Fermentable Sugar Ingestion, Gas Production, and Gastrointestinal and Central Nervous System Symptoms in Patients With Functional Disorders.

BACKGROUND & AIMS: Functional gastrointestinal disorders (FGID) are defined by broad phenotypic descriptions and exclusion of recognizable disease. FGIDs cause multi-organ symptoms and abnormal results in a wide range of laboratory tests, indicating broad mechanisms of pathogenesis. Many patients with FGID develop symptoms following ingestion of fermentable sugars; we investigated the associations between symptoms and intestinal gas production following sugar provocation tests to elucidate mechanisms of FGID. METHODS: We performed fructose and lactose breath tests in 2042 patients with a diagnosis of FGID (based on Rome III criteria), referred to a gastroenterology practice from January 2008 through December 2011. Medical and diet histories were collected from all subjects. Breath samples were collected before and each hour after, for 5 hours, subjects ingested fructose (35 g) and lactose (50 g) dissolved in 300 mL water. Hydrogen and methane gas concentrations were measured and GI and non-GI symptoms were registered for 5 hours following sugar ingestion. Symptom and gas time profiles were compared, treelet transforms were used to derive data-related symptom clusters, and the symptom severity of the clusters were analyzed for their association with breath gas characteristics. RESULTS: We identified 11 GI and central nervous system (CNS) symptom profiles and hydrogen and methane breath concentrations that changed significantly with time following sugar ingestion. Treelet transform analysis identified 2 distinct clusters, based on GI and CNS symptoms. The severity scores for the GI and CNS symptoms correlated following ingestion of sugars (all, P < .0001). However, only the GI symptoms associated with hydrogen and methane gas production (all, P < .0001). CONCLUSIONS: In an analysis of breath test results from more than 2000 patients with FGIDs, we identified clusters of GI and CNS symptoms in response to fructose of lactose ingestion. The association between specific symptoms and breath gas concentrations indicate distinct mechanisms of FGID pathogenesis, such as changes in the microbiome or mechanical and chemical sensitization. ClinicalTrials.gov ID: NCT02085889.

Symptoms of mast cell activation syndrome in functional gastrointestinal disorders.

Objectives: Mast cell involvement is evident in functional gastrointestinal disorders (FGID). FGID and mast cell activation syndrome (MCAS) are associated with multi-organ symptoms. An overlap has not been assessed.Methods: MCAS symptoms were determined by questionnaires in 2083 FGID patients.Results: The median number of MCAS symptoms ([IQR] (range 0-16)) was 6 [4-8] in all FGID, and in functional dyspepsia (FD) patients, 7 [5-9] in overlapping irritable bowel syndrome and FD (IBS+FD), 5 [3-8] in IBS and 5 [3-6] in non-IBS/non-FD (p < .001 vs. FD and IBS + FD) patients. MCAS symptoms in ≥2 organ-systems existed in 1773 (85%) of all patients.Conclusions: MCAS symptoms are common in FGID warranting further mechanistic investigation.

Longitudinal study of gastroesophageal reflux and erosive tooth wear.

BACKGROUND: Approximately 60% of patients presenting to dentists with erosive tooth wear have significant gastroesophageal reflux (GERD), despite minor reflux symptoms. No longitudinal studies of reflux-associated erosive tooth wear and of reflux characteristics have been reported to date. The aim of this study was to characterize the longitudinal course of GERD and of associated erosive tooth wear, as well as factors predictive of its progression, in a large group of patients. METHODS: Seventy-two patients presenting to dentists with clinically significant erosive tooth wear and increased esophageal acid exposure by 24-h multichannel intraluminal pH-impedance measurement (MII-pH) were re-assessed clinically and by MII-pH after 1 year treatment with esomeprazole 20 mg twice-daily. Predictive factors for erosive tooth wear were assessed by logistic regression. RESULTS: At follow-up, no further progression in erosive tooth wear was observed in 53 (74%) of patients. The percentage of time with a pH < 4, the number of acid reflux episodes and the percentage of proximal esophageal reflux off-PPI did not change significantly after one year, but the number of weakly acidic reflux episodes decreased significantly in the large subgroup without progression. None of the baseline demographic, clinical, endoscopic or esophageal acid exposure characteristics were significantly associated with progression of erosive tooth wear at follow-up. CONCLUSIONS: In this longitudinal study in patients with erosive tooth wear and oligosymptomatic GERD receiving esomeprazole for one year, erosive tooth wear did not progress further in the majority of patients. Background acidic esophageal reflux exposure appeared stable over time, whereas weakly acidic exposure decreased significantly in patients without erosion progression. MII-pH measurements on-PPI and with healthy controls will be useful in the further elucidation of the causal role of reflux in erosive tooth wear. TRIAL REGISTRATION: ClinicalTrials.gov , retrospectively registered: NCT02087345 .

Blueberries Improve Abdominal Symptoms, Well-Being and Functioning in Patients with Functional Gastrointestinal Disorders.

Blueberries beneficially modulate physiologic mechanisms relevant to the pathogenesis of functional gastrointestinal disorders (FGID). Forty-three patients with FGID received freeze-dried blueberries (equivalent to 180 g fresh blueberries) or sugar and energy-matched placebo in a double-blind, randomized, cross-over study. After 6 weeks of treatment, the differences in Gastrointestinal Clinical Rating Scale (GSRS) scores and abdominal symptom relief were compared as primary outcome measures. The quality of life and life functioning ratings (OQ45.2 questionnaire), Bristol stool scales, and fructose breath test results constituted secondary outcome measures. Blueberry treatment resulted in more patients with relevant abdominal symptom relief compared to placebo (53% vs. 30%, p = 0.03). Total and pain GSRS scores improved insignificantly (mean treatment differences [95% CI]: -3.4 [-7.4 to 0.6] (p = 0.09) and -1.0 [-2.2 to 0.1] (p = 0.08), respectively). OQ45.2 scores improved during blueberry treatment compared to placebo (treatment difference -3.2 [95% CI: -5.6 to -0], p = 0.01). Treatment effect differences for the further measures did not reach statistical significance. Blueberries relieved abdominal symptoms and improved general markers of well-being, quality of life, and life functioning more than placebo in patients with FGID. Consequently, the polyphenol and fiber components of blueberries exert broad beneficial effects separate from the sugars present in both treatments.

Fructose intolerance is not associated with malabsorption in patients with functional gastrointestinal disorders.

BACKGROUND: Symptoms following fructose ingestion, or fructose intolerance, are common in patients with functional gastrointestinal disorders (FGID) and are generally attributed to intestinal malabsorption. The relationships between absorption, symptoms, and intestinal gas production following fructose ingestion were studied in patients with FGID. METHODS: Thirty FGID patients ingested a single dose of fructose 35 g or water in a randomized, double-blind, crossover study. Blood and breath gas samples were collected, and gastrointestinal symptoms rated. Plasma fructose metabolites and short-chain fatty acids were quantified by targeted liquid chromatography-tandem mass spectrometry. Patients were classified as fructose intolerant or tolerant based on symptoms following fructose ingestion. KEY RESULTS: The median (IQR) areas under the curve of fructose plasma concentrations within the first 2 h (AUC0-2 h ) after fructose ingestion were similar for patients with and without fructose intolerance (578 (70) µM·h vs. 564 (240) µM·h, respectively, p = 0.39), as well as for the main fructose metabolites. There were no statistically significant correlations between the AUC0-2 h of fructose or its metabolites concentrations and the AUCs of symptoms, breath hydrogen, and breath methane. However, the AUCs of symptoms correlated significantly and positively with the AUC0-2 h of hydrogen and methane breath concentrations (r = 0.73, r = 0.62, respectively), and the AUCs of hydrogen and methane concentrations were greater in the fructose-intolerant than in the fructose-tolerant patients after fructose ingestion (p ≤ 0.02). CONCLUSIONS & INFERENCES: Fructose intolerance in FGID is not related to post-ingestion plasma concentrations of fructose and its metabolites. Factors other than malabsorption, such as altered gut microbiota or sensory function, may be important mechanisms.

Extragastrointestinal Symptoms and Sensory Responses During Breath Tests Distinguish Patients With Functional Gastrointestinal Disorders.

INTRODUCTION: Patients with functional gastrointestinal disorders (FGIDs) are classified based on their gastrointestinal (GI) symptoms, without considering their frequent extra-GI symptoms. This study defined subgroups of patients using both GI and extra-GI symptoms and examined underlying mechanisms with fructose and lactose breath tests. METHODS: Latent class analysis defined distinct clusters of patients with FGID based on their long-term GI and extra-GI symptoms. Sensory and breath gas responses after fructose and lactose ingestion were compared across symptom clusters to investigate differences in sensory function and fermentation by intestinal microbiota. RESULTS: Six symptom clusters were identified in 2,083 patients with FGID. Clusters were characterized mainly by GI fermentation-type (cluster 1), allergy-like (cluster 2), intense pain-accentuated GI symptoms (cluster 3), central nervous system (cluster 4), musculoskeletal (cluster 5), and generalized extra-GI (cluster 6) symptoms. In the 68% of patients with complete breath tests, the areas under the curve of GI and central nervous system symptoms after fructose and lactose ingestion differed across the clusters (P < 0.001). The clusters with extensive long-term extra-GI symptoms had greater symptoms after the sugars and were predominantly women, with family or childhood allergy histories. Importantly, the areas under the curves of hydrogen and methane breath concentrations were similar (P > 0.05) across all symptom clusters. Rome III criteria did not distinguish between the symptom clusters. DISCUSSION: Patients with FGID fall into clusters defined extensively by extra-GI symptoms. Greater extra-GI symptoms are associated with evidence of generalized sensory hypersensitivity to sugar ingestion, unrelated to intestinal gas production. Possible underlying mechanisms include metabolites originating from the intestinal microbiota and somatization.

Repeatability and effect of blinding of fructose breath tests in patients with functional gastrointestinal disorders.

BACKGROUND: Breath tests are used as measures of sugar intolerance or malabsorption in patients with functional gastrointestinal disorders (FGID), although the repeatability or anticipatory bias have not been adequately studied. We examined the repeatability and anticipatory bias during fructose breath testing using a nocebo-controlled, randomized, cross-over, and double-blind study design. METHODS: Gastrointestinal symptoms and breath concentrations of hydrogen and methane were documented during breath tests with fructose (given open twice and blinded once), water (blind neutral nocebo) and a cyclamate/saccharine sweetener (blind sweet nocebo) on 5 days in patients with FGID. Repeatability of fructose breath tests (16 patients) and differences between open and blinded substrate groups (31 patients) was assessed using thresholds for intolerance and malabsorption, and areas-under-the-curve (AUC) of symptoms and breath gas concentrations. KEY RESULTS: Fructose breath tests showed moderate repeatability for intolerance status (absolute agreement 87%, kappa 0.72), but limited repeatability for malabsorber status (absolute agreement 53%, kappa 0.05). Repeatability of AUCs of GI symptoms, hydrogen and methane breath concentrations was moderate (intraclass correlation coefficients 0.70, 0.57, and 0.57, respectively). There were no significant differences between open and blinded fructose breath tests in intolerance or malabsorber status, or in AUCs of GI symptoms, hydrogen and methane concentrations. CONCLUSIONS & INFERENCES: Fructose breath tests showed moderate repeatability for intolerance status and for AUCs of symptoms and gas concentrations, lying within the range of accepted gastrointestinal sensory and transit tests. Repeatability for malabsorption status was inadequate and requires revisiting. The fructose breath test can be used unblinded in FGID.

Breath methane concentrations and markers of obesity in patients with functional gastrointestinal disorders.

BACKGROUND: Obesity is associated with changes in the intestinal microbiome and methane-producing archaea may be involved in energy homeostasis. OBJECTIVE: The objective of this article is to investigate the associations between intestinal methane production, waist circumference and body mass index (BMI) as biomarkers for obesity. METHODS: Breath methane and hydrogen concentrations were measured over five hours following fructose or lactose ingestion in 1647 patients with functional gastrointestinal disorders. The relationships between gas concentrations and measures of obesity were investigated by stratifying gas concentration-time profiles by BMI and waist circumference, and, conversely, BMI and waist circumference by peak breath hydrogen and methane concentrations. RESULTS: Following fructose ingestion, patients with lower BMI and lesser waist circumference had greater breath methane concentrations (all p < 0.003). Conversely, patients with increased methane concentrations had lower BMI (p < 0.001) and waist circumference (p = 0.02). After lactose ingestion, BMI and waist circumference were not associated with significant differences in methane. However, greater methane concentrations were associated with a lower BMI (p < 0.002), but not with waist circumference. CONCLUSION: In this large group of patients mainly negative associations between breath methane concentrations and anthropometric biomarkers of obesity were evident. Studies investigating microbial methane production and energy homoeostasis in different populations are of substantial interest to distinguish epiphenomena from true causality.A follow-up study was registered at Clinical trials.gov NCT02085889.

Gastro-oesophageal reflux is common in oligosymptomatic patients with dental erosion: A pH-impedance and endoscopic study.

BACKGROUND: Dental erosion is a complication of gastro-oesophageal reflux disease (GORD) according to the Montreal consensus statement. However, GORD has not been comprehensively characterized in patients with dental erosions and pH-impedance measures have not been reported. OBJECTIVES: Characterize GORD in patients with dental erosions using 24-h multichannel intraluminal pH-impedance measurements (pH-MII) and endoscopy. METHODS: This single-centre study investigated reflux in successive patients presenting to dentists with dental erosion using pH-MII and endoscopy. RESULTS: Of the 374 patients, 298 (80%) reported GORD symptoms <2 per week, 72 (19%) had oesophagitis and 59 (16%) had a hiatal hernia. In the 349 with pH-MII the mean percentage time with a pH <4 (95% CI) was 11.0 (9.3-12.7), and 34.4% (31.9-36.9) for a pH <5.5, a critical threshold for dental tissue. The mean numbers of total, acidic and weakly acidic reflux episodes were 71 (63-79), 43 (38-49) and 31 (26-35), respectively. Of the reflux episodes, 19% (17-21) reached the proximal oesophagus. In 241 (69%) patients reflux was abnormal using published normal values for acid exposure time and reflux episodes. No significant associations between the severity of dental erosions and any reflux variables were found. The presence of GORD symptoms and of oesophagitis or a hiatal hernia was associated with greater reflux, but not with increased dental erosion scores. CONCLUSIONS: Significant oligosymptomatic gastro-oesophageal reflux occurs in the majority of patients with dental erosion. The degree of dental erosion did not correlate with any of the accepted quantitative reflux indicators. Definition of clinically relevant reflux parameters by pH-MII for dental erosion and of treatment guidelines are outstanding. Gastroenterologists and dentists need to be aware of the widely prevalent association between dental erosion and atypical GORD.