosis of functional dyspepsia in those with immune related disorders such as rheumatological autoimmune diseases including rheumatoid arthritis, seronegative arthritis, psoriatic arthritis and ankylosing spondylitis. 8 Autoimmune conditions such as rheumatoid arthritis and psoriasis have a predominant T-helper-1 and T-helper-17 type immune response. 10-11 An excessive T-helper-1 response has also been observed in some cases of IBS. 12 Most of these studies however have been patient based and it is unknown whether these and other autoimmune diseases such as psoriasis and scleroderma are also associated with a diagnosis of IBS and FD in the general population.

By contrast, atopy is characterised by a predominant T-helper-2 type immune response. In atopy (including asthma, eczema rhinitis/hay fever) an underlying disordered T-helper-2 immune responses occurs 13 and this also may happen in a subset of FGIDs. 14 Data obtained from birth cohort studies and patient- based studies have suggested that atopy is associated with both IBS and FD. 9,13-21 However, the role of specific allergies in FGIDs is less clear. A reaction to wheat proteins has received attention as a possible trigger for IBS symptoms. 22 There are few population-based data available on pollen and animal allergy in FGIDs, although exposure to herbivore pets in childhood has been linked to the development of both IBS and FD. 23

The potential role of psychological distress in explaining the link between allergic and immune disorders and FGIDs is unknown. IBS, asthma and food allergy for example are each associated with increased psychological distress. 24-26 Moreover, enhanced proinflammatory cytokine release has also been shown to be significantly associated with anxiety in patients with IBS. 27 We have shown in a prospective cohort that psychological disorders preceded functional gastrointestinal symptoms in two thirds of health care seekers with IBS, whereas half with IBS fromAuthor Manuscript the general population had gut symptoms prior to developing psychological distress. 28 However, no studies have examined whether the relationship between atopy and FGIDs is independent of psychological factors.

This article is protected by copyright. All rights reserved In a large cross-sectional population-based study we aimed to determine if there is an association between FD and IBS and a range of self- reported doctor diagnosed allergic (asthma and food, pollen and animal allergies) and autoimmune disorders (scleroderma, psoriasis, rheumatoid arthritis and diabetes mellitus), and whether any potential association is independent of psychological distress.

Methods Participants: Participants (n=3542) were a random population sample from Newcastle and Gosford, NSW, Australia, who responded to a postal survey (the Digestive Health & Wellbeing survey) in 2015.

Measures The Digestive Health & Wellbeing survey contained the following measures: 29 • An abbreviated Rome Questionnaire, which is a self-report instrument that measures functional gastrointestinal symptoms experienced over the past 3 months. Previous testing has shown this instrument to be reliable and valid. 29 This measure was used to diagnose modified Rome III (6-month criteria were not applied) IBS including IBS- constipation predominant and diarrhea predominant, and FD including epigastric pain subtype and post prandial distress subtype. In addition, we asked whether abdominal and bowel problems occurred within 3 months of gastroenteritis or a course of antibiotics.

• Self-reported medical diagnoses were preceded by the question “Have you ever been told by a doctor that you have any of the following conditions?” Responses were grouped into the following categories: a) allergic conditions (asthma, food allergy, pollen allergy and animal allergy) and b) immune related conditions (scleroderma, psoriasis, rheumatoid arthritis and diabetes mellitus) 30 • PsychologicalAuthor Manuscript distress was assessed using the validated Kessler 6 scale. This scale measures non-specific psychological distress according to a 5 point Likert scale ranging from none of the time to all of the time. A high score of >20 out of 30 on the Kessler scale represented severe psychological distress.

This article is protected by copyright. All rights reserved • Lifestyle factors included smoking including both ‘ever’ smoked (yes/no) and current smoking (less often than weekly, at least weekly, at least daily), body mass index and current intake of any proton pump inhibitor. We also obtained data on age and gender. Definitions: Irritable bowel syndrome (IBS) and functional dyspepsia including their subtypes were diagnosed according to modified Rome III criteria 29 (see Appendix 1). FD was subtyped to FD- post prandial distress syndrome (PDS) and epigastric pain syndrome, (EPS) and IBS to constipation predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS-mixed. Post infectious IBS (PI IBS) was defined by reporting a bout of gastroenteritis in the 3 months preceding the onset of symptoms.

Procedures: The study was approved by the Hunter New England Human Ethics Committee. A total of 8499 participants (7499 from the Newcastle electoral divisions and 1000 from Gosford electoral divisions) randomly selected from the Australian Electoral Roll were sent the Digestive Health & Well-being survey by post. We used the Dillman Total Design Method 31 for the follow-up of non-responders. The follow-up protocol included a reminder/thank you letter sent to all participants at week 1, a replacement survey sent out to non-responders at week 4 and a reminder/thank you letter sent at week 5 to those non-responders identified at week 4. Additional measures to maximise response rates included a personalised cover letter personally signed by the chief investigator, and an easy to understand attractive single page, double sided questionnaire. Participants did not receive any remuneration for participation.

Statistical Analyses

A case-control approach has been adopted in understanding the association between FD and IBS with immune and other factors. Unconditional logistic regression was used to differentiate individuals who met criteria for a given Rome FGID, or subtype, from those

who did not (TablesAuthor Manuscript 1-4). Univariate models are reported that describe the association between each risk factor and each outcome while multivariate models indicate which potential risk factors provide statistically independent, significant discrimination. Multivariate logistic modelling was used to evaluate the extent to which allergic and

This article is protected by copyright. All rights reserved autoimmune conditions considered jointly discriminate individuals having each FGID from those who do not. Since there are seven independent variables and missing values accumulate, models were estimated using multiple imputation with 10 replicate imputations. 32 Stata V15 software was used for analysis

Results

Response rate

Of 8499 surveys sent out, 282 were ineligible and removed (return to sender and deaths) and 3542 of the remaining 8217 were returned, an overall response rate of 43.1%. An analysis of responders compared with non-responders showed that responders were marginally more likely to be female (52.4% vs. 48.3%, p<0.001) and older (48.5% of non-responders aged <45 years compared with 22% of responders, p<0.001).

Sociodemographics of the sample The sample comprised 52.7% females, mean age was 57.9 (standard deviation 16.5) years. People with a reported diagnosis of ulcerative colitis (56, 1.6% (95%CI 1.1-2.0) and Crohn’s disease (21, 0.6% (95%CI 0.4-0.9) were omitted from the dataset.

Psychological characteristics of the sample People with IBS scored significantly higher on the Kessler scale compared with those without IBS (Mean=6.05 (SD=5.12) vs. Mean=3.0 (SD=3.80), P<0.001). Similarly, people with FD compared to people without FD scored significantly higher on the Kessler scale (Mean=5.46 (SD=5.13) vs. Mean=3.0 (SD=3.78), P<0.001).

Prevalence of FGIDs, IBS and FD Among the general population, 13.4% (95% CI 12.3-14.6) fulfilled the Rome criteria for IBS, 2.6% (95% CI 2.1-3.2) met criteria for constipation-predominant IBS (IBS-C), 3.4% (95% CI 2.8-4.0) met criteria for diarrhea-predominant IBS (IBS-D), 7.0 % (95% CI 7.0% (95% CI 6.1-7.9)) met criteria for mixed IBS and 0.3% (95%CI 0.2-0.6) had post-infectious IBS (PI-

IBS). Author Manuscript The Rome criteria for FD were fulfilled by 16.9% (95% CI 15.6,18.2), 13.3% (95% CI 12.2,14.4) met criteria for the FD subtype of post-prandial distress syndrome (PDS), and 8.2% (95% CI 7.3, 9.2%) met criteria for the FD subtype of epigastric pain syndrome (EPS)

Prevalence of allergic and autoimmune disorders The prevalence of allergic conditions in the sample were as follows: asthma (16.0%; 95%CI 14.8-17.3), food allergy (6.3%; 95CI% 5.5-7.1), pollen allergy (7.5%; 95%CI 6.6-8.4) and animal allergy (3.7%; 95%CI 3.1-4.4). With respect to autoimmune disorders, the prevalence rates were as follows: rheumatoid arthritis (6.5%; 95%CI 5.7-7.4), diabetes mellitus (10.4%; 95%CI9.4- 11.8), scleroderma (0.3%;95%CI 0.1-0.4) and psoriasis (4.3%;95%CI 3.7-5.0).

Univariate associations

The proportion of people with IBS was significantly higher in people with rheumatoid arthritis. Similarly, the prevalence of people with FD was significantly higher in people with rheumatoid arthritis compared with people without rheumatoid arthritis. Rheumatoid arthritis was significantly associated with IBS and IBS-M but not IBS-C, IBS-D or PI IBS or FD including both FD-PDS and FD-EPS.

IBS was present in almost a quarter of people with psoriasis. Psoriasis was significantly associated with IBS, IBS-D, IBS-M and PI IBS but not IBS-C. Psoriasis was also significantly associated with FD-PDS.

There were no significant associations of scleroderma and diabetes mellitus and IBS or IBS subgroups or FD and FD subgroups (Table 1 and 2).

Univariate associations with atopy Tables 3 and 4 shows the univariate associations with atopy. The prevalence of IBS was significantly higher in people with asthma than those without asthma but only IBS-C and IBS-M was associated among the subtypes. Food allergy was significantly associated with IBS (IBS-C, IBS-D and IBS-M) and FD (PDS and EPS) with moderate effect sizes but not

PI-IBS. A pollen allergyAuthor Manuscript was also significantly associated with IBS including IBS-D and PI- IBS but not IBS-C or IBS-M. There was a substantial moderate significant effect size of 4.68 for pollen allergy in PI IBS. A self-reported animal allergy was significantly associated with IBS, IBS-M and PI-IBS but not IBS-C or IBS-D (Table 3).

Asthma was significantly associated with FD as well as FD-PDS and FD-EPS. Food allergy was significantly associated with FD and FD-PDS with moderate effect sizes as well as FD- EPS. A pollen allergy was also significantly associated with FD and FD-PDS but not FD-EPS (Table 4).

Multivariate Model A multivariate model that included both allergic conditions (asthma, food, pollen and animal allergy) and autoimmune diseases (scleroderma, psoriasis and rheumatoid arthritis) was conducted to determine if these are independent predictors of meeting criteria for IBS and FD and their respective subgroups. A second multivariate model that included both allergic and autoimmune diseases as well as age, sex and psychological distress was also conducted.

IBS Asthma (OR=1.55; 95%CI 1.20,1.99, P=0.001), food allergy (OR=1.85; 95%CI 1.31,2.61, P<0.001), psoriasis (OR=2.04; 95%CI 1.38,3.02, P<0.001), and rheumatoid arthritis (OR=1.58; 95%CI 1.121,2.23, P=0.009) were significantly and independently associated with IBS. Food allergy (OR=1.66; 95%CI 1.15,2.40, P=0.007), psoriasis (OR=1.81; 95%CI 1.19,2.74, P<0.001), and rheumatoid arthritis (OR=1.68; 95%CI 1.15,2.45, P=0.007), but not asthma, pollen or animal allergy or scleroderma remained significant even after controlling for age, sex and psychological distress (Figure 1). In terms of the IBS subgroups, these associations were only seen for IBS-D but asthma was an independent predictor of IBS-M.

FD Asthma (OR=1.48; 95%CI 1.18,1.87, P=0.001) and food allergy (OR=1.98;95%CI 1.44,2.73, P=0.001) were significantly and independently associated with FD. However, pollen or animal allergy, scleroderma, psoriasis and rheumatoid arthritis were not significant in the model. Asthma (OR=1.32; 95%CI 1.04,1.68, P=0.025), and food allergy (OR=1.78; 95%CI 1.28,2.49, P=0.001) remained significant even after controlling for age, sex and

psychological distressAuthor Manuscript in the model (Figure 2). Similar associations, for the most part, were found regardless of FD subtype.

This article is protected by copyright. All rights reserved Discussion There is a growing body of literature that suggests that IBS and FD are disorders of immune activation. 3-7 In this large population-based study, we found both atopic (asthma) and autoimmune (psoriasis and rheumatoid arthritis) conditions were independently associated with FD and IBS. Further, while FGIDs are associated with increased anxiety and over half of IBS cases are secondary to psychological disorders, 28 we found associations between FD, IBS and immune disorders to be independent of psychological distress. These findings suggest that certain subsets with FGIDs may arise from an atopic predisposition or autoimmune disease.

In this epidemiological investigation, we found a modest association between both IBS and FD and allergic conditions. Asthma was found to be an independent risk factor for IBS and FD diagnosis by Rome criteria, with one fifth of people with asthma also having IBS. Food allergy was also found to be an independent risk factor for both IBS and FD. These findings confirmed previous patient-based studies suggesting a link between atopy and IBS 9,14-21 but importantly, this current population is not affected by selection and referral bias found in hospital and general practice cohorts. 9-21 Atopy, by definition, suggests a genetic basis for allergic predisposition and genome wide association studies have identified single nucleotide polymorphisms conferring risk to FGIDs that are common to allergic diseases 33-35. There is a long-standing appreciation that atopic asthma is associated with polymorphisms in the HLA locus in chromosome, in particular alleles of HLA-DRB1 and HLA-DQ. 33-34 These same single nucleotide polymorphisms have been identified as risk factors for IBS and motility disorders perhaps suggesting a genetic background linking atopy and FGIDs. 35 In a similar fashion HLA-DRB1 and DQA1-DQB1 haplotypes have been associated with autoimmune diseases, including rheumatoid arthritis and type 1 diabetes. 36

Here we confirm previous findings that IBS is a common condition reported by patients with rheumatoid arthritis. 8 We found that approximately 20% of people in the community with

rheumatoid arthritisAuthor Manuscript also meet criteria for IBS and that rheumatoid arthritis and IBS were independently associated. We also found that rheumatoid arthritis was independently associated with epigastric pain subtype of FD. These finding are in contrast to a previous general practice cohort where only FD was reported to be linked to rheumatoid arthritis. 8 We

This article is protected by copyright. All rights reserved also found IBS to be commonly reported in people with psoriasis. Interestingly, patients with psoriasis have elevated levels of serum eosinophil cationic protein, increased numbers of EG2 positive eosinophils and tryptase positive mast cells in the duodenal stroma 37 and patients with IBS and FD also have been found to have elevated eosinophils, mast cells and immune dysregulation. 38 Neither scleroderma nor diabetes were found to be associated with FGIDs in our population study. It is likely that prevalence of scleroderma in the population were very low and unlikely to produce a significant result. While gastrointestinal symptoms have been found to be more common in people with diabetes mellitus when compared with controls 39-40 our survey did not discriminate between Type 1 and Type 2 diabetes and by age range, it is likely most subjects had Type 2 rather than Type 1 autoimmune type diabetes.

Psychological distress is now considered an important determinant in the development of FGIDs 26 and is also associated with allergic conditions such as asthma 25 and food allergy. 26 Using multivariate analyses to determine whether the relationship between allergic and immune disorders and FD and IBS is linked to psychological distress, we found that asthma and food allergy were associated with FD, independent of psychological distress, while food allergy was independently associated with IBS. These findings are partly supported by a previous patient-based study of almost 30,000 primary care patients showing that FD and IBS and atopic conditions asthma, eczema, allergic rhinitis/hay fever and conjunctivitis share a connection that is partly, but not completely, explained via a common association with anxiety and depression.9We did not find support for the association between atopy and FD and IBS occurring via psychological distress, and it is important to point out the current population-based sample was not impacted by anxiety or depression driving people to consult which may explain the previously observed link seen in primary care patients. There were other clear differences in the two studies including data collected over a 5-year period versus the cross-sectional nature of the current study, the inclusion of different atopic conditions and different data collection methods for example medical records versus self-report. We conclude the association between atopy and FD and IBS is unlikely to be explained by psychological distress.

The strength of ourAuthor Manuscript study lies in the evaluation of a large sample that was obtained from the electoral roll, which by law in Australia requires that all persons be registered and was therefore unbiased. A modified version of the Rome criteria 29 were used to define IBS and FD. While we did not assess medication usage, it is possible that some people with

This article is protected by copyright. All rights reserved autoimmune conditions may experience GI symptoms because of prescription medication for their condition. However, the prevalence rates of IBS and FD obtained using modified Rome III criteria were expected based on previous epidemiological studies.1,28 Validated measures of psychological distress 30 and IBS and FD 29 including the exclusion of inflammatory bowel disease in which symptoms can mimic IBS.

Limitations include the reliance on self-report for the diagnosis of allergic and immune disorders. Nevertheless, we did ask about whether the participant had ever been told by a doctor that they had a specific condition to avoid reliance on self-diagnosis. There is support for the accuracy of self-reports as a measure of prevalent chronic diseases from validation studies. 41-43 Leikauf et al, 2009 found substantial agreement (kappa=0.66) between self- report and medical chart documentation for asthma among older adults. 43 The prevalence rates of some of these conditions were similar to those previously reported in the Australian 2014-2015 National Health Survey where 20% of Australians had a self-report diagnosis of an allergic condition 44 including 11% with asthma 45 and 5% of Australians had an autoimmune condition. 44 However our self-reported prevalence rate of 10% for diabetes is higher than the Australian reported figures of 5% for Type II diabetes, however we did not specify the type of diabetes. 44 Similarly, we had a higher rate of rheumatoid arthritis of 6% compared with 2% as reported in the 2014-15 National Health Survey. 44 This may have been due to our older sample of responders.

With respect to food allergy the gold standard for determining the presence of food allergy in an individual is a double-blind, placebo-controlled oral food challenge or by measuring specific IgE concentrations to multiple foods with the latter having been shown to correlate poorly with self-report food allergy. 46 These methods however were not feasible in this large epidemiological study. While the prevalence of true food allergy may have been overestimated in the current study, we have been careful to separate a self-assessment of food allergy from reporting of a doctor-diagnosed food allergy. Australia has some of the highest rates of food allergy in the world with challenge-proved food allergy prevalence rates for peanut, raw egg and sesame at 4 years of age to be 3.8%. 47 In adults, one Australian study Author Manuscript estimated that 1.3% of those aged 20–45 years suffered from food allergy when assessed by medical history and diagnostic allergy testing, but without food challenge. The rate of reported doctor diagnosis of food allergy of 6.3% in this study is similar to self-reported food

This article is protected by copyright. All rights reserved allergy rates of 5% reported from the 2014 Australian Health Survey. 48 Future studies should also examine other allergic conditions including eczema and conjunctivitis.

We did find a modest difference in the age of responders compared with nonresponders which is a source of potential bias, and hence we may have underestimated the rate of these allergic and autoimmune conditions because of a lower response rate in younger adults. In addition, we assessed psychological distress rather than those meeting DSM criteria for an anxiety or depression disorder. Furthermore, we did not assess somatisation which may also be a confounding factor in the current study. As this was a cross sectional study, the timing of whether IBS/FD and allergic conditions came first is not clear.

In summary, specific atopic and autoimmune diseases are risk factors for IBS and FD that are not accounted for by psychological distress. This suggests different peripheral pathways may be involved in the pathogenesis of certain FGIDs.

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Table 1. Univariate associations of auto immune conditions and IBS and IBS subgroups

Self-reported Scleroderma Psoriasis Rheumatoid arthritis Diabetes Mellitus (n=9) (n=150) (n=227) (n=362)

IBS 2 (22.2) vs. 462 (13.3) 37 (24.6) vs. 427 (12.9) 46 (20.3) vs 418 (12.9) 41 (11.3) vs. 423 (13.6) Yes n (%) vs. No n (%) 1.85 (0.38,8.95), P=0.4 2.22 (1.51,3.26), P<0.001 1.72 (1.22, 2.41), P=0.002 0.81 (0.58,1.14), P=0.2 CI (95%CI), P value

IBS-C 1 (11.1) vs. 89 (2.57) 6 (4.0) vs. 84 (2.5) 10 (4.4) vs. 80 (2.5) 9 (2.5) vs. 81 (2.6) Yes n (%) vs. No n (%) 4.74 (0.59,38.30), P=0.1 1.61 (0.69,3.74), P=0.3 1.82 (0.93,3.57), P=0.08 0.95 (0.47,1.92), P=0.9 CI (95%CI), P value IBS- D 0 (0) vs. 117 (3.4) 13 (8.6) vs. 104 (3.1) 10 (4.4) vs. 107 (3.3) 13 (3.6) vs. 104 (3.3) Yes n (%) vs. No n (%) 1 n/a 2.94 (1.61,5.36), P<0.001 1.35 (0.70,2.62), P=0.4 1.08 (0.60, 1.94), P=0.8 CI (95%CI), P value IBS-M 1 (11.1) vs.241( 7.0) 17 (11.3) vs. 225 (6.8) 25 (11.0) vs. 217 (6.7) 18 (4.5) vs. 224 (7.2) Yes n (%) vs. No n (%) 1.67 (0.21,13.41), P=0.6 1.76 (1.04,5.36), P<0.001 1.73 (1.11,2.67), P=0.02 0.67 (0.41, 1.10), P=0.1 CI (95%CI), P value IBS- PI 0 (0) vs. 11 (0.3) 2 (1.3) vs. 9 (0.3) 2 (0.9) vs 9 (0.3) 2 (0.6) vs. 9 (0.3) Yes n (%) vs. No n (%) 1 n/a 4.97 (1.07,23.23), P=0.04 3.20 (0.69,14.88), P=0.1 1.91 (0.41,8.89), P=0.4 Author Manuscript CI (95%CI), P value

Self-reported Scleroderma Psoriasis Rheumatoid arthritis Diabetes Mellitus (n=9) (n=150) (n=227) (n=362)

Table 2. Univariate associations of auto immune conditions and FD and FD subgroups

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FD 2 (22.2) vs. 584 (16.9) 33 (22.0) vs. 553 (16.6) 50 (322.0) vs 536 (16.5) 69 (19.1) vs. 517 (16.6) Yes n (%) vs. No n (%) 1.41 (0.29,6.80), P=0.7 1.41 (0.9 1.43 (1.03, 1.98), P=0.03 1.18 (0.89,1.56), P=0.2 Self-reported Asthma Food Allergy Pollen Allergy Animal Allergy CI (95%CI), P value 52.10), P=0.08 (n=554) (n=217) (n=260) (n=130)

FD-EPS 2 (22.2) vs. 459 (13.3) 23 (15.3) vs. 438 (13.1) 40 (17.6) vs. 421 (13.0) 57 (15.8) vs. 404 (13.0) Yes n (%) vs. No n (%) 1.87 (0.39,9.03), P=0.4 0.28 (0.76, 1.88), P=0.4 1.44 (1.00,2.05), P=0.047 1.25 (0.93,1.69), P=0.1 CI (95%CI), P value FD-PDS 2 (22.2) vs. 283 (8.2) 25 (16.7) vs. 260 (7.8) 29 (12.8) vs. 256 (7.9) 36 (9.9) vs. 249 (8.0) Yes n (%) vs. No n (%) 3.21 (0.66,15.53), P=0.1 2.36 (1.51,3.69), P<0.001 1.71 (1.14,2.58), P=0.01 1.27(0.88, 1.83), P=0.2 CI (95%CI), P value

Table 3.Univariate associations of allergic conditions and IBS and IBS subgroups Author Manuscript

IBS 111 (20.0) vs. 353 (12.1) 53 (24.4) vs. 411 (12.6) 53 (20.4) vs 411 (12.8) 28 (21.5) vs. 436 (13.1) Yes n (%) vs. No n (%) 1.82 (1.44,2.30), P<0.001 2.23 (1.61,3.10), P<0.001 1.74 (1.27, 2.40), P=0.001 1.83 (1.19,2.81), P=0.006 Self-reported Asthma Food Allergy Pollen Allergy Animal Allergy CI (95%CI), P value (n=554) (n=217) (n=260) (n=130)

IBS-C 23 (4.1) vs. 67 (2.3) 1 (5.1) vs. 79 (2.4) 10 (3.8) vs. 80 (2.5) 3 (2.3) vs. 87 (2.6) Yes n (%) vs. No n (%) 1.84 (1.13,2.97), P=0.01 2.15 (1.13, 4.10), P=0.02 1.57 (0.80,3.06), P=0.2 0.88 (0.28,2.83), P=0.8 CI (95%CI), P value IBS- D 25 (4.5) vs. 92 (3.2) 15 (6.9) vs. 102 (3.1) 15 (5.8) vs. 102 (3.2) 4 (3.1) vs. 113 (3.4) Yes n (%) vs. No n (%) 1.45 (0.92,2.28), P=0.1 2.30 (1.31, 4.02), P=0.004 1.87 (1.07,3.26), P=0.03 0.91 (0.33, 2.50), P=0.9 CI (95%CI), P value IBS-M 61 (11.0) vs. 181 (6.2) 25 (11.5) vs. 217 (6.7) 26 (10.0) vs. 216 (6.7) 20 (15.4) vs.222 (6.6) Yes n (%) vs. No n (%) 1.87 (1.37,2.53), P<0.001 1.82 (1.17, 2.83), P=0.007 1.54 (1.0,2.36), P=0.05 2.55 (1.56, 4.19), P<0.001 CI (95%CI), P value IBS- PI 3 (0.5) vs. 8 (0.3) 1 (0.5) vs. 10 (0.3) 3 (1.1) vs 8 (0.2) 2 (1.5) vs. 9 (0.3) Yes n (%) vs. No n (%) 1.98 (0.52,7.47), P=0.3 1.50 (0.19,11.79), P=0.7 4.68 (1.23,17.73), P=0.02 5.79 (1.24,27.05), P=0.03 CI (95%CI), P value Table 4. Univariate associations of allergic conditions and FD and FD subgroups Author Manuscript

FD 129 (23.2) vs. 457 (15.7) 64 (29.4) vs. 522 (16.0) 58 (22.3) vs 528 (16.4) 27 (20.8) vs. 559 (16.7) Yes n (%) vs. No n (%) 1.63 (1.30,2.03), P<0.001 2.19 (1.61,2.98), P<0.001 1.46 (1.07, 1.98), P=0.02 1.31 (0.85,2.01), P=0.2 CI (95%CI), P value

FD-PDS 103 (18.5) vs. 358 (12.3) 54 (24.9) vs. 407 (12.5) 49 (18.8) vs. 412 (12.8) 23 (17.7) vs. 428 (13.1) Yes n (%) vs. No n (%) 1.63 (1.28,2.07), P<0.001 2.32 (1.68,3.21), P<0.001 1.58 (1.14,2.19), P=0.006 1.43 (0.90,2.26), P=0.1 CI (95%CI), P value FD-EPS 63 (11.3) vs.222 (7.6) 29 (13.4) vs. 256 (7.9) 19 (7.3) vs. 266 (8.3) 7 (5.4) vs. 278 (8.3) Yes n (%) vs. No n (%) 1.55 (1.15,2.09), P=0.004 1.81 (1.20, 2.73), P=0.005 0.87 (0.54,1.42), P=0.6 0.63 (0.29, 1.36), P=0.2 CI (95%CI), P value

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Figure 1. Adjusted (controlling for health conditions considered conjointly, age, gender and psychological distress) and unadjusted models of atopicAuthor Manuscript and autoimmune conditions and IBS

Figure 2. Adjusted (controlling for health conditions considered conjointly, age, gender and psychological distress) and unadjusted

models of atopicAuthor Manuscript and autoimmune conditions and FD

Appendix 1: Modified Rome criteria for diagnoses of IBS and FD including subtypes from the Digestive Health and Wellbeing Questionnaire.

Irritable bowel syndrome

• Defined as the presence of pain or discomfort anywhere in the belly or tummy (abdomen) on at least one day per week in the last 3 months, and; o The pain was sometimes/ often/ most of the time or always made better by having a bowel movement, or; o The following features were associated with the pain when it began (sometimes/ often/ most of the time or always); . More bowel motions than usual, or; . Less bowel motions than usual, or; . Harder bowel motions than usual, or; . Looser bowel motions than usual Irritable bowel syndrome subtypes

• All IBS subtypes fulfilled the above criteria for a diagnosis of IBS, in addition to the following symptoms being present in the last 3 months: Constipation predominant irritable bowel syndrome (IBS-C)

• Lumpy or hard stools sometimes/ often/ most of the time or always, and; • Loose or watery stools never or rarely Diarrhoea predominant irritable bowel syndrome (IBS-D)

• Lumpy or hard stools never or rarely, and; • Loose or watery stools sometime/ often/ most of the time or always Mixed constipation and diarrhoea irritable bowel syndrome (IBS-M)

• Lumpy or hard stools sometimes/ often/ most of the time or always, and; • Loose or watery stools sometime/ often/ most of the time or always •

Functional dyspepsiaAuthor Manuscript o Fulfill criteria for either the post prandial distress or epigastric pain syndrome subtypes as detailed below

Functional dyspepsia- post prandial distress subtype

• Defined by the presence of one of the following being present on three of more days per week in the last 3 months; o Inability to finish a regular sized meal, or; o Feeling uncomfortably full after a regular sized meal Functional dyspepsia- epigastric pain syndrome subtype

• Defined as the presence of pain or burning in the stomach or upper tummy (above your belly button but not in the chest) being present on more than one day per week in the last 3 months, AND; o The presence of heartburn (a burning discomfort or burning pain in your chest) on less than one day per month, AND; o The pain is never/ rarely made better or stopped by having a bowel movement Author Manuscript