Madhusudan Grover

Background: Gastrointestinal symptom events (GISE) are common with glucagon‐like peptide‐1 receptor agonists (GLP‐1RA). We aimed to determine the prevalence of GISE and clinical factors associated with GISE. Methods: An integrated platform database was used to collect real‐world data. Using a retrospective cohort study design, Kaplan–Meier analysis was used to estimate GISE‐free survival over 60 months. To identify predictors of GISE, the cohort was randomly split 80/20 into training and testing sets. A LASSO‐penalized Cox model was used to identify relevant associations, after which main‐effect and interaction models were constructed. Gastric emptying scintigraphy (GES) of solids was extracted from electronic medical records, where available. Results: Among 78,277 patients, 87% reported no baseline GI symptoms. At 60 months, 53% reported at least one GISE, most commonly abdominal pain (28%) and nausea (25%). Women were at higher risk of GISE than men (Kaplan–Meier HR 1.4). In the prediction model, baseline diarrhea, constipation, abdominal pain, and nausea were associated with higher GISE risk (HRs 2.2, 2.0, 1.7, and 1.6, respectively), and male sex with lower risk (HR 0.79). Concomitant baseline use of metoclopramide (HR 1.6) was also associated with higher risk of GISE, with weaker associations for tricyclic antidepressants, GABA analogs, and opioids (HRs 1.1–1.2). Model discrimination was modest (C‐index 0.64 training, 0.63 testing). Among 696 symptomatic patients clinically referred for GES after GLP‐1RA initiation, 34.6% ( N = 241) exhibited delayed GE. Constipation was more prevalent in those with delayed GE. Conclusion: The 5‐year incidence of GISE among patients initiating GLP‐1RA therapy was over 50%. While the ability to predict GISE was modest, female sex, baseline GI symptoms, and concomitant medications were associated with an increased risk. Among the small, symptom‐selected subgroup referred for testing, only a third had delayed GE.

Introduction: Although pain is recognized as an important symptom in gastroparesis, it has not been well studied and characterized. Quantitative sensory testing (QST) is a psychophysical method that has the potential to provide a measure of pain processing, as well as insight into pain pathophysiology and the prediction of response to specific therapies. We aimed to characterize somatic QST in a well‐characterized cohort of patients with gastroparesis. Methods: Adults with scintigraphically defined gastroparesis underwent abdominal QST with assessment of mechanical pain: pain sensitivity (thresholds and tolerance) and pain facilitation (temporal summation). The Patient Assessment of Upper GI Symptoms (PAGI‐SYM) upper and lower abdominal pain scales were used. Results: QST was performed on 264 participants (87% female; age = 18–78 years). In both the upper and lower abdomen, smaller pain thresholds and lower pain tolerance were significantly associated with greater PAGI‐SYM upper abdominal pain severity ( b 's = 0.07–0.15; p 's = 0.007–0.02), but not lower abdominal pain severity. Scores on the PAGI‐SYM upper and lower abdominal pain scales were moderately correlated ( r = 0.48, p < 0.0001). No significant associations were found for temporal summation. Conclusions: Our findings suggest self‐reported upper abdominal pain severity correlated with both lower and upper abdominal mechanical pain sensitivity—possibly reflecting secondary sensitization of the abdominal wall, due to viscerosomatic convergence in upper abdominal somatic segments. Lower abdominal pain severity association with only upper (but not lower) abdominal QST may be due to cross‐organ sensitization. Further investigations are needed to test the clinical utility of abdominal QST in gastric sensorimotor disorders. Trial Registration: ClinicalTrials.gov : NCT01696747

Background: Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective: To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design: We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results: Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions: This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

Interstitial cells of Cajal (ICC) regulate gastrointestinal motility by generating electrical slow waves that orchestrate downstream calcium (Ca ^{2 +} ) waves and coordinate smooth muscle contractions. A reduced ICC number has been reported in diabetic gastroparesis patients and in mouse models of delayed gastric emptying (DGE). However, functional changes in ICC propagating across the gastric regions in intact stomach are not well understood. The aim of this study was to develop an imaging approach to visualize ICC Ca ²⁺ waves in mouse stomach and determine spatiotemporal changes in mice with DGE. Tamoxifen‐treated B6.GCaMP5‐KitCreERT2 female mice were used as non‐diabetic controls (Non‐Db), while mice treated with streptozocin to induce diabetes were categorized as having normal (Db‐NGE) or delayed (Db‐DGE) gastric emptying based on emptying of solids. The ICC Ca ²⁺ network was imaged from excised intact mouse stomachs and subsequently opened along the lesser curvature and pinned flat. ICC Ca ²⁺ waves typically propagated along the greater curvature from the fundus–corpus line toward the antrum. The propagation length of ICC Ca ²⁺ activity was significantly decreased in Db‐DGE compared to Non‐Db and Db‐NGE and correlated to longer GE times. There was also a decrease in frequency, and the velocity was significantly faster in stomachs from Db‐DGE compared to Non‐Db and Db‐NGE. All experimental groups exhibited similar proportions of aberrant Ca ²⁺ propagation patterns (e.g., retrograde waves), but ectopic initiation only occurred in Db‐DGE stomachs. Thus, DGE is possibly driven by dysfunction in Ca ²⁺ activity in the ICC network that propagates rapidly over short distances, resulting in uncoordinated, non‐phasic muscle activity. image Key points: Dysfunction of the interstitial cells of Cajal (ICC) has been implicated in diabetic gastroparesis but the changes in spatiotemporal properties of ICC network activity are not known. We developed an ex vivo Ca ²⁺ imaging approach to visualize ICC network activity across the entire stomach and determined changes in ICC Ca ²⁺ activity in a diabetic mouse model of delayed gastric emptying (GE). Decreased frequency and increased velocity of ICC Ca ²⁺ activity was observed in stomachs of diabetic mice with delayed GE. Ectopic initiation was a key feature associated with delayed GE. The propagation length of ICC Ca ²⁺ activity was inversely correlated to GE times and significantly reduced in stomach preparations from diabetic mice with delayed GE.

INTRODUCTION: Bloating, distention, and gas-related gastrointestinal (GI) symptoms are frequently reported by patients across the spectrum of disorders of gut-brain interaction (DGBI). We aimed to characterize these using latent class modeling in a large multinational survey. METHODS: A nationwide survey of adults in the United States, United Kingdom, and Mexico used quota sampling for demographic balance. It included Rome IV diagnostic questions, Intestinal Gas Questionnaire, Patient Health Questionnaires for anxiety and depression (PHQ-4) and somatization (PHQ-12), quality of life (PROMIS Global-10), and lifestyle questions. Latent class analysis was performed using “depmix” in RStudio 4.2.3. RESULTS: A total of 3,471 subjects experiencing bloating and/or distention (mean age 43 years, 57% female) were included. Using 42 demographic and pertinent clinical variables, latent class analysis revealed 6 distinct clusters. The first 2 clusters demonstrated limited-to-moderate impairment in health-related quality of life (HRQoL), with both characterized by some degree of dietary and supplement associations; however, cluster 2 lacked specific triggers observed in other clusters. The subsequent 2 clusters showed favorable HRQoL and mild gas-related symptoms, with only cluster 4 exhibiting distinct dietary triggers. The final 2 clusters, associated with bowel dysfunction, showed a higher prevalence of irritable bowel syndrome (IBS) with constipation and IBS mixed in cluster 5, and IBS with diarrhea in cluster 6. These bowel dysfunction clusters exhibited severe gas symptoms in the preceding 24 hours and greater HRQoL impairment compared with the other 4 clusters. Notably, cluster 5 was linked to dietary triggers, whereas cluster 6 was defined by psychosocial comorbidities. DISCUSSION: Bloating and distention patients are likely driven by variable influences of dietary, psychological, and bowel dysfunction. Further studies are needed to identify mechanisms and titrate treatment suited to specific mechanistic drivers.