Craig A. Friesen

Introduction: Meal‐related symptoms are commonly identified in disorders of gut–brain interaction (DGBIs). Gastroduodenal low‐grade inflammation involving mucosal eosinophils and/or mast cells has been previously described in patients with DGBIs. In children with DGBIs, we sought to determine potential relationships between gastric and duodenal mucosal eosinophils and mast cells with specific meal‐related and non‐GI somatic symptoms. Methods: Two hundred eight youth with AP‐DGBI were evaluated. All patients underwent esophagogastroduodenoscopy (EGD) with biopsies taken from the gastric antrum and duodenum. Patients completed symptom and BASC‐3 questionnaires to evaluate somatization and the presence of specific meal‐related and non‐GI somatic symptoms. A single observer blinded to clinical data reported maximum density of eosinophils and mast cells. Key Results: Mucosal eosinophil and mast cell counts did not differ between FD and IBS nor between FD subtypes. After correction for multiple comparisons, there were no associations between eosinophil or mast cell counts with meal‐related symptoms. In contrast, duodenal mast cells were positively associated with headaches, dizziness, fatigue, and rhinitis, with predominantly medium effect sizes. Conclusions and Inferences: Meal‐related symptoms are common in youth with DGBIs, but do not appear to be associated with mucosal eosinophils and mast cell counts. The positive associations of duodenal mast cells with non‐GI somatic complaints suggest future studies should determine whether treatments targeting mast cells are beneficial for ameliorating these symptoms in youth with DGBIs.

Introduction: Many children with abdominal pain‐associated disorders of gut‐brain interaction (AP‐DGBI) have meal‐related symptoms. The aim of the current study was to determine if meal‐related symptoms defined specific mutually exclusive subgroups (classes) and, if so, whether these relate to other pathophysiologic factors. Methods: Between 2020 and 2022, 289 children with AP‐DGBI completed questionnaires evaluating gastrointestinal symptoms, psychosocial variables (e.g., somatization), and health‐related quality of life (HRQoL). Latent class analysis (LCA) evaluated symptom patterns using 10 gastrointestinal symptoms, while univariable latent class regression (LCR) analyzed associations with covariates. Key Results: Three latent classes emerged: Class 1 (characterized by low meal‐ and stool‐related symptom burden, 35.0%), Class 2 (exhibiting meal‐related symptoms, 32.2%), and Class 3 (manifesting meal‐ and stool‐related symptoms, 32.8%). Compared to Class 1, odds of belonging to Class 2 were significantly associated with increasing age, female sex, and lower HRQoL in physical and school functioning. Compared to Class 1, odds of belonging to Class 3 were similarly associated with increasing age, female sex, somatization, and with reduced HRQoL in physical, social, and psychosocial domains. There were no group differences with respect to depression, social stress, or anxiety. Conclusions and Inferences: In youth with AP‐DGBI, three distinct phenotypic groups are identified. Two of these distinct groups experience meal‐related symptoms: one with associated bowel symptoms and the other without. These two meal‐related symptom groups are associated with increasing age, female sex, somatization, and reduced HRQoL (particularly physical). These findings underscore the distinctness and importance of identifying the drivers of meal‐related symptoms in children with AP‐DGBI.

Objective: Irritable bowel syndrome (IBS) is divided into subcategories recognizing differences in stool frequency and form. The third IBS symptom, a change in pain with stools may also introduce heterogeneity and has not been well described in youth with IBS. The current study was undertaken to assess changes in pain with stooling and the presence of nocturnal stools. Methods: We assessed 300 patients with a diagnosis of abdominal pain‐associated disorder of gut–brain interaction (AP‐DGBI). Patients were queried regarding Rome IV AP‐DGBI criteria along with characterizing changes in pain with stooling (direction, frequency and degree of change) and the occurrence of nocturnal stools. Additionally, we reviewed the findings from 140 patients who underwent colonoscopies. Results: Regarding pain with stooling, 59% reported no difference, 26.7% reported decreased pain, and 14.3% reported increased pain. There was significant variability in both frequency and degree of change in pain. Increased pain with stools was associated with a change in stool frequency and form. Nocturnal stools were reported in 19.7% of participants. Colonic mucosal inflammation or more often low‐grade mucosal eosinophilia was found more frequently in those reporting nocturnal stools (33% vs. 15.4%; p = 0.02). Conclusions: We found significant heterogeneity regarding changes in pain with bowel movements in IBS including the direction of change, degree of change and frequency of change. Increase in pain with stools appears to be a better fit with the other cardinal symptoms of IBS than is decreased pain with stooling. Nocturnal stooling was not uncommon in AP‐DGBI and may be associated with low‐grade eosinophilia in some patients.

Objective: In functional dyspepsia patients, duodenal mucosal eosinophilia has been associated with early satiety but is not present in all patients suggesting varied pathways to symptom generation. The objective of the current study was to explore metabolic differences comparing those with duodenal mucosal eosinophilia to those without eosinophilia.Methods: This study was conducted utilizing an existing biorepository. Patients had plasma samples obtained at the time of endoscopy. All had undergone endoscopy for dyspepsia and reported early satiety. Two groups were identified including those with peak duodenal mucosal eosinophil densities above 30/high power field (N = 28) and those below 30 (N = 16). The fasting plasma samples were analyzed by liquid chromatography/high‐resolution mass spectrometry. Significant differences between groups were determined.Results: The eosinophilia group demonstrated significant elevations in several gamma‐glutamyl amino acids. The eosinophilia group had elevations of metabolites associated with oxidative stress including glutathione metabolites (cysteinlyglycine and cys‐gly oxidized), and metabolites related to nitric oxide synthesis (arginine, citrulline, ornithine, and dimethylarginine). Eosinophilia was also associated with alterations in lipid metabolism including several long‐chain acylcarnitine conjugated fatty acids. Carnitine levels were lower in the eosinophilia group. Lastly, vanillymandelate, a derivative of norepinephrine and epinephrine was elevated in the eosinophilia group.Conclusions: In patients with dyspepsia and early satiety, duodenal mucosal eosinophilia is associated with metabolites levels which are consistent with increased oxidative stress and alterations in lipid metabolism. Eosinophilia was also associated with lower carnitine levels. These alterations may contribute to pathophysiology and represent therapeutic targets.

Alarm symptoms are widely used in pediatric gastroenterology to discern when abdominal pain needs further workup. Despite wide use, the data supporting the validity of these symptoms are not well established. This study explored one alarm symptom—nighttime waking with pain—and its associations with histologic inflammation of the upper gastrointestinal tract, psychological dysfunction, and disordered sleep. This retrospective study evaluated 240 patients with abdominal pain-related disorders of the gut–brain axis (AP-DGBI). Patients underwent questionnaires related to sleep disturbance, behavioral assessment, and gastrointestinal symptoms, including Rome IV criteria for AP-DGBI. Routine upper endoscopy with standardized biopsies was performed in 205 patients. Endoscopy results showed no association between esophageal, gastric, or duodenal histologic inflammation and nighttime waking with pain. Nocturnal pain was associated with increased scores for both psychological and sleep disorders, including social stress, depression, disorders of initiation and maintenance of sleep (DIMS), disorders of daytime somnolence (DOES), and sleep hyperhidrosis (SHY). This study concluded that nocturnal pain is not a reliable predictor of upper gastrointestinal inflammation but may be a prognosticator for psychological distress and sleep disturbances.

The aims of the current study were to determine the frequencies of specific sleep disturbances in youth with abdominal pain-associated disorders of gut-brain interaction (AP-DGBIs) and to assess relationships with psychological dysfunction. This was a retrospective evaluation of 226 consecutive patients diagnosed with an AP-DGBI. All had undergone a systematic evaluation of gastrointestinal symptoms, the Sleep Disturbance Scale for Children, and the Behavior Assessment System for Children. Disorders of initiation and maintenance of sleep (DIMS; 40%) and disorders of excessive daytime somnolence (DOES; 14%) were each present in more than 10% of the patients. Both DIMS and DOES scores were more likely to be elevated in patients with anxiety and/or depression scores in the at-risk or elevated-risk ranges. Sleep disorders are common in youth with AP-DGBIs and are associated with anxiety and depression, even in those patients with anxiety and depression in the at-risk range.

The purpose of the current study was to assess the frequency of overactive bladder syndrome (OBS) symptoms and their relationship to gastrointestinal symptoms in youth with abdominal pain-associated disorders of gut–brain interaction (AP-DGBI). This is a retrospective study of 226 youth diagnosed with an AP-DGBI. As part of standard care, all patients completed a symptom questionnaire regarding gastrointestinal and non-gastrointestinal symptoms including increased urinary frequency, nighttime urination, and urinary urgency. Overall, 54% of patients reported at least one OBS symptom. Increased frequency of urination was reported by 19%, urinary urgency by 34%, and nighttime urination by 36%. Increased frequency of urination and urinary urgency were associated with a change in stool form, a change in stool frequency, and in those fulfilling criteria for IBS. Increased frequency of urination was reported more frequently in those reporting predominantly loose stools (33% vs. 12%). Urinary symptoms are common in youth with AP-DGBI. Increased urinary frequency and urinary urgency are specifically associated with IBS, with increased urinary frequency being primarily associated with diarrhea predominant IBS. Further studies are needed to determine the impact of OBS on AP-DGBI severity and quality of life, and whether they impact DGBI treatment.