Pasricha, Pankaj J.

ABSTRACT Background Patients with gastroparesis (Gp) can have a variety of symptoms. Apart from use of prokinetics, symptomatic therapies for the predominant symptom (PrS) are used. Aims (1) To classify Gp patients based on their PrS; (2) To determine differences in Gp symptoms, gastric emptying (GE), quality of life (QOL), treatments, and symptom improvement among Gp patients with different PrS. Methods Gp patients were enrolled in a multicenter registry and followed for 96‐weeks. Patients recorded their PrS and completed questionnaires assessing symptoms and QOL at enrollment and at follow up visits. Results Of 1013 Gp patients (361 diabetic, 607 idiopathic, 45 post‐fundoplication), the PrS were nausea (31%), vomiting (20%), abdominal pain (20%), bloating (9%), fullness (4%), GERD (4%), constipation (3%). Abdominal pain was more often a PrS in idiopathics, whereas vomiting was more often a PrS in diabetics. QOL scores were lower in the abdominal pain PrS group. PrS was associated with greater use of directed symptomatic treatment (antiemetic agents and gastric electrical stimulation for nausea and vomiting, prokinetic agents for vomiting and fullness, and constipation medications for constipation). Of 555 patients followed over 48 weeks, GCSI improved by ≥ 1 in 26% overall, more often in patients with initial PrS of nausea (32%) and bloating (35%) and less often for initial PrS of fullness (13%) or abdominal pain (15%). Conclusions In Gp patients, the most common PrS were nausea, vomiting, and abdominal pain. PrS is associated with QOL, treatments utilized, and patient outcomes. Thus, the PrS of a patient with Gp provides useful information about their present condition and future outcome.

Proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) disrupts key GI functions, including bowel motility. However, in many IBD patients, motility disorders persist even during remission, suggesting an irreversible ENS defect secondary to IBD. Here, we show that postinflammatory GI motility dysfunction arises from structural remodeling of the ENS, driven by a combination of neuronal loss and neurogenesis. During mucosal inflammation, enteric neurons upregulate CCL2 expression, facilitating the recruitment of monocytes into the myenteric plexus within the intestinal muscle. Monocyte-derived macrophages infiltrate the myenteric ganglia, contributing to excessive ENS remodeling and postinflammatory motility dysfunction. This neuroimmune axis is counterbalanced by a hypoxia-induced stress response in enteric neurons mediated by HIF1α. Enhancing the neuron-intrinsic hypoxia pathway limits ENS remodeling and preserves motility. In summary, this study presents a mechanistic model of postinflammatory GI motility dysfunction and proposes a therapeutic strategy to maintain ENS integrity and function during inflammation.

INTRODUCTION: Chronic neurogastroduodenal disorders are heterogeneous and thought to lie on a spectrum of disease encompassing both sensory and neuromuscular pathologies. Abnormalities of interstitial cells of Cajal (ICC), a subset of which generate pacemaker signals and subsequently motility, have been implicated in their pathophysiology. We systematically reviewed the literature to pool ICC deficits observed in chronic neurogastroduodenal disorders. METHODS: Studies quantifying gastric ICC from the corpus or antrum, in adult patients with gastroparesis, functional dyspepsia (FD), or chronic nausea and vomiting syndromes (CNVS) were analyzed (PROSPERO: CRD42024613226). MEDLINE, Embase and CENTRAL databases were searched systematically. Random effects meta-analyses were used to compare ICC counts by disorder group with subgroup analysis by quantification methodology. RESULTS: Overall, 2,158 studies were screened and 22 included. Comparative studies (n = 12) showed patients with chronic neurogastroduodenal disorders (n = 167 with gastroparesis, n = 19 with FD ± CNVS) had lower ICC counts than nondiabetic controls (n = 130); standardized mean difference −1.58, 95% confidence interval −2.09 to −1.07, P < 0.0001, with more severe deficits in gastroparesis compared to FD ± CNVS (standardized mean difference [SMD] −0.44, P = 0.048). A spectrum of ICC deficits was evident in a subgroup of studies using gold-standard methods with c-KIT antibody and 4',6-diamidino-2-phenylindole-stained nuclei confirmation (7 studies, 246 patients: mean ICC counts 2.29 in gastroparesis vs 3.49 in FD ± CNVS, and 5.27 in controls; P < 0.001 all comparisons). Most studies were at high risk of bias (n = 21). DISCUSSION: Marked depletion of ICC is a consistent finding in neurogastroduodenal disorders. A spectrum of disease is revealed, with greater depletion associated with delayed emptying. Techniques for clinically defining ICC-driven gastric neuromuscular dysfunction should be prioritized.

Objective: The recent advances in computational power have enabled the use of in-silico approaches in studying physiological flows. In this study, we aim to develop a digital twin of the human stomach, StomachSim, to simulate gastric biomechanics in case of motility disorders and surgery. Methods: A physiologically realistic model of the stomach, including the antral motility, is synthesized based on in-vivo imaging data. The mixing and gastric emptying are simulated using computational fluid dynamics (CFD). Fundic accommodation, terminal antral contraction, and the phasic opening of the pyloric sphincter are incorporated into the model. The enlargement and disruption of pyloric sphincter due to pyloric intervention procedures or pyloric incompetence is also implemented. The influence of food properties (density and viscosity), motility disorders (50% reduced amplitude of antral contractions), and pyloric intervention procedures on gastric mixing, duodenogastric reflux, and solid-food trituration is investigated. The gastric emptying rate and the transpyloric pressure gradient predicted by the model were in good agreement with existing in-vivo measurements in the literature. Results: Reduced antral motility led to inefficient mixing of gastric contents and 49% lower pressure forces and 33% reduced hydrodynamic shear stresses on solid food particles. In cases with pyloric incompetence, reduced motility resulted in 66% lower duodenogastric reflux rate. When the gastric contents were of higher viscosity, the proximal stomach applied a higher pressure to achieve the same emptying rate resulting in reduced duodenogastric reflux. Higher viscosity also led to over 7 times increased shear stresses on solid food particles. Food density, on the other hand, primarily affected the transport of refluxed contents – when the gastric contents were lighter, duodenal contents entering the stomach settled along the lower antrum, and when the gastric contents were heavier, the reflux contents were transported proximally towards the esophagus. Conclusion: The digital-twin model presented in this study allows the exploration of a wide set of parameters related to gastric function. Our simulations quantify the consequences of motility disorders on gastric digestion and duodenogastric reflux. The model also reports detailed force characteristics of solid food particles undergoing trituration. StomachSim offers a novel and potentially effective modality for examining the effect of gastric conditions and gastric surgical procedures on gastric function. The authors acknowledge support from NSF award CBET 2019405. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Background and Aims Visceral pain is a cardinal symptom of many disorders affecting the gut. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate colonic pain but the specific contribution of peripheral GABAA receptors remains unclear as these agents have prominent central effects. Methods Using medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent benzodiazepine-based positive allosteric modulator (PAM) of GABAA receptors, Li633, with no significant central nervous system (CNS) penetration. Results The locomotor activity of rats placed in an open field was unchanged with Li633 at doses up to 30 mg/kg, confirming its lack of a CNS effect. LI-633 produced robust potentiation of GABA-induced inward current, with EC50 values ranging from 8 nM (α5β2γ2) to 128 nM (α3β2γ2). In vitro electrophysiological studies confirmed its ability to reduce excitability of human dorsal root ganglion (DRG) neurons. LI-633 potentiated muscimol-induced GABAergic currents in rat DRG neurons in a dose-dependent manner, with an EC 50 of 70.4 nM. In vivo, LI-633 significantly attenuated visceral hypersensitivity and pain behavior in a rat model of irritable bowel syndrome (IBS) and functional dyspepsia (FD). In the IBS model, administration of the drug also resulted in decreased excitability of colon-specific DRG neurons and significantly reduced the colonic afferent response to balloon distention as measured by recordings of neural activity in dorsal ganglia rootlets. Conclusions These findings highlight the potential of targeting peripheral GABAA receptors for pain management in IBS and other disorders associated with visceral hypersensitivity.

Type 2 diabetes (T2D) and obesity are chronic metabolic diseases with global morbidity and mortality. Decades of evidence from surgical and endoscopic procedures bypassing the duodenum underscore the duodenum’s critical role in regulating glycemia and body weight. Although metabolic surgeries and endoscopic procedures are effective, their invasiveness, cost, and scalability limit patient access. We developed an orally administered mucin complexing polymeric (MCP) drug, designed to replicate duodenal exclusion physiology. MCPs, intended to have electrostatic and covalent cross-linkages with mucin glycoproteins, form extended network structures with resulting alteration of mucus barrier properties. Selective targeting of the duodenum is achieved via pH-based activation chemistry. Following screening for physiochemical properties, pharmacokinetics, and efficacy, GLY-200 emerged as the lead drug candidate replicating duodenal exclusion physiology with improved glycemia, reduced body weight, and modulation of gut hormones in rodent models. This targeted oral therapy holds promise for treatment of T2D and obesity by mimicking duodenal exclusion without the invasiveness of surgery or endoscopic procedures.

INTRODUCTION: There is an urgent need for effective and safe treatment of gastroparesis. Metopimazine, a selective, peripherally restricted dopamine D 2 receptor antagonist, is used in France for the symptomatic treatment of nausea and vomiting and chemotherapy-induced nausea and vomiting. The aim of this study is to assess the safety and efficacy of oral NG101, the mesylate salt of metopimazine, for the treatment of gastroparesis. METHODS: We conducted a 12-week phase 2 multicenter trial with NG101 5, 10, and 20 mg 4 times a day versus placebo. The primary end point was the change in mean nausea severity from the Diabetic and Idiopathic Gastroparesis Symptoms Daily Diary (DIGS-DD) during weeks 7–12 of the Treatment Period from baseline. The DIGS-DD measured nausea, abdominal pain, early satiety, postprandial fullness, and vomiting at their worst in the past 24 hours using a 0-10 point numeric rating scale. Patient Global Impression of Change questionnaires, including nausea, were assessed weekly using a 7-point balanced ordinal score. RESULTS: Of 161 randomized participants (45.3% diabetic and 54.7% idiopathic), mean DIGS-DD nausea severity scores decreased from baseline during weeks 7–12 in all treatment groups, but these improvements were not statistically significant compared with placebo. However, there were statistically significant improvements in nausea Patient Global Impression of Change during weeks 1–12 for all treatment groups compared with placebo. Trends in safety and efficacy favored patients with idiopathic gastroparesis compared with those with diabetic gastroparesis. DISCUSSION: While NG101 did not meet statistical significance in its primary end point for reducing nausea severity, it demonstrated a favorable safety profile and significant improvement in some secondary end points. Further study is needed to determine whether NG101 is an effective treatment for patients with idiopathic gastroparesis.

An in silico model of the stomach is presented to study the phenomenon of duodenogastric reflux. We use the model to investigate the role of pyloric incompetence, food properties, and gastroparesis on reflux. This first-ever in silico study of duodenogastric reflux provides new insights into the mechanisms and factors implicated in this reflux and the sequelae of conditions that result from the exposure of the stomach lumen to bile.

INTRODUCTION: We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD). METHODS: AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder with at least 1 positive seromarker of autoimmunity or at least 2 positive seromarkers by themselves. Three cohorts were studied: (i) retrospective (n = 300), (ii) prospective validation cohort (n = 133), and (iii) treatment cohort (n = 40), administered open-label intravenous immunoglobulin (IVIG). RESULTS: AIM positivity was found in 40% and 29% of the retrospective and prospective cohorts, the majority of whom (71% and 69%, respectively) had autoinflammatory disorder. Significantly more patients with AIM had elevations of C-reactive protein (31% vs 15%, P < 0.001) along with an increased proportion of cardiovascular autonomic dysfunction (48% vs 29%; P < 0.001), small fiber neuropathy (20% vs 9%; P = 0.002), and HLADQ8 positivity (24% vs 13%, P = 0.01). Patients with JH/HSD were more likely to have AIM (43% vs 15%, P = 0.001) along with more severe autonomic and gastrointestinal (GI) symptom scores. IVIG treatment was associated with robust improvement in pain, GI, and autonomic symptoms, but adverse events were experienced by 62% of patients. DISCUSSION: Autoimmune markers and autonomic dysfunction are common in patients with unexplained GI symptoms, especially in those with JH/HSD. Many patients seem to respond to IVIG treatment, but this needs to be confirmed by controlled trials. These results highlight the need for vigilance for autoimmune and autonomic factors and JH/HSD in patients with neurogastroenterological disorders. Clinicaltrials.gov, NCT04859829.