BACKGROUND & AIMS:Visceral pain is a cardinal symptom of many disorders affecting the gut and other abdominal organs. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate such pain but the specific contribution of peripheral GABA-A receptors (GABRAs) remains unclear as current agonists have prominent central effects. METHODS:Using medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent positive allosteric modulator (PAM), LI-633, with no significant central nervous system (CNS) penetration. RESULTS:The locomotor activity of rats placed in an open field was unchanged with LI-633 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 by GABA. LI-633 potentiated muscimol-induced GABAergic currents in rat DRG neurons in a dose-dependent manner, with an EC50 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), indicating the presence of physiologically relevant concentrations of GABA in the colon and stomach. 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 GABRAs for pain management in disorders associated with visceral hypersensitivity.

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.

BACKGROUND & AIMS:Patients with gastroparesis (Gp) can be high users of the medical system. In this study, we characterized patients with Gp symptoms who had frequent emergency department (ED) visits and hospitalizations. METHODS:Patients with symptoms of Gp underwent history and physical examination, gastric emptying scintigraphy (GES), and questionnaires capturing number of ED visits and hospitalizations over the prior year, GI symptoms (Patient Assessment of Upper GI Symptoms [PAGI-SYM]), anxiety and depression [Hospital Anxiety and Depression Scale (HADS)], somatization [Patient Health Questionnaire (PHQ-15)], and quality of life (SF-36v2 and Patient Assessment of Upper GastroIntestinal Disorders-Quality of Life [PAGI-QOL]). RESULTS:Of 406 patients with symptoms of Gp (294; 72.4%) had delayed gastric emptying (33% diabetic, 61% idiopathic, 6% postfundoplication), 159 patients (39%) had prior ED visits. Baseline characteristics that were independently associated with ED visits over the prior year included younger age, Black race, lower income, higher gastric retention on GES at 4 hours, antiemetic medication use, cannabis use, jejunostomy tube presence, and higher nausea/vomiting scores. Ninety-two patients (23%) had hospitalizations due to symptoms of Gp over the prior year. The most frequent reasons for hospitalizations included nausea (83%), vomiting (78%), abdominal pain (70%), and dehydration (59%). Baseline characteristics that were independently associated with increased hospitalizations were younger age, Black race, lower income, diabetic etiology, greater 4-hour gastric retention, prokinetic use, cannabis use, jejunostomy tube presence, higher nausea/vomiting scores, and higher depression scores. CONCLUSIONS:Our study of patients with symptoms of Gp revealed a sizeable subset have had Gp-related ED visits and hospitalizations over the past year. Several factors related to etiology, GE delay, GI symptom severity, depression severity, race, and lower income were associated with ED visits and hospitalizations. CLINICALTRIALS:gov Identifier: N3CT01696747.

Nausea exacerbations in patients with gastroparesis and functional dyspepsia (FD) require the use of rescue medications with concomitant adverse effects. We hypothesized that non-invasive vagal nerve stimulation (nVNS) may provide an effective and safer alternative for such symptoms. This pilot study included 41 patients with chronic nausea, attributed to gastric etiology with or without delayed gastric emptying. After a one-week observation period, patients self-administered nVNS for exacerbations of nausea: 4 weeks on one side of the neck (left or right based on the patient’s preference), followed by a 2-week washout and then another 4 weeks of nVNS on the other side. The primary endpoint was a reduction in the use of anti-nausea rescue medications. Compared to baseline, nVNS reduced the average number of rescue medications used per day by half. The initial side of stimulation did not appear to influence the outcome. Although the use of nVNS in this study was not designed to influence chronic sustained symptoms, robust changes were also seen in abdominal pain, reflux, indigestion, constipation, depression, and some autonomic symptoms. Paradoxically, daily vomiting episodes increased during the 4-week period after nVNS was initiated but remained steady thereafter. “As-needed” nVNS may reduce the use of rescue medications for exacerbations of nausea. Additionally, several relatively unexpected benefits across a variety of other symptoms were observed. These results should inform larger randomized sham-controlled trials in these disorders with limited therapeutic alternatives. ClinicalTrials.gov registration number NCT04857281. Date of registration, 2021–04–20.

Abdominal pain is a frequent symptom occurring in patients with inflammatory bowel disease (IBD), and, unfortunately, as many as 50% of patients in endoscopic remission experience persistent chronic pain. Despite this high prevalence, no targeted therapeutics are available to manage pain in IBD. Agents including acetaminophen, non-steroidal anti-inflammatory medications (NSAIDs) and opioids remain in high utilization, despite their known adverse gastrointestinal side effect profiles and, in some cases, limited analgesic efficacy. Glutamate carboxypeptidase II (GCPII) is upregulated in IBD, where it may be a unique therapeutic target for pain management. GCPII is a membrane-associated zinc metallopeptidase capable of regulating glutamatergic neurotransmission; Excess GCPII activity has been implicated in numerous pain disorders, including neuropathic pain and cancer-associated pain, where its inhibition is analgesic in preclinical models. However, GCPII has not yet been examined in the context of visceral pain. GCPII will be upregulated in rodent models of post-inflammatory chronic visceral hypersensitivity (CVH) and treatment with oral, gut-restricted, GCPII inhibitor (S)-IBD3540 will be analgesic. Oral GCPII inhibitor (S)-IBD3540 was evaluated in 2 murine models of post-inflammatory, chronic visceral hypersensitivity (CVH): acetic acid-induced CVH of neonatal mice and TNBS-induced CVH of adult mice. In each model, (S)-IBD3540 (2.75 – 275 mg/kg) was administered once daily for 7 days preceding measurement of abdominal visceromotor response (VMR) to graded colorectal distension (CRD) (n=5-7/group). Alongside functional measurements, MPO ELISA and GCPII immunohistochemistry were performed to validate absence of inflammation and quantify colon mucosal GCPII expression. Oral (S)-IBD3540 treatment was significantly analgesic in both models, attenuating hyperalgesia to baseline at doses as low as 2.75 mg/kg, and displaying comparable efficacy to oral gabapentin (2-way ANOVA with Holm-Šídák multiple comparisons test). MPO ELISA confirmed absence of active inflammation at the time of VMR/CRD measurement. Mucosal GCPII expression was found to be significantly increased in both models (2-tailed t-test; TNBS-CVH, p=0.0044; AA-CVH, p=0.0063). There is a large unmet clinical need for chronic pain management in IBD. Here, we provide encouraging preclinical evidence that inhibition of GCPII has potent analgesic effects in relevant rodent models of post-inflammatory visceral pain. Studies interrogating GCPII dysregulation in biopsies of IBD patients experiencing chronic pain in IBD are actively ongoing within our laboratory.

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.

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: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.

The stomach is responsible for physically and chemically processing the ingested meal before controlled emptying into the duodenum through the pyloric sphincter. An incompetent pylorus allows reflux from the duodenum back into the stomach, and if the amount of reflux is large enough, it could alter the low pH environment of the stomach and erode the mucosal lining of the lumen. In some cases, the regurgitated contents can also reach the esophagus leading to additional complications. In this work, “StomachSim”, an in-silico model of the fluid dynamics of the stomach, is used to study the mechanism of duodenogastric reflux. The effects of variations in food properties and motility disorders on reflux are investigated. The simulations show that the primary driver of reflux is the relaxation of the antrum after a stomach contraction terminates near the pylorus. The region of the stomach walls exposed to the regurgitated contents depends significantly on the density of the stomach contents. For stomach contents of higher viscosity, the increased pressure required to maintain gastric emptying reduces the amount of duodenogastric reflux. Concomitant stomach motility disorders that weaken the relaxation of the walls also affect the amount of reflux. The study illustrates the utility of in-silico models in analyzing the factors at play in gastrointestinal diseases.

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.

ABSTRACT The proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) dysregulates GI physiology, including bowel movements (motility), but in many IBD patients, GI motility disorders persist in remission through a poorly understood pathological process. Here we uncover that post-inflammatory GI dysmotility (PI-GID) stems from structural ENS remodeling driven by a combination of neuronal loss and neurogenesis. Enteric neurons respond to mucosal inflammation by upregulating CCL2 expression and facilitating the recruitment of CCR2 + monocytes into the neural myenteric plexus within the intestinal muscle. This is followed by the expansion of monocyte-derived macrophages and their migration into the myenteric ganglia and phagocytosis of neurons. However, excessive recruitment of monocytes results in disproportionate ENS remodeling and PI-GID. The expansion of inflammatory cells is known to promote tissue hypoxia. We find that enteric neurons become hypoxic upon colitis, but hypoxia-induced signaling via HIF1α initiates an adaptation program in enteric neurons to attenuate CCL2 expression and limit monocyte recruitment. We demonstrate that reinforcing HIF1α signaling in enteric neurons prevents PI-GID by reducing colitis-associated monocyte recruitment in the myenteric plexus and protecting against ENS remodeling. In summary, our findings unveil PI-GID pathogenesis and identify a regulatory axis for its prevention. One Sentence Summary Intestinal mucosal inflammation engages enteric neurons in the inflammatory response leading to neurogenic recruitment of monocytes into the extra-mucosal myenteric plexus followed by pathological structural remodeling of the enteric nervous system by monocyte-derived macrophages.

Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied. To determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp. 25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and dysrhythmic ranges, was recorded using electrogastrography. Overall, vitamin D levels were low (< 30 ng/ml) in 288 of 513 (56.1

COVID-19 increases the risk of neurological and gastrointestinal sequelae, but it is unclear if it does so more than other infections. Using a multicenter record network, we matched 649,478 COVID-19 patients to negative controls (NCs) and patients infected with influenza, human herpesvirusses, and lyme's disease (LD) to compare new-onset gastrointestinal (GISx), autonomic (ANSx), sensory (SNSx), and motor (MNSx) symptoms 3-12 months after infection. ANSx showed significant increases compared to NCs (odds ratio (OR) 1.34; confidence interval (CI) 1.31-1.36) and most other investigated infections (LD, influenza, infectious mononucleosis, and herpes zoster; OR 1.40, 1.13, 1.11, and 1.05, respectively). SNSx (OR 1.35; CI 1.31-1.39), MNSx (OR 1.32; CI 1.28-1.36) and GISx (OR 1.36; CI 1.33-1.38) were increased but varied more compared with other infections. COVID-19 vaccination reduced the risk of GISx, ANSx, and SNSx. Sequelae frequently ascribed to COVID-19 may manifest with similar or higher frequency after other infections, except ANSx. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Johns Hopkins Medicine Institutional Review Boards (IRB) have exempted this study from IRB review, as it involves aggregated and de-identified medical record data which is not considered human subjects research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript and supplemental material.

Pyloric interventions are surgical procedures employed to increase the gastric emptying rate in gastroparesis patients. In this study, we use an in silico model to investigate the consequences of pyloric intervention on gastric flow and emptying for two phenotypes of gastroparesis: antral hypomotility and decreased gastric tone. The transpyloric pressure gradient predicted by the in silico model, based on viscous fluid flow equations, is compared against in vivo measurements. Both phenotypes exhibit a similar pre-procedural emptying rate reduction, but after pyloric surgery, antral hypomotility case with preserved gastric tone shows significant improvements in emptying rates, up to 131%, accompanied by bile reflux from the duodenum into the stomach. Conversely, severely reduced gastric tone cases exhibited a post-procedural reduction in the net emptying rate due to the relatively larger bile reflux. In cases with a combination of antral hypomotility and reduced gastric tone, post-procedural improvements were observed only when both conditions were mild. Our findings highlight the pivotal role of the relative increase in pyloric orifice diameter in determining post-operative emptying rates. The study suggests a possible explanation for the selective response of patients toward these procedures and underscores the potential of in silico modelling to generate valuable insights to inform gastric surgery.

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling. NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.