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Background: Psychological and lifestyle factors have been associated with gastrointestinal (GI) symptoms in individuals with diabetes mellitus, but it remains unclear whether they explain the relationship over time. We aimed to determine in two independent population-based studies whether diabetes is an independent risk factor for GI symptoms at a 1- and 3-year follow-up, adjusting for these factors., Methods: In study 1, 1900 individuals completed a baseline and 1-year follow-up survey, while in study 2, 1322 individuals completed a baseline and 3-year follow-up survey. Both studies asked about self-reported diagnoses of diabetes and GI symptoms over the previous 3 months. Psychological, lifestyle factors (body mass index [BMI], smoking) and age and sex were assessed., Key Results: The baseline prevalence of diabetes was 7.8% in Survey 1 and 8.9% in Survey 2. In a multivariate model that included age, sex, BMI, anxiety, depression and smoking status at follow-up, reporting diabetes at baseline was an independent predictor of at least weekly early satiation (OR 1.58, 95% CI 1.05, 2.39, p = 0.03; OR = 1.67, 95% CI 1.14, 2.45, p = 0.009), fecal urgency (OR 1.44,95% CI 1.06, 1.95, p = 0.02; OR = 2.17, 95% CI 1.47, 3.22, p = 0.0001), > 3 bowel motions a day (OR 1.50, 95% CI 1.08, 2.07, p = 0.02; OR = 1.67, 95% CI 1.11, 2.51, p = 0.01), and loose stools (OR 1.40, 95% CI 1.04, 1.90, p = 0.03; OR = 1.68, 95% CI 1.13, 2.51, p = 0.01) at the 1- and 3-year follow-ups, respectively., Conclusions & Inferences: Diabetes is an independent risk factor for a greater frequency of early satiation and diarrhea, adjusting for lifestyle and psychological factors., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Functional gastrointestinal disorders (FGID) are linked to a variety of potential causes, and treatments include reassurance, life-style (including diet), psychological, or pharmacologic interventions., Aims: To assess whether a multidisciplinary integrated treatment approach delivered in a dedicated integrated care clinic (ICC) was superior to the standard model of care in relation to the gastrointestinal symptom burden., Methods: A matched cohort of 52 consecutive patients with severe manifestation of FGID were matched with 104 control patients based upon diagnosis, gender, age, and symptom severity. Patients in the ICC received structured assessment and 12-weeks integrated treatment sessions provided as required by gastroenterologist and allied health team. Control patients received standard medical care at the same tertiary center with access to allied health services as required but no standardized interprofessional team approach. Primary outcome was reduction in gastrointestinal symptom burden as measured by the Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS). Secondary outcome was reduction in anxiety and depressive symptoms as measured by the Hospital Anxiety and Depression Scale (HADS)., Results: Mixed models estimated the within ICC change in SAGIS total as -9.7 (95% CI -13.6, -5.8; p < 0.0001), compared with -1.7 (95% CI -4.0, 0.6; p = 0.15) for controls. The difference between groups reached statistical significance, -7.6 (95% CI -11.4, -3.8; p < 0.0001). Total HADS scores in ICC patients were 3.4 points lower post-intervention and reached statistical significance (p = 0.001)., Conclusion: This matched cohort study demonstrates superior short-term outcomes of FGID patients in a structured multidisciplinary care setting as compared to standard care., (© 2022. Crown.)

Background: Functional dyspepsia (FD) is a common and debilitating gastrointestinal disorder attributed to altered gut-brain interactions. While the etiology of FD remains unknown, emerging research suggests the mechanisms are likely multifactorial and heterogenous among patient subgroups. Small bowel motor disturbances, visceral hypersensitivity, chronic microinflammation, and increased intestinal tract permeability have all been linked to the pathogenesis of FD. Recently, alterations to the gut microbiome have also been implicated to play an important role in the disease. Changes to the duodenal microbiota may either trigger or be a consequence of immune and neuronal disturbances observed in the disease, but the mechanisms of influence of small intestinal flora on gastrointestinal function and symptomatology are unknown., Purpose: This review summarizes and synthesizes the literature on the link between the microbiota, low-grade inflammatory changes in the duodenum and FD. This review is not intended to provide a complete overview of FD or the small intestinal microbiota, but instead outline some of the key conceptual advances in understanding the interactions between altered gastrointestinal bacterial communities; dietary factors; host immune activation; and stimulation of the gut-brain axes in patients with FD versus controls. Current and emerging treatment approaches such as dietary interventions and antibiotic or probiotic use that have demonstrated symptom benefits for patients are reviewed, and their role in modulating the host-microbiota is discussed. Finally, suggested opportunities for diagnostic and therapeutic improvements for patients with this condition are presented., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background & Aims: Functional gastrointestinal disorders are common and costly to the healthcare system. In the Multidisciplinary Treatment of Functional Gastrointestinal Disorders study, we demonstrated that multidisciplinary care resulted in superior clinical and cost outcomes, when compared with standard gastroenterologist-only care at end of treatment. In this study we evaluate the longer-term outcomes., Methods: In a single-center, pragmatic trial patients with Rome IV criteria-defined functional gastrointestinal disorders were randomized 1:2 to a gastroenterologist-only standard care vs a multidisciplinary clinic comprising gastroenterologists, dietitians, gut hypnotherapists, psychiatrists, and biofeedback physiotherapists. Outcomes in this study were assessed 12 months after the end of treatment. Global symptom improvement was assessed by using a 5-point Likert scale. Symptoms, specific disorder status, psychological state, quality of life, and cost were additional outcomes. A modified intention-to-treat analysis was performed., Results: Of 188 randomized patients, 143 (46 standard care, 97 multidisciplinary) formed the longer-term modified intention-to-treat analysis. Sixty-two percent of multidisciplinary clinic patients saw allied clinicians. Sixty-five percent (30/46) standard care versus 76% (74/97) multidisciplinary clinic patients achieved global symptom improvement 12 months after end of treatment (P = .17), whereas 20% (9/46) versus 37% (36/97) rated their symptoms as "5/5 much better" (P = .04). A ≥50-point reduction in Irritable Bowel Syndrome Severity Scoring System occurred in 38% versus 66% (P = .02), respectively, for irritable bowel syndrome patients. Anxiety and depression were greater in the standard care than multidisciplinary clinic (12 vs 10, P = .19), and quality of life was lower in standard care than the multidisciplinary clinic (0.75 vs 0.77, P =·.03). An incremental cost-effectivness ratio found that for every additional 3555AUD spent in the multidisciplinary clinic, a further quality-adjusted life year was gained., Conclusions: Twelve months after the completion of treatment, integrated multidisciplinary clinical care achieved a greater proportion of patients with improvement of symptoms, psychological state, quality of life, and cost, compared with gastroenterologist-only care., Clinical Trials: gov: number NCT03078634., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: There is limited empirical evidence of the magnitude of the discrepancy between prospectively recorded gastrointestinal symptom burden and that reported in recall questionnaires. Further, potential sources of the discrepancy are largely unknown. This study sought to quantify the discrepancy and to evaluate the potential role of mood disorder and emotion regulation in the discrepancy., Methods: One hundred and forty nine subjects (mean age 20 years, 75% female) who met Rome IV criteria for irritable bowel syndrome and/or functional dyspepsia completed a 7-day prospective recording of the symptoms on a smartphone implemented ecological momentary assessment app, and then on day 8 were asked to recall their symptoms for the preceding 7 days., Key Results: Gastrointestinal symptom burden assessed by recall was exaggerated relative to that recorded prospectively. The discrepancy was moderate for overall score (Cohen d = 0.52), abdominal pain (d = 0.61) and indigestion (d = 0.49). The discrepancy was generally larger among subjects who reported a physician diagnosis of a gastrointestinal condition with d = 0.87 for overall score and d = 0.89 for abdominal pain. A number of correlations between the discrepancy and psychological traits were identified, including neuroticism with diarrhea discrepancy (r = 0.23, p = 0.004) and visceral-specific anxiety with abdominal pain discrepancy (r = -0.18, p = 0.03). There was no evidence of recency or Hawthorne (observer) effects., Conclusions and Inferences: Reports of gastrointestinal symptoms obtained via recall are likely to be exaggerated relative to the actual patient experience, particularly among healthcare seekers. While psychological traits are likely to play some role, much more needs to be understood about the discrepancy., (© 2021 John Wiley & Sons Ltd.)

Frequently, patients with functional gastrointestinal disorders (FGIDs) report intolerance of wheat products. We compared gastrointestinal symptoms, sensory function, psychiatric comorbidities, gut-homing immune cells, and duodenal mucosa-associated microbiome (d-MAM) in FGID patients and controls with and without self-reported wheat sensitivity (SR-NCWS). We recruited 40 FGID patients and 20 controls referred by GPs for treatment. Gastrointestinal/extraintestinal symptoms, visceral sensory function, psychological comorbidities, and SR-NCWS were assessed in a standardized approach. Peripheral gut homing T-cells (CD4 + α4 + β7 + CCR9 + /CD8 + α4 + β7 + CCR9 + ) were quantified, and the d-MAM was assessed by DNA sequencing for 46 subjects. Factors of bacterial genera were extracted utilizing factor analysis with varimax rotation and factors univariately associated with FGID or SR-NCWS included in a subsequent multivariate analysis of variance to identify statistically independent discriminators. Anxiety scores (p < .05) and increased symptom responses to a nutrient challenge (p < .05) were univariately associated with FGID. Gut homing T-cells were increased in FGID patients with SR-NCWS compared to other groups (p all <0.05). MANOVA revealed that anxiety (p = .03), visceral sensory function (p = 0.007), and a d-MAM factor comprise members of the Alloprevotella, Prevotella, Peptostreptococcus, Leptotrichia , and Veillonella lineages were significantly (p = .001) associated with FGID, while gut homing CD4 + α4 + β7 + CCR9 + T-cells were associated (p = .002) with SR-NCWS. Compared to controls, patients with and without SR-NCWS show that there are shifts in the amplicon sequence variants within specific bacterial genera between the FGID subgroups (particularly Prevotella and Streptococcus ) as well as distinct bacterial taxa discriminatory for the two different FGID subtypes. Compared to controls, both FGID patients with and without SR-NCWS have an increased symptom response to a standardized nutrient challenge and increased anxiety scores. The FGID patients with SR-NCWS - as compared to FGID without SR-NCWS (and controls without SR-NCWS) - have increased gut homing T-cells. The d-MAM profiles suggest species and strain-based variations between the two FGID subtypes and in comparison to controls.

Background: Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability., Methods: As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis., Results: The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46-0.74), self-rated health (d = -0.42) and depression (d = -0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P < 0.0001)., Conclusion: A naturalistic classification of individuals challenges consensus criteria in showing that some IBS individuals have a symptom experience not unlike health. The proposed approach has demonstrated temporal stability over time, unlike consensus criteria. A naturalistic disease classification system may have practical advantages over consensus criteria when supported by a decision-analytic system., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Debate continues as to whether an attentional bias towards threat displayed by sufferers of functional gastrointestinal disorders (FGIDs) is conscious and, thus, more amenable to change through psychological therapy. We compared the amplitudes of early (unconscious) and later (conscious) electroencephalographic (EEG) event-related potentials following silent reading of symptom-related, emotionally neutral, and emotionally negative nouns across two participant groups: 30 female FGID-sufferers who met diagnostic criteria for irritable bowel syndrome or functional dyspepsia, and 30 female healthy controls. Analogous indices based on alpha desynchronization were also examined, as were correlations between the EEG-based indices and a range of psychosocial variables. FGID-sufferers displayed marginally significantly higher occipital EPN amplitudes for all nouns, indicating marginally higher levels of unconscious attention in the task. FGID-sufferers also displayed, for negative as compared to neutral nouns, significantly lower central N400 amplitudes indicative of higher conscious attention. The result was only apparent in post-hoc pairwise comparisons, however. Uniquely among FGID-sufferers, central N400 was strongly negatively correlated with a range of negative psychosocial traits and states. The findings provide preliminary evidence of hypervigilance to general (as opposed to symptom-specific) threat among FGID-sufferers. Amidst concerns over Type I error, recommendations are made for fine-tuning the operationalisation of unconscious and conscious attentional bias in this population., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Functional gastrointestinal disorders (FGIDs) encompass a range of complex conditions with similar clinical characteristics and no overt pathology. Recent recognition of sub-clinical pathologies in FGIDs, in conjunction with physiological and biochemical abnormalities including increased intestinal permeability, microbial profile alterations, differences in metabolites and extra-intestinal manifestations of disease, call into question the designation of these conditions as 'functional'. This is despite significant heterogeneity in both symptom profile and specifics of reported physiological abnormalities hampering efforts to determine defined mechanisms that drive onset and chronicity of symptoms. Instead, the literature demonstrates these conditions are disorders of homeostatic imbalance, with disruptions in both host and microbial function and metabolism. This imbalance is also associated with extraintestinal abnormalities including psychological comorbidities and fatigue that may be a consequence of gastrointestinal disruption. Given the exploitation of such abnormalities will be crucial for improved therapeutic selection, an enhanced understanding of the relationship between alterations in function of the gastrointestinal tract and the response of the immune system is of interest in identifying mechanisms that drive FGID onset and chronicity. Considerations for future research should include the role of sex hormones in regulating physiological functions and treatment responses in patients, as well as the importance of high-level phenotyping of clinical, immune, microbial and physiological parameters in study cohorts. There is opportunity to examine the functional contribution of the microbiota and associated metabolites as a source of mechanistic insight and targets for therapeutic modulation., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Introduction: While the etiopathogenesis of functional gastrointestinal disorders (FGIDs) is not completely understood, alterations of the intestinal microbiome have been observed. Antibiotics can induce dysbiosis, but whether antibiotics are a risk factor for the onset of FGIDs is uncertain. Antibiotics have been reported as both a risk factor for new onset FGID but also as a therapy for existing FGID. This study aimed to estimate the fraction of cases where antibiotics provoked the onset of FGID., Method: Electronic medical records were obtained from general practices (primary care) in the United Kingdom. Dates of antibiotic prescription (AP) were compared with first date of FGID diagnosis and contrasted across three prevalent FGIDs and controls without gastrointestinal disorders., Results: There were 10,926 GI healthy controls, 4326 IBS alone, 3477 FD alone, 340 chronic constipation and 4402 with overlap of multiple conditions. Both the prevalence of AP and rate were higher in FGID patients and increased with diagnosis of multiple FGIDs. 7%-14% of FGID patients were prescribed their first recorded antibiotic in the 12 months prior to their first FGID diagnosis and 20%-33% were prescribed an antibiotic in the same period. Differences between FGID groups were not accounted for by social deprivation and only rate of AP was moderated by social deprivation. In contrast, only 5%-10% of patients ever had a gastrointestinal infection recorded and only 1.5%-3.5% prior to their first FGID diagnosis., Conclusion: These data indicate that antibiotics are prescribed prior to FGID diagnosis in a significant minority of care-seeking FGID patients, opening the potential for this medication to contribute to the pathophysiology. APs appears to mostly be for non-gastrointestinal conditions., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Due to important biases, conventional end-of-day and end-of-week assessment methods of gastrointestinal symptoms in functional dyspepsia (FD) are considered suboptimal. Real-time symptom assessment based on the experience sampling method (ESM) could be a more accurate measurement method. This study aimed to evaluate validity and reliability of an ESM-based patient-reported outcome measure (PROM) for symptom assessment in FD., Methods: Thirty-five patients with FD (25 female, mean age 44.7 years) completed the ESM-based PROM (a maximum of 10 random moments per day) and an end-of-day symptom diary for 7 consecutive days. On day 7, end-of-week questionnaires were completed including the Nepean Dyspepsia Index (NDI) and Patient Assessment of Gastrointestinal Symptom Severity Index (PAGI-SYM)., Key Results: Experience sampling method and corresponding end-of-day scores for gastrointestinal symptoms were significantly associated (ICCs range 0.770-0.917). However, end-of-day scores were significantly higher (Δ0.329-1.031) than mean ESM scores (p < 0.05). Comparing ESM with NDI and PAGI-SYM scores, correlations were weaker (Pearson's r range 0.467-0.846). Cronbach's α coefficient was good for upper gastrointestinal symptoms (α = 0.842). First half-week and second half-week scores showed very good consistency (ICCs range 0.913-0.975)., Conclusion and Inferences: Good validity and reliability of a novel ESM-based PROM for assessing gastrointestinal symptoms in FD patients was demonstrated. Moreover, this novel PROM allows to evaluate individual symptom patterns and can evaluate interactions between symptoms and environmental/contextual factors. ESM has the potential to increase patients' disease insight, provide tools for self-management, and improve shared decision making. Hence, this novel tool may aid in the transition toward personalized health care for FD patients., (© 2021 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

The European Society for Neurogastroenterology and Motility's (ESNM) consensus document on functional dyspepsia (FD) has provided a critical review of the evidence for 36 statements highly relevant to the diagnosis and treatment of FD. We provide here our expert opinion on the North American, Australian and Asian assessments of the same topics discussed, and provide evidence where the ESNM consensus may deviate from those in the other continents. New and exciting data about the pathogenesis of FD are emerging including the possible central role of duodenal micro-inflammation (most notably eosinophilic duodenitis and intestinal mast cell disease), but this is a very dynamic field with several gaps remaining in our understanding that are summarized in this review. Identification of non-invasive biomarkers and testing of targeted therapies, including assessing the benefits of multidisciplinary teams in the management of FD, should be future priorities., (© 2021 John Wiley & Sons Ltd.)

Background: Patients presenting with gastrointestinal symptoms can be challenging in terms of determining etiology and management strategies. Identifying likely organic pathology is important since it can be treated and may result in further, long-term harm to the patient if not treated. Currently, organic pathology is often identified via invasive procedures such as endoscopy or referral to a medical imaging service. We report on an approach that offers a first step at identifying patients with an organic gastrointestinal disease based on the SAGIS, a validated symptom questionnaire., Methods: 8,922 patients referred to a tertiary care hospital were classified as having either functional gastrointestinal disease or an organic gastrointestinal disease. A model was developed to distinguish organic from functional symptoms on one random split half of the sample and validated on the other half. The incremental benefit of including psychological conditions and extra-gastrointestinal conditions was also evaluated., Key Results: Functional gastrointestinal patients scored higher on average than organic patients on all dimensions of the SAGIS and reported higher rates of psychological and extra-gastrointestinal conditions. All five dimensions of the SAGIS provided statistically independent discrimination of organic from functional diagnoses with good overall discrimination (AUC = 0.75). However, there was no noticeable incremental benefit of adding either psychological or extra-gastrointestinal conditions. Model performance was highly reproducible., Conclusions and Inferences: The proposed algorithm for identifying likely organic gastrointestinal disease applied to symptoms as recorded in the SAGIS questionnaire provides a useful tool for the clinician in deciding what or if further diagnostic testing is required., (© 2021 John Wiley & Sons Ltd.)

Gastrointestinal symptoms are highly prevalent, but many people who have them will have no organic explanation for their symptoms. Most of these people will be labelled as having a functional gastrointestinal disorder, such as irritable bowel syndrome, functional dyspepsia, or functional constipation. These conditions affect up to 40% of people at any one point in time, and two-thirds of these people will have chronic, fluctuating symptoms. The pathophysiology of functional gastrointestinal disorders is complex, but involves bidirectional dysregulation of gut-brain interaction (via the gut-brain axis), as well as microbial dysbiosis within the gut, altered mucosal immune function, visceral hypersensitivity, and abnormal gastrointestinal motility. Hence, nomenclature refers to the conditions as disorders of gut-brain interaction. Psychological comorbidity is common; however, whether or not this predates, or is driven by, symptoms is not clear. Patients with functional gastrointestinal disorders can feel stigmatised, and often this diagnosis is not communicated effectively by physicians, nor is education provided. Prompt identification and treatment of these conditions is crucial as they have a considerable impact on health-care systems and society as a whole because of repeated consultations, unnecessary investigations and surgeries, prescriptions and over-the-counter medicine use, and impaired health-related quality of life and ability to work. Symptom-based criteria are used to make a diagnosis, with judicious use of limited investigations in some patients. The general principles of treatment are based on a biopsychosocial understanding and involve management of physical symptoms and, if present, psychological comorbidity. In the future, treatment approaches to functional gastrointestinal disorders are likely to become more personalised, based not only on symptoms but also underlying pathophysiology and psychology., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Psychological distress is associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD) but only evidence from prospective longitudinal and treatment studies can indicate whether the link between FGIDs and psychological distress is causal. Emerging evidence suggests underlying biological mechanisms may explain the association of psychological distress with FGIDs., Areas Covered: This review critically evaluates whether anxiety and/or depression and FGIDs are causally related including evidence for a temporal sequence, strength and specificity of the association, biological gradient, and biological plausibility., Expert Opinion: Accumulating evidence suggests that psychological factors are causal for symptoms in a subset of FGID patients and not explained by health care seeking behavior (brain-gut disorder). In other cases, psychological factors may arise secondary to intestinal disease (gut-brain disorder). Prospective population-based studies are needed in FGIDs other than IBS and FD to determine if a similar brain-gut and gut-brain syndrome exists. Treatment studies have not phenotyped FGIDs according to brain-gut versus gut-brain origins which may be important in understanding true treatment efficacy. Future research needs to unravel biological mechanisms that may explain the link between psychological factors and FGIDs but promising data in the area of the brain-gut-immune-microbe axis is emerging.

Background: Functional gastrointestinal disorders are common and costly to the health-care system. Most specialist care is provided by a gastroenterologist, but only a minority of patients have improvement in symptoms. Although they have proven to be effective, psychological, behavioural, and dietary therapies are not provided routinely. We aimed to compare the outcome of gastroenterologist-only standard care with multidisciplinary care., Methods: In an open-label, single-centre, pragmatic trial, consecutive new referrals of eligible patients aged 18-80 years with Rome IV criteria-defined functional gastrointestinal disorders were randomly assigned (1:2) to receive gastroenterologist-only standard care or multidisciplinary clinic care. The multidisciplinary clinic included gastroenterologists, dietitians, gut-focused hypnotherapists, psychiatrists, and behavioural (biofeedback) physiotherapists. Randomisation was stratified by Rome IV disorder and whether referred from gastroenterology or colorectal clinic. Outcomes were assessed at clinic discharge or 9 months after the initial visit. The primary outcome was a score of 4 (slightly better) or 5 (much better) on a 5-point Likert scale assessing global symptom improvement. Modified intention-to-treat analysis included all patients who attended at least one clinic visit and who had answered the primary outcome question. This study is registered with ClinicalTrials.gov, NCT03078634., Findings: Between March 16, 2017, and May 10, 2018, 1632 patients referred to the hospital gastrointestinal clinics were screened, of whom 442 were eligible for a screening telephone call and 188 were randomly assigned to receive either standard care (n=65) or multidisciplinary care (n=123). 144 patients formed the modified intention-to-treat analysis (n=46 in the standard-care group and n=98 in the multidisciplinary-care group), 90 (63%) of whom were women. 61 (62%) of 98 patients in the multidisciplinary-care group patients saw allied clinicians. 26 (57%) patients in the standard-care group and 82 (84%) patients in the multidisciplinary-care group had global symptom improvement (risk ratio 1·50 [95% CI 1·13-1·93]; p=0·00045). 29 (63%) patients in the standard-care group and 81 (83%) patients in the multidisciplinary-care group had adequate relief of symptoms in the past 7 days (p=0·010). Patients in the multidisciplinary-care group were more likely to experience a 50% or higher reduction in all Gastrointestinal Symptom Severity Index symptom clusters than were patients in the standard-care group. Of the patients with irritable bowel syndrome, a 50-point or higher reduction in IBS-SSS occurred in 10 (38%) of 26 patients in the standard care group compared with 39 (66%) of 59 patients in the multidisciplinary-care group (p=0·017). Of the patients with functional dyspepsia, a 50% reduction in the Nepean Dyspepsia Index was noted in three (11%) of 11 patients in the standard-care group and in 13 (46%) of 28 in the multidisciplinary-care group (p=0·47). After treatment, the median HADS scores were higher in the standard-care group than in the multidisciplinary-care group (13 [8-20] vs 10 [6-16]; p=0·096) and the median EQ-5D-5L quality of life visual analogue scale was lower in the standard-care group compared with the multidisciplinary-care group (70 [IQR 50-80] vs 75 [65-85]; p=0·0087). The eight SF-36 scales did not differ between the groups at discharge. After treatment, median Somatic Symptom Scale-8 score was higher in the standard-care group than in the multidisciplinary-care group (10 [IQR 7-7] vs 9 [5-13]; p=0·082). Cost per successful outcome was higher in the standard-care group than the multidisciplinary-care group., Interpretation: Integrated multidisciplinary clinical care appears to be superior to gastroenterologist-only care in relation to symptoms, specific functional disorders, psychological state, quality of life, and cost of care for the treatment of functional gastrointestinal disorders. Consideration should be given to providing multidisciplinary care for patients with a functional gastrointestinal disorder., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The human gastrointestinal tract harbors most of the microbial cells inhabiting the body, collectively known as the microbiota. These microbes have several implications for the maintenance of structural integrity of the gastrointestinal mucosal barrier, immunomodulation, metabolism of nutrients, and protection against pathogens. Dysfunctions in these mechanisms are linked to a range of conditions in the gastrointestinal tract, including functional gastrointestinal disorders, ranging from irritable bowel syndrome, to functional constipation and functional diarrhea. Irritable bowel syndrome is characterized by chronic abdominal pain with changes in bowel habit in the absence of morphological changes. Despite the high prevalence of irritable bowel syndrome in the global population, the mechanisms responsible for this condition are poorly understood. Although alterations in the gastrointestinal microbiota, low-grade inflammation and immune activation have been implicated in the pathophysiology of functional gastrointestinal disorders, there is inconsistency between studies and a lack of consensus on what the exact role of the microbiota is, and how changes to it relate to these conditions. The complex interplay between host factors, such as microbial dysbiosis, immune activation, impaired epithelial barrier function and motility, and environmental factors, including diet, will be considered in this narrative review of the pathophysiology of functional gastrointestinal disorders., (Copyright © 2020 Carco, Young, Gearry, Talley, McNabb and Roy.)

Background: Small intestinal bacterial overgrowth may play a role in gastrointestinal and non-gastrointestinal diseases., Aims: To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results., Methods: In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta-actin expression. Standard glucose breath test and nutrient challenge test were performed., Results: The duodenal microbial load was higher in patients with FGID (0.22 ± 0.03) than controls (0.07 ± 0.05; P = 0.007) and patients with UC (0.01 ± 0.05) or CD (0.02 ± 0.09), (P = 0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non-users (P < 0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r = 0.21, P < 0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR., Conclusions: Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge., (© 2020 John Wiley & Sons Ltd.)

Chronic unexplained gastrointestinal symptoms impact more than 1 in 5 Americans and their families; these disorders include the irritable bowel syndrome (IBS) and functional dyspepsia (FD), currently classified by Rome IV as functional gastrointestinal disorders. By definition, IBS and FD have no established pathology, but emerging evidence suggests this paradigm may need revision. Immune activation and, in subsets, subtle intestinal pathology have been identified in FD (most notably, postprandial distress syndrome) and IBS-diarrhea. A disease model is proposed that accounts for all of the intestinal and extraintestinal symptoms, relationship to food and infection, and the overlap with gastroesophageal reflux disease. It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the intestine with low-grade intestinal inflammation and subsequently neuronal structural and functional alterations, producing regional intestinal hypersensitivity and motor dysfunction. Immune activation may explain the female predominance and fluctuations in immune activity for symptom variability over time. In the future, as further evidence accumulates, the management paradigm may potentially shift to objective pathology-based subtyping based on serological, microbiological, and clinical assessments to identify when targeted therapies should be deployed in subsets. Potential targeted interventions may include therapies to dampen down immune activation or block release of key mediators such as histamine, specific microbial targeted treatments that may reverse disease, and dietary advice to eliminate relevant food antigens after objective in vivo testing. Only by identifying causation can we eventually anticipate cure, and as the true pathology unravels in subsets, this may become a reality.

Food ingestion is heavily implicated in inducing symptoms of irritable bowel syndrome (IBS) and functional dyspepsia (FD), which affect over one-third of adults in developed countries. The primary aim of this paper was to assess the alignment of dietary assessment and symptom-reporting capture periods in diet-related studies on IBS or FD in adults. Secondary aims were to compare the degree of alignment, validity of symptom-reporting tools and reported significant associations between food ingestion and symptoms. A five-database systematic literature search resulted in 40 included studies, from which data were extracted and collated. The food/diet and symptom capture periods matched exactly in 60% ( n = 24/40) of studies, overlapped in 30% ( n = 12/40) of studies and were not aligned in 10% ( n = 4/40) of studies. Only 30% ( n = 12/40) of studies that reported a significant association between food and global gastrointestinal symptoms used a validated symptom-reporting tool. Of the thirty (75%) studies that reported at least one significant association between individual gastrointestinal symptoms and dietary intake, only four (13%) used a validated symptom tool. Guidelines to ensure that validated symptom-reporting tools are matched with fit-for-purpose dietary assessment methods are needed to minimise discrepancies in the alignment of food and symptom tools, in order to progress functional gastrointestinal disorder research.

Background: Functional gastrointestinal disorders (FGIDs) are the commonest reason for gastroenterological consultation, with patients usually seen by a specialist working in isolation. There is a wealth of evidence testifying to the benefit provided by dieticians, behavioral therapists, hypnotherapists and psychotherapists in treating these conditions, yet they rarely form a part of the therapeutic team, and these treatment modalities are rarely offered as part of the therapeutic management. There has been little examination of different models of care for FGIDs. We hypothesize that multi-disciplinary integrated care is superior to standard specialist-based care in the treatment of functional gut disorders., Methods: The "MANTRA" (Multidisciplinary Treatment for Functional Gut Disorders) study compares comprehensive multi-disciplinary outpatient care with standard hospital outpatient care. Consecutive new referrals to the gastroenterology and colorectal outpatient clinics of a single secondary and tertiary care hospital of patients with an FGID, defined by the Rome IV criteria, will be included. Patients will be prospectively randomized 2:1 to multi-disciplinary (gastroenterologist, gut-hypnotherapist, psychiatrist, behavioral therapist ('biofeedback') and dietician) or standard care (gastroenterologist or colorectal surgeon). Patients are assessed up to 12 months after completing treatment. The primary outcome is an improvement on a global assessment scale at the end of treatment. Symptoms, quality of life, psychological well-being, and healthcare costs are secondary outcome measures., Discussion: There have been few studies examining how best to deliver care for functional gut disorders. The MANTRA study will define the clinical and cost benefits of two different models of care for these highly prevalent disorders., Trial Registration Number: Clinicaltrials.govNCT03078634 Registered on Clinicaltrials.gov, completed recruitment, registered on March 13th 2017. Ethics and Dissemination: Ethical approval has been received by the St Vincent's Hospital Melbourne human research ethics committee (HREC-A 138/16). The results will be disseminated in peer-reviewed journals and presented at international conferences. Protocol version 1.2., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Primary atopic disorders can be classified as heritable genetic disorders presenting with deregulated pathogenic allergic effector responses irrespective of sensitization. In the last decade, there are parallel rises in the burden of atopic and gastrointestinal (GI) diseases. Areas covered: There is increasing recognition of an association between atopy and GI disease through immune dysregulation, the microbiome and shared genetic pathways. Since the first article on atopy and the GI tract in 2014 in this journal, many more studies have shed light on the shared pathways in these diseases, particularly in the field of eosinophilic GI disease, functional GI disorders, and inflammatory bowel disease. Expert opinion: Understanding the links with common mechanisms in atopy and GI diseases that may lead to better targeting of treatment through manipulation of immune mechanisms, the microbiome, genetics, food allergens and specific GI diseases such as inflammatory bowel disease, functional GI disorders.

Background: Gastroenteritis is a risk factor for irritable bowel syndrome (IBS), but its role in other functional gastrointestinal disorders (FGIDs) is less clear. The aim of this study was to determine the prevalence of FGIDs in Gulf War (GW) Veterans before, during, and after deployment and to determine whether gastroenteritis was a risk factor for upper and lower FGIDs., Methods: The Veterans who served during the Persian GW were mailed validated questionnaires inquiring about their bowel habits, psychological and extra-intestinal symptoms, and quality of life (QOL). The lactulose hydrogen breath test (LBT) was performed for small intestinal bacterial overgrowth., Key Results: Data were analyzed from 468 GW Veterans. The prevalence of FGID before, during, and 16 years after deployment was 15.7%, 49.9%, and 64.2%, respectively. New FGIDs during deployment was reported by 41.2%, and during 16 years after deployment, 43.7% acquired new FGIDs. FGIDs were associated with psychological disorders, extra-intestinal symptoms, and lower QOL. Gastroenteritis was reported by 44.3% of deployed Veterans and was a risk factor for IBS, dyspepsia, and functional diarrhea post-deployment. The cases and controls did not differ significantly in the frequency of positive LBT., Conclusions and Inferences: There is an increase in the prevalence of FGIDs during deployment, and it persists after deployment. There is a further increase in the prevalence of FGIDs after deployment. In addition to IBS, gastroenteritis during deployment is a risk factor for dyspepsia and functional diarrhea post-deployment. Therefore, prevention of gastroenteritis during deployment and screening of Veterans for FGIDs post-deployment would be of value for Veterans' long-term health., (© 2019 John Wiley & Sons Ltd.)

Goals: The goal of this study is to evaluate the association between early life infections and subsequent adult onset irritable bowel syndrome (IBS)., Background: Infections during adulthood are a known risk factor for adult-onset IBS. This investigation examined the role of childhood infections and infection risk factors in the development of IBS symptoms., Study: In total, 1010 subjects (509 outpatients with IBS, 501 matched controls) were mailed questionnaires regarding early-life infections during infancy (0 to 12 mo), toddler years (1 to 3 y), and child years (4 to 18 y). Comparisons between cases and controls were performed using logistic regression adjusting for age, gender, and somatization score., Results: Around 648 (64.2%) subjects responded. The median age was 51.3 years (range, 18.0 to 70.7 y) and 535 (83%) were female. Childhood (below 18 y) infections were common in cases and controls (98% vs. 98%; P=0.465), with no differences between cases and controls during infant, toddler, and child-age periods. For gastrointestinal infections experienced below 18 years, no differences were observed by infection type (bacterial, viral, or parasitic) or age group. Cases were more likely to report bronchitis by age 18 [43% vs. 25%; P=0.003; odds ratio, 1.73 (1.20-2.51)], but not other common infections. Regular antibiotic exposure was greater amongst cases (43%) than controls (30%) [P=0.09; odds ratio, 1.37 (0.96-1.96)]. The association between bronchitis and IBS case status remained significant after adjusting for antibiotic use (P=0.01)., Conclusions: Greater early childhood gastrointestinal infections rates were not observed in adult individuals with IBS compared with adult controls. The study does not support a statistically significant link between early life infections and IBS aside from bronchitis.

Competing Interests: Competing interests: NJT served as Chair of the Gastroduodenal Committee for Rome IV and received grant support from Rome Foundation; Abbott Pharmaceuticals; Datapharm; Pfizer; Salix; Prometheus Laboratories; Janssen, Commonwealth Laboratories and Falk. Consultant/Advisory Boards: Adelphi Values (Functional dyspepsia (patient-reported outcome measures)); GI therapies; Sax Institute; Allergens; Napo Pharmaceutical; Outpost Medicine; Samsung Bioepis; Yuhan; Synergy; Theravance. 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’). GJH served on the Gastroduodenal Committee for Rome III and received unrestricted educational support from Bayer and the Falk Foundation. Research support was provided via the Princess Alexandra Hospital, Brisbane by GI Therapies, Takeda Development Center Asia, Eli Lilly Australia, F Hoffmann-La Roche, MedImmune, Celgene, Celgene International II Sarl, Gilead Sciences, Quintiles, Vital Food Processors, Datapharm Australia, Commonwealth Laboratories, Prometheus Laboratories, Falk, Nestle, and Mylan. Patent Holder: A biopsy device to take aseptic biopsies (US 20150320407 A1).

Background: Cigarette smoking is a known risk factor in a number of gastrointestinal (GI) diseases in which the microbiota is implicated, including duodenal ulcer and Crohn's disease. Smoking has the potential to alter the microbiota; however, to date, the impact of smoking on the mucosa-associated microbiota (MAM), and particularly that of the upper GI tract, remains very poorly characterised. Thus, we investigated the impact of smoking on the upper small intestinal MAM. A total of 102 patients undergoing upper GI endoscopy for the assessment of GI symptoms, iron deficiency, or Crohn's disease, but without identifiable lesions in the duodenum, were recruited. Smoking status was determined during clinical assessment and patients classified as current (n = 21), previous smokers (n = 40), or having never smoked (n = 41). The duodenal (D2) MAM was profiled via 16S rRNA gene amplicon sequencing., Results: Smoking, both current and previous, is associated with significantly reduced bacterial diversity in the upper small intestinal mucosa, as compared to patients who had never smoked. This was accompanied by higher relative abundance of Firmicutes, specifically Streptococcus and Veillonella spp. The relative abundance of the genus Rothia was also observed to be greater in current smokers; while in contrast, levels of Prevotella and Neisseria were lower. The MAM profiles and diversity of previous smokers were observed to be intermediate between current and never smokers. Smoking did not impact the total density of bacteria present on the mucosa., Conclusions: These data indicate the duodenal MAM of current smokers is characterised by reduced bacterial diversity, which is partially but not completely restored in previous smokers. While the precise mechanisms remain to be elucidated, these microbiota changes may in some part explain the adverse effects of smoking on mucosa-associated diseases of the GI tract. Smoking status requires consideration when interpreting MAM data.

Background and Aims: The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances., Methods: A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs., Results: Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism., Conclusion: Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Attempts to categorize distinct functional gastrointestinal disorders based on reported symptoms continue but symptoms frequently overlap. The study objective was to use latent class analysis (LCA) which accommodates both continuous and discrete manifest variables to determine mutually exclusive subgroup assignments of a population-based sample using gastrointestinal symptom and patient data., Materials and Methods: A validated bowel disease questionnaire and somatic symptom questionnaire were mailed to an age and gender stratified randomly selected community sample. Responses to the symptom questions were dichotomized as frequent vs. infrequent based on Rome IV criteria. A LCA model was developed using a calibration subset and the results applied to the validation subset., Results: There were 3831 total respondents (48%) with 3425 having complete data. The LCA algorithm was run for each of 10 (random) splits of the dataset and 2-6 latent classes were specified. Using the values of Akaike's Information Criterion coefficient c to determine fit of the data, 4 latent classes yielded better values resulting in four subgroups: 'asymptomatic,' 'upper' abdominal symptoms, 'lower' abdominal symptoms, and 'mixed' (upper and lower abdomen)., Conclusions: Latent class analysis identified 4 groups based on symptoms. This approach resulted in differentiation by anatomical region rather than the Rome IV classification of symptoms.

If you haven't measured something, you really don't know much about it.-Karl Pearson (attributed)Gastrointestinal (GI) symptoms represent an important and often unappreciated cause of morbidity in diabetes, although the significance of this burden across the spectrum of patients and the underlying pathophysiology, including the relationship of symptoms with glycemic control, remain poorly defined. The relevance of GI symptoms and the necessity for their accurate assessment have increased with the greater focus on the gut as a therapeutic target for glucose lowering. This review addresses the prevalence, assessment, pathogenesis, and management of GI symptoms in diabetes, beginning with broad principles and then focusing on specific segments of the GI tract. We initially performed a literature search of PubMed by using synonyms and combinations of the following search terms: "gastrointestinal symptoms", "diabetes", "prevalence", "pathogenesis", "diagnosis", and "management". We restricted the search results to English only. Review papers and meta-analyses are presented as the highest level of evidence where possible followed by randomized controlled trials, uncontrolled trials, retrospective and observational data, and expert opinion., (© 2018 by the American Diabetes Association.)

Background: The clinical assessments of patients with gastrointestinal symptoms can be time-consuming, and the symptoms captured during the consultation may be influenced by a variety of patient and non-patient factors. To facilitate standardized symptom assessment in the routine clinical setting, we developed the Structured Assessment of Gastrointestinal Symptom (SAGIS) instrument to precisely characterize symptoms in a routine clinical setting., Aims: We aimed to validate SAGIS including its reliability, construct and discriminant validity, and utility in the clinical setting., Methods: Development of the SAGIS consisted of initial interviews with patients referred for the diagnostic work-up of digestive symptoms and relevant complaints identified. The final instrument consisted of 22 items as well as questions on extra intestinal symptoms and was given to 1120 consecutive patients attending a gastroenterology clinic randomly split into derivation (n = 596) and validation datasets (n = 551). Discriminant validity along with test-retest reliability was assessed. The time taken to perform a clinical assessment with and without the SAGIS was recorded along with doctor satisfaction with this tool., Results: Exploratory factor analysis conducted on the derivation sample suggested five symptom constructs labeled as abdominal pain/discomfort (seven items), gastroesophageal reflux disease/regurgitation symptoms (four items), nausea/vomiting (three items), diarrhea/incontinence (five items), and difficult defecation and constipation (2 items). Confirmatory factor analysis conducted on the validation sample supported the initially developed five-factor measurement model ([Formula: see text], p < 0.0001, χ 2 /df = 4.6, CFI = 0.90, TLI = 0.88, RMSEA = 0.08). All symptom groups demonstrated differentiation between disease groups. The SAGIS was shown to be reliable over time and resulted in a 38% reduction of the time required for clinical assessment., Conclusions: The SAGIS instrument has excellent psychometric properties and supports the clinical assessment of and symptom-based categorization of patients with a wide spectrum of gastrointestinal symptoms.

Background & Aims: Understanding the interactions between brain and gastrointestinal disorders requires analysis of the order of disease onset. We analyzed data from 2 independent studies to determine the proportion of individuals with diagnoses of functional gastrointestinal disorders (FGIDs) before diagnoses of mood or anxiety disorders (gut to brain), and vice versa (brain to gut)., Methods: We collected data from a retrospective study of 4966 patients diagnosed with a FGID (irritable bowel syndrome, dyspepsia, or constipation) and mood or anxiety disorder at general practices in the United Kingdom (health care seekers) over an average period of 13.1 years; we recorded which diagnosis appeared first and compared these with patients' sex and socioeconomic factors. We also collected data from a population study of 1002 randomly selected individuals in Australia (non-heath care seekers) followed from 1997 through 2009; we determined whether subjects were free of either FGID or an anxiety or mood disorder at baseline but developed either one after a 12-year follow-up period., Results: Among the 4966 health care seekers, 3279 patients were diagnosed with a mood or anxiety disorder before an FGID (ratio of 2:1). This ratio increased with socioeconomic disadvantage. The time period between diagnosis of mood or anxiety disorder and FGID was longer (median, 3.5 years) than time period between diagnosis of an FGID and a mood or anxiety disorder (median, 1.8 years). Among non-heath care seekers (population study), equal proportions were diagnosed with a mood or anxiety disorder before versus after an FGID., Conclusions: In an analysis of data from a study of patients and a population-based study of individuals with these diagnoses, we found 2-fold more patients to receive a diagnosis of a mood or anxiety disorder before an FGID, but equal proportions of individuals in the population to be diagnosed with the mood or anxiety disorder before versus after an FGID. Among patients, the mood or anxiety disorder was on average diagnosed more than 3 years before the FGID, offering opportunity for prevention. Our findings support a role for adverse socioeconomic factors in development of FGIDs in patients with psychological disorders., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota-gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut-brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.

Background: Traditionally, functional gastrointestinal disorders (FGIDs) are conceptualised as originating in the brain via stress pathways (brain-to-gut). It is uncertain how many with irritable bowel syndrome (IBS) and functional dyspepsia (FD) have a gut origin of symptoms (gut-to-brain pathway)., Aims: To determine if there is a distinct brain-to-gut FGID (where psychological symptoms begin first) and separately a distinct gut-to-brain FGID (where gut symptoms start first)., Methods: A prospective random population sample from Newcastle, Australia who responded to a validated survey in 2012 and completed a 1-year follow-up survey (n = 1900). The surveys contained questions on Rome III IBS and FD and the Hospital Anxiety and Depression Scale., Results: We found that higher levels of anxiety and depression at baseline were significant predictors of developing IBS (OR = 1.31; 95% CI 1.06-1.61, P = 0.01; OR = 1.54; 95% CI 1.29-1.83, P < 0.001) and FD (OR = 1.28; 95% CI 1.05-1.55, P = 0.01; OR = 1.55, 95% CI 1.32-1.83, P < 0.001), respectively, at the 1-year follow-up. Among those people who did not have elevated levels of anxiety and depression at baseline, subjects at baseline with documented IBS (mean difference 0.34; 95% CI 0.13-0.55, P = 0.002; 0.81; 95% CI 0.47-1.15, P < 0.001) and FD (0.38; 95% CI 0.14-0.63, P = 0.002; 0.92; 95% CI 0.57-1.27, P < 0.001), reported significantly higher levels of anxiety and depression at the 1-year follow-up. We calculated in one-third of individuals a mood disorder precedes FGID but in two-thirds an FGID precedes the mood disorder., Conclusion: While brain-gut pathways are bidirectional, a major subset begin with gut symptoms first and only then psychological distress develops, implicating primary gut mechanisms as drivers of the gut and extra-intestinal features in many cases., (© 2016 John Wiley & Sons Ltd.)

Background: Colonoscopic biopsies are taken to make a diagnosis of inflammation, dysplasia or malignancy, to assess treatment success and to monitor patients' progression., Objective: This aim of this article is to provide a guide to understanding histology reports sent to the general practitioner (GP) from the colonoscopy and anatomical pathology departments for the diagnosis of increasingly prevalent gastrointestinal (GI) diseases., Discussion: Many diseases in the lower GI tract are increasing in prevalence and new diseases are emerging that require biopsy for diagnosis. Cancer surveillance programs require colonoscopy for polyp detection, and histology to evaluate polyps and subsequent cancer risk in the large bowel. Inflammatory bowel disease is also increasing in incidence, and patients are diagnosed and monitored with endoscopy and biopsy. Drugs can also affect the GI tract and endoscopy can detect damage with confirmation by biopsy.

Background: Reduced sleep quality has been linked to obesity; however, no studies have assessed the impact of gastrointestinal (GI) symptoms on sleep quality among obese individuals. This study aims to determine the role of gastrointestinal symptoms on sleep among obese individuals in a community-based sample., Methods: A validated questionnaire was sent to 5000 randomly selected subjects in Western Sydney, Australia. Assessed were five GI symptoms that might wake individuals from sleep (abdominal pain, diarrhea, chest pain, acid regurgitation, and heartburn). Sleep quality was measured using the validated Pittsburgh Sleep Quality Index (PSQI). Additional measures included socioeconomic status (SES) and body mass index (BMI)., Results: The response rate was 60 %. There were 647 (25.13 %) obese individuals. Prevalence estimates for general quality of sleep were reported as very good (18.51 %), fairly good (53.19 %), fairly bad (20.68 %), and very bad (7.62 %). Obese individuals reported less hours of actual sleep than nonobese individuals (OR = 0.87; 95 % CI 0.81-0.94). Quality of sleep was worse for obese compared to nonobese individuals (OR = 1.25; 95 % CI 1.12-1.40). Univariate analysis found that all GI symptoms were more likely to wake obese people from their sleep; however, only two GI symptoms (chest pain: OR = 1.60; 95 % CI 1.25-2.04) and (acid regurgitation: OR = 1.27; 95 % CI 1.05-1.53) were independent predictors of sleep disturbance., Conclusions: Gastrointestinal symptoms did not predict waking in nonobese individuals. Chest pain and acid regurgitation are major GI symptoms associated with waking obese individuals from sleep. Overall, obese individuals have a worse quality of sleep compared to nonobese individuals.

Gastrointestinal conditions may be broadly classified into two: organic and functional disease, with functional disorders accounting for the majority of patients with chronic gastrointestinal symptoms. Functional gastrointestinal disorders (FGIDs) present with no obvious pathology or well-accepted biochemical mechanism and, as such, treatment strategies are limited and focus on symptoms rather than cure. Irritable bowel syndrome and functional dyspepsia are the most widely recognised FGIDs, and there is a growing body of evidence to suggest an underlying inflammatory phenotype in subsets with these conditions. Here, we discuss the current knowledge of immune involvement in FGIDs and the commonalities between the different manifestations of FGIDs and propose a new hypothesis, potentially defining an underlying immunopathological basis of these conditions., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Gastrointestinal infections are risk factors for irritable bowel syndrome (IBS) and functional dyspepsia (FD). We investigated whether non-enteric infections and antibiotic exposure are also associated with the development of functional gastrointestinal disorders (FGIDs)., Methods: In a nested case-control study, random samples of Olmsted County, MN, were mailed valid self-report questionnaires from 1988 through 1994, and then follow-up questionnaires from 1995 through 2003. Survey responders who did not report any FGID symptoms at baseline, but then reported such symptoms in at least one subsequent survey, were classified as new-onset cases. Age-matched controls were individuals who did not have symptoms at either the initial or subsequent surveys., Key Results: The overall response rate was 78% to the initial survey and 52% to the follow-up survey. Based on the responses, 316 participants had a new onset of an FGID (43 IBS constipation, 95 IBS diarrhea, 25 IBS mixed, and 153 other FGIDs, including FD) and 250 did not (controls). Around 76% (241/316) of cases reported a non-enteric infection vs 66% (166/250) of the controls. The frequency of enteric infections was similar between the two groups. Of the new FGID cases, 83% had a non-enteric infection that was treated with antibiotic. In a logistic regression model, treatment with antibiotics for a non-gastrointestinal infection was associated with the development of an FGID (odds ratio = 1.90; 95% CI: 1.21-2.98; p = 0.005), after adjusting for age and sex., Conclusions & Inferences: Based on a case-control study, treatment of a non-gastrointestinal infection with antibiotics appears to be a risk factor for development of an FGID., (© 2015 John Wiley & Sons Ltd.)

Background & Aims: Celiac disease has been linked to irritable bowel syndrome (IBS)-like symptoms in outpatient clinics. Guidelines recommend that all patients with IBS-like symptoms undergo serologic testing for celiac disease, but there is controversy over whether celiac disease is more prevalent in populations with IBS-like symptoms. We aimed to determine whether positive results from serologic tests for celiac disease are associated with IBS and other functional gastrointestinal disorders (FGIDs) in a large U.S. white population., Methods: Validated, self-report bowel disease questionnaires (BDQs) were sent to randomly selected cohorts of Olmsted County, Minnesota residents. In separate protocols, serum samples were collected from more than 47,000 Olmsted County residents without a prior diagnosis of celiac disease; we performed serologic tests for celiac disease on stored serum samples from residents who completed the BDQ. Logistic regression was used to test for the association between serologic markers of celiac disease (positive vs negative) and individual FGIDs., Results: A total of 3202 subjects completed the BDQ and had serum available for testing. IBS was identified in 13.6% of these subjects (95% confidence interval [CI], 12.4%-14.8%), and any gastrointestinal symptom occurred in 55.2% (95% CI, 53.5%-56.9%). The prevalence of celiac disease on the basis of serologic markers was 1.0% (95% CI, 0.7%-1.4%). IBS was less prevalent in patients with celiac disease (3%) than patients without celiac disease (14%), although the difference was not statistically significant (odds ratio, 0.2; 95% CI, 0.03-1.5). Abdominal pain, constipation, weight loss, and dyspepsia were the most frequent symptom groups in subjects who were seropositive for celiac disease, but none of the gastrointestinal symptoms or disorders were significantly associated with celiac disease serology., Conclusions: Symptoms indicative of FGIDs and seropositive celiac disease are relatively common in a U.S. white community. Testing for celiac disease in patients with IBS in the community may not have a significantly increased yield over population-based screening in the United States., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Few instruments have been developed and validated for the evaluation of multi-dimensional GI symptoms. The Gastrointestinal Symptoms Severity Index (GISSI), a multi-dimensional, self-report instrument, was designed as a brief measure of the frequency, severity, and bothersomeness of individual GI and pelvic floor/urogynecologic symptoms., Aim: To report the psychometric properties of the GISSI subscales, including factorial structure, validity, and internal consistency., Methods: The GISSI included 32 items that assessed upper and lower GI symptoms and seven items related to pelvic floor/urogynecologic symptoms. A total of 934 patients presenting for upper and lower GI complaints completed the questionnaire between January 2013 and December 2013. The sample was randomly split into derivation (n = 466) and validation datasets (n = 468). A non-patient sample of 200 was collected separately., Results: Exploratory factor analysis supported a six-factor model for the derivation sample that accounted for 69.3 % of the total variance. The six GI symptom clusters were labeled as constipation/difficult defecation (five items), abdominal pain/discomfort (four items), dyspepsia (four items), diarrhea/anal incontinence (four items), GERD/chest symptoms (four items), and nausea/vomiting (two items). Inclusion of additional items related to female pelvic floor/urogynecologic symptoms resulted in a separate factor. Confirmatory factor analysis of the validation dataset supported the a priori hypothesized six-factor measurement model (Χ (2)(428) = 1462.98; P < 0.001; GFI = .88; RMSEA = .051)., Conclusion: The GISSI demonstrated good to excellent psychometric properties and provided multi-dimensional scaling of prominent GI symptom clusters. Further validation may provide an efficient, valid, and reliable measure of patient-reported clinical outcomes.

Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lacking. Traditionally FGIDs have been conceptualized as brain-gut disorders, with subgroups of patients demonstrating visceral hypersensitivity and motility abnormalities as well as psychological distress. However, it is becoming apparent that there are certain structural or biochemical gut alterations among subsets with the common FGIDs, most notably functional dyspepsia (FD) and irritable bowel syndrome (IBS). For example, a sodium channel mutation has been identified in IBS that may account for 2 % of cases, and subtle intestinal inflammation has been observed in both IBS and FD. Other research has implicated early life events and stress, autoimmune disorders and atopy and infections, the gut microbiome and disordered mucosal immune activation in patients with IBS or FD. Understanding the origin of symptoms in FGIDs will allow therapy to be targeted at the pathophysiological changes, not at merely alleviating symptoms, and holds hope for eventual cure in some cases. For example, there are promising developments in manipulating the microbiome through diet, prebiotics and antibiotics in IBS, and testing and treating patients for Helicobacter pylori infection remains a mainstay of therapy in patients with dyspepsia and this infection. Locally acting drugs such as linaclotide have been an advance in treating the symptoms of constipation-predominant IBS, but do not alter the natural history of the disease. A role for a holistic approach to patients with FGIDs is warranted, as brain-to-gut and gut-to-brain pathways appear to be activated.

Objective: The rich interconnectedness between gut and brain is increasingly being identified. This article reviews the evidence for brain-gut and gut-brain syndromes, particularly recent epidemiological evidence, and animal studies demonstrating bi-directionality at the formative stage of development., Method: Narrative literature review with selection for relevance and quality., Results: Population surveys show a strong correlation between anxiety, depression, and functional gastrointestinal disorders, contradicting early suspicions that the high prevalence of anxiety and depression in the clinic was mainly due to neurotic health seeking behaviour. Five and 12 year follow-up shows that psychological distress can predict later onset of a functional gastrointestinal disorder and vice versa. Brain-gut pathways include the autonomic nervous system, hypothalamic-pituitary-adrenal axis including corticotrophin releasing factor directly acting on the gut. Gut-brain pathways include ascending pain pathways, cytokines including tumour necrosis factor alpha in response to bacterial translocation and inflammation, 5-hydroxytryptamine secretion by entero-endocrine cells and psychoactive chemicals of bacterial origin which may enter the blood stream, such as gamma-aminobutyric acid, fatty acids and 5-hydroxytryptamine precursors. The ability to control rodent temperament and HPA responsiveness with early modification of gastrointestinal flora, and the effects of early stress on the barrier function of the gastrointestinal tract and flora, suggests an ability of both systems to prime each other in early life for later problems. This hypothesis seems to be supported by a possible protective effect of a probiotic strain of bacteria in a model of early rat psychological trauma., Conclusion: Psychological treatments are known to improve functional gastrointestinal disorders, the next wave of research may involve preventative microbiological gut based treatments for primary psychological presentations, both to treat the presenting complaint and inoculate against later functional gastrointestinal disorders., (© The Royal Australian and New Zealand College of Psychiatrists 2015.)

In many parts of the world, there continues to be a long-standing tradition of prescribing herbal products for a range of gastrointestinal conditions. Scientific evidence supporting the use of all herbal preparations is imperfect, however, and available studies are plagued by methodological limitations. For functional gastrointestinal disorders, there is limited evidence supporting the use of some well-characterized preparations. A number of herbals have immunomodulatory activity, and in inflammatory bowel disease there are limited positive placebo-controlled trials; other studies used active controls with suboptimal doses of the comparators. Like all drugs, herbals can lead to serious adverse events (eg, hepatic failure). Quality control is a serious issue to consider when prescribing herbal medicines. Many herbal preparations are marketed without evidence for stringent adherence to good manufacturing practice guidelines. Unpredictable environmental conditions may affect the composition and the concentration of the active ingredients of plant extracts. Further, commercial herbal products usually combine a variable plethora of chemical families with possible medicinal utility. While some of these ingredients might be of benefit, the concentration and dose of these constituents needs to be closely monitored. Physicians and regulators need to remain very cautious about the use of herbal remedies. Appropriate scientific evidence for the claimed clinical benefits should become mandatory worldwide, and the standards for production and safety monitoring should comply with established standards for chemically defined products. If these principles were adopted, the full value of herbal remedies may come to light, particularly as the individually bioactive compounds present in these preparations become recognized., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence of gastrointestinal (GI) and non-GI comorbidities and the risk of incident comorbidities among patients with and without chronic constipation (CC)., Research Design and Methods: Adults with CC were identified from a large retrospective US claims database. Each CC patient was matched 1:3 to CC-free patients by birth year, sex, and region of residence., Main Outcome Measures: Prevalence of GI and non-GI comorbidities was measured over a 1-year period. Relative risk of new comorbidities was also estimated among patients who were free of the studied comorbidity prior to the index date., Results: Mean age was 61.9 years; 33.3% of patients were male. The 1-year prevalence of GI comorbidities was significantly higher in CC (N = 28,854) vs. CC-free (N = 86,562) patients (all p < 0.05). The risk of developing new GI conditions was also significantly higher in CC patients for all studied conditions except ulcerative colitis: megacolon (hazard ratio [95% confidence interval] HR [CI] = 11.96 [8.16-17.53]), intestinal impaction (10.56 [9.22-12.10]), volvulus (7.12 [5.42-9.35]), other specified functional intestinal disorders (6.67 [5.57-8.00]), and other unspecified functional disorders of intestine (4.60 [3.61-5.87]). Similarly, 1-year prevalence of non-GI comorbidities was higher in CC patients, as was the risk of developing new conditions: depression and mood disorder (HR [CI] = 1.84 [1.77-1.90]), neurological disorders (1.68 [1.62-1.74]), iron deficiency anemia (1.52 [1.47-1.57]), hypothyroidism (1.40 [1.34-1.46]), and peripheral vascular disorders (1.40 [1.34-1.46])., Limitations: An algorithm was used to define CC as there is no specific diagnosis code to identify CC., Conclusions: CC patients had significantly higher prevalence and were at increased risk of developing new GI and non-GI comorbidities than age-, gender- and region-matched CC-free patients. Future research is warranted to better understand these associations.

Background: There is increasing evidence that impaired mucosal defence mechanisms are implicated in the pathogenesis of the functional gastrointestinal disorders (FGIDs), allowing inappropriate immune activation., Aim: To test the hypothesis that an excess of autoimmune disorders among sufferers, using a large primary care database to examine this., Methods: Cases were diagnosed with FGIDs - irritable bowel syndrome (IBS), functional dyspepsia (FD), chronic idiopathic constipation (CIC), and multiple FGIDs. Controls were those without FGIDs. Prevalence of autoimmune disorders was compared between cases and controls using odds ratios (ORs) and 95% confidence intervals (CIs)., Results: We included 23,471 patients (mean age 51.4 years, 66.1% female). Prevalence of autoimmune disorders was greater among all FGIDs, compared with controls without. In those with FD (OR 1.35; 95% CI 1.12-1.63), CIC (OR 1.75; 95% CI 1.11-2.75), or multiple FGIDs (OR 1.49; 95% CI 1.25-1.77) this was statistically significant after controlling for age and gender. Rheumatological autoimmune disorders were significantly more frequent in those with FD (OR 1.44; 95% CI 1.15-1.80), CIC (OR 1.84; 95% CI 1.08-3.13), or multiple FGIDs (OR 1.53; 95% CI 1.24-1.88), after controlling for age and gender. However, endocrine autoimmune disorders were no more frequent in those with FGIDs, after controlling for age and gender., Conclusions: In a large sample of primary care patients, there was a significantly higher prevalence of autoimmune disorders among those with FD, CIC, or multiple FGIDs not explained by differences in age or gender. We were unable to control for concomitant drug use, which may partly explain this association., (© 2014 John Wiley & Sons Ltd.)

In addition to diseases conventionally associated with atopy there is increasing recognition that atopy is also linked to a spectrum of gastrointestinal (GI) manifestations, including food allergy, primary eosinophilic GI disease, functional gastrointestinal disorders, gluten interactions, gastroesophageal reflux disease and inflammatory bowel disease. These associations may be underpinned by shared genetic susceptibilities, initiation of related immune pathways and common patterns of exposure to environmental cues, including allergen/pathogen encounters and variations in the composition of the intestinal microbiota. Further scrutiny of GI diseases with prominent allergic-type immune responses may yet redefine treatment paradigms for these common and important atopy-associated diseases. Looking forward, interventions by manipulation of the microbiota or host immune responses hold promise, but there is still room for further exploration of this novel field of host susceptibility, host-microbe interactions and atopy-associated GI diseases.

Backgrounds: The development of a reliable biomarker for irritable bowel syndrome (IBS) remains one of the major aims of research in functional gastrointestinal disorders (FGIDs) and is complicated by the absence of a perfect reference standard. Previous efforts based on genetic and immune markers have showed promise, but have not been robust., Aim: To evaluate an extensive panel of gene expression and serology markers combined with psychological measures in differentiating IBS from health and between subtypes of IBS., Methods: Of subjects eligible for analysis (N = 244), 168 met criteria for IBS (60 IBS-C, 57 IBS-D and 51 mixed), while 76 were free of any FGID. A total of 34 markers were selected based on pathways implicated in pathophysiology of IBS or whole human genome screening. Psychological measures were recorded that covered anxiety, depression and somatisation. Models differentiating disease and health were based on unconditional logistic regression and performance assessed through area under the receiver-operator characteristic curve (AUC), sensitivity and specificity., Results: The performance of a combination of 34 markers was good in differentiating IBS from health (AUC = 0.81) and was improved considerably with the addition of four psychological markers (combined AUC = 0.93). Of the 34 markers considered, discrimination was derived largely from a small subset. Good discrimination was also obtained between IBS subtypes with the best being observed for IBS-C vs. IBS-D (AUC = 0.92); however, psychological variables provided almost no incremental discrimination subtypes over biological markers (combined AUC = 0.94)., Conclusions: A combination of gene expression and serological markers in combination with psychological measures shows exciting progress towards a diagnostic test for IBS compared with healthy subjects, and to discriminate IBS-C from IBS-D., (© 2014 John Wiley & Sons Ltd.)