A Minority of Childhood Disorders of Gut-Brain Interaction Persist Into Adulthood: A Risk-Factor Analysis.

INTRODUCTION: Disorders of gut-brain interaction (DGBIs) may originate in childhood. There are currently limited data on persistence of DGBI into adulthood and risk factors for persistence. Furthermore, there are no data on this question from general practice, where the majority of DGBIs are diagnosed and managed. This study documents the proportion of childhood-diagnosed DGBIs that persisted into adulthood and what factors were associated with persistence. METHODS: General practice records were obtained for more than 60,000 patients whose medical record spanned both childhood and adulthood years. Patients with diagnosed organic gastrointestinal disorder were excluded. Medical records were also interrogated for potential risk factors. RESULTS: Eleven percent of patients with irritable bowel syndrome (IBS) and 20% of patients with functional dyspepsia (FD) diagnosed in childhood had repeat diagnoses of the same condition in adulthood. Female sex (odds ratio [OR] 2.02) was associated with persistence for IBS, while a childhood diagnosis of gastritis (OR 0.46) was risk-protective. Childhood non-steroidal anti-inflammatory drug use (OR 1.31, 95% confidence interval [CI] 1.09-1.56) was a risk factor for persistence in IBS. For FD, a childhood diagnosis of asthma (OR 1.30, 95% CI 1.00-1.70) was a risk factor, as was anxiety for both IBS (OR 1.24, 95% CI 1.00-1.54) and FD (OR 1.48 95% CI 1.11-1.97) with a similar finding for depression for IBS (OR 1.34, 95% CI 1.11-1.62) and FD (OR 1.88 95% CI 1.47-2.42). DISCUSSION: Childhood DGBIs persist into adulthood in 10%-20% of patients, suggesting that management monitoring should continue into adulthood. Those diagnosed with anxiety or mood disorders in childhood should receive particular attention, and prescription of non-steroidal anti-inflammatory drugs in children should be made judiciously.

Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia.

OBJECTIVE: Functional dyspepsia (FD) is a complex disorder, with debilitating epigastric symptoms. Evidence suggests alterations in gastrointestinal (GI) motility, visceral hypersensitivity, permeability and low-level immune activation in the duodenum may play a role. However, we still have a relatively poor understanding of how these factors interact to precipitate the onset of FD symptoms which are frequently meal related. The duodenal microbiota, in combination with specific dietary substrates, may be important mediators in disease pathophysiology; however, these interlinked factors have not been thoroughly investigated in FD. DESIGN: Eighty-six individuals (56 FD, 30 controls) undergoing endoscopy were consecutively recruited and underwent detailed clinical assessment, including upper GI symptoms, gastric emptying and dietary assessment. Duodenal biopsies were obtained aseptically, and the mucosa-associated microbiota (MAM) analysed via 16S rRNA gene amplicon sequencing. RESULTS: The relative abundances of predominant members of the Firmicutes, Bacteroidota and Fusobacteriota phyla were linked to symptom burden in FD. Inverse relationships between the relative abundances of Streptococcus and Prevotella, and the relative abundance of Veillonella spp with gastric emptying time, were also observed. No significant differences in long-term nutrient intake or diet quality were found between FD and controls, and there appeared to be limited association between habitual diet and duodenal MAM profiles. CONCLUSION: This study suggests a link between the duodenal MAM, gastric emptying and FD symptoms, and this is largely independent of long-term dietary intake.

Diabetes mellitus is an independent risk factor for a greater frequency of early satiation and diarrhea at one and three years: Two prospective longitudinal population-based studies.

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.

The duodenal mucosa associated microbiome, visceral sensory function, immune activation and psychological comorbidities in functional gastrointestinal disorders with and without self-reported non-celiac wheat sensitivity.

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+ß7+CCR9+/CD8+α4+ß7+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+ ß7+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.

Evaluation of a Multidisciplinary Integrated Treatment Approach Versus Standard Model of Care for Functional Gastrointestinal Disorders (FGIDS): A Matched Cohort Study.

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.

Overlap of heartburn, functional dyspepsia, and irritable bowel syndrome in a population sample: Prevalence, temporal stability, and associated comorbidities.

BACKGROUND: Co-occurring (overlapping) irritable bowel syndrome (IBS), functional dyspepsia (FD), and heartburn has been observed. However, whether it is a distinct entity has not been established, nor what clinical, demographic, lifestyle, and psychological traits are associated with it. This study sought to estimate the prevalence and temporal stability of this overlap and to identify features specific to it in order to gain some insights into the potential etiopathogenesis. METHODS: Two waves of a survey to a population-representative sample were conducted 3 years apart, recruiting 1312 individuals for this study. The chance-expected probability of complete overlap (CO) was calculated and compared with the observed CO. A range of demographic, lifestyle factors, medical diagnoses, sleep quality, and psychological distress were tested to identify predictors of overlap using logistic regression. KEY RESULTS: CO was observed in 2.1% (95% confidence interval 1.9, 3.7) of the sample and was closely replicated in wave 2 at 2.0%. The observed CO was greater than expected by chance (0.2%) to a statistically significant extent (p < 0.001). Overlap between IBS subtypes, FD subtypes, and heartburn was also elevated above chance expectation. Individuals with CO were separately differentiated from others with respect to elevated rates of self-reported medically diagnosed asthma, elevated psychological distress score, and elevated impact on sleep quality. The discrimination provided by these factors was further independent of age and sex. CONCLUSIONS AND INFERENCES: Overlap between IBS, FD, and heartburn (GERD) appears to be a distinct entity that has a profile including psychological morbidity, sleep disturbance, and elevated rates of atopy.

Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia.

Background: Functional dyspepsia is characterised by chronic symptoms of post-prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cells have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific phenotype was associated with FD. Objective: This study aimed to characterise T cell populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology. Methods: We identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry using a surface marker antibody panel. We also analysed T cell populations in peripheral blood from 37 controls and 61 patients. Where available, we examined the number of duodenal eosinophils in patients and controls. Results: There was a shift in the duodenal T helper cell balance in FD patients compared to controls. For example, patients had increased duodenal mucosal Th2 populations in the effector (13.03 ± 16.11, 19.84 ± 15.51, p=0.038), central memory (23.75 ± 18.97, 37.52 ± 17.51, p=0.007) and effector memory (9.80±10.50 vs 20.53±14.15, p=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75, p=0.03) and effector memory (11.95±8.42 vs 18.44±15.63, p=0.027) subsets. Peripheral T cell populations were unchanged between FD and control. Conclusion: Our findings identify an association between lymphocyte populations and FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.

The role of mood state and emotion regulation in the discrepancy between gastrointestinal symptom burden recorded prospectively and via recall questionnaire.

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.

Antibiotic use but not gastrointestinal infection frequently precedes first diagnosis of functional gastrointestinal disorders.

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.