Enteric Nervous System in Neonatal Necrotizing Enterocolitis.

BACKGROUND: The pathophysiology of necrotizing enterocolitis (NEC) is not clear, but increasing information suggests that the risk and severity of NEC may be influenced by abnormalities in the enteric nervous system (ENS). OBJECTIVE: The purpose of this review was to scope and examine the research related to ENS-associated abnormalities that have either been identified in NEC or have been noted in other inflammatory bowel disorders (IBDs) with histopathological abnormalities similar to NEC. The aim was to summarize the research findings, identify research gaps in existing literature, and disseminate them to key knowledge end-users to collaborate and address the same in future studies. METHODS: Articles that met the objectives of the study were identified through an extensive literature search in the databases PubMed, EMBASE, and Scopus. RESULTS: The sources identified through the literature search revealed that: (1) ENS may be involved in NEC development and post-NEC complications, (2) NEC development is associated with changes in the ENS, and (3) NEC-associated changes could be modulated by the ENS. CONCLUSION: The findings from this review identify the enteric nervous as a target in the development and progression of NEC. Thus, factors that can protect the ENS can potentially prevent and treat NEC and post-NEC complications. This review serves to summarize the existing literature and highlights a need for further research on the involvement of ENS in NEC.

Utilizing functional lumen imaging probe in directing treatment for post-fundoplication dysphagia.

BACKGROUND: Esophagogastric junction obstruction (EGJO) post-fundoplication (PF) is difficult to identify with currently available tests. We aimed to assess the diagnostic accuracy of EGJ opening on functional lumen imaging probe (FLIP) and dilation outcome in FLIP-detected EGJO in PF dysphagia. METHODS: We prospectively collected data on PF patients referred to Esophageal Clinic over 18 months. EGJO diagnosis was made by (a) endoscopist's description of a narrow EGJ/wrap area, (b) appearance of wrap obstruction or contrast/tablet retention on esophagram, or (c) EGJ-distensibility index (DI) < 2.8 mm2/mmHg on real-time FLIP. In patients with EGJO and dysphagia, EGJ dilation was performed to 20 mm, 30 mm, or 35 mm in a stepwise fashion. Outcome was assessed as % dysphagia improvement during phone call or on brief esophageal dysphagia questionnaire (BEDQ) score. RESULTS: Twenty-six patients were included, of whom 17 (65%) had a low EGJ-DI. No patients had a hiatal hernia greater than 3 cm. Dysphagia was the primary symptom in 17/26 (65%). In 85% (κ = 0.677) of cases, EGJ assessment (tight vs. open) was congruent between the combination of endoscopy (n = 26) and esophagram (n = 21) vs. EGJ-DI (n = 26) on FLIP. Follow-up data were available in 11 patients who had dilation based on a low EGJ-DI (4 with 20 mm balloon and 7 with ≥ 30 mm balloon). Overall, the mean % improvement in dysphagia was 60% (95% CI 37.7-82.3%, p = 0.0001). Nine out of 11 patients, including 6 out of 7 undergoing pneumatic dilation, had improvement ≥ 50% in dysphagia (mean % improvement 72.2%; 95% CI 56.1-88.4%, p = 0.0001). CONCLUSIONS AND INFERENCES: Functional lumen imaging probe is an accurate modality for evaluating for EGJ obstruction PF. FLIP may be used to select patients who may benefit from larger diameter dilation.

Eosinophilic esophagitis: updates on key unanswered questions.

Eosinophilic esophagitis (EoE) is a clinicopathologic disease characterized by symptoms of esophageal dysfunction and esophageal eosinophilia. In the last decade, there has been a dramatic increase in its prevalence for reasons that are not completely understood. The underlying pathophysiology involves an antigen-mediated TH 2 immune response that draws eosinophils to the esophagus, causing mucosal inflammation, esophageal remodeling, and fibrosis. This ultimately leads to esophageal dysfunction that most commonly manifests as dysphagia. In this review, we will discuss updates on key questions regarding the diagnosis and treatment of EoE.

Caspase-11-mediated enteric neuronal pyroptosis underlies Western diet-induced colonic dysmotility.

Enteric neuronal degeneration, as seen in inflammatory bowel disease, obesity, and diabetes, can lead to gastrointestinal dysmotility. Pyroptosis is a novel form of programmed cell death but little is known about its role in enteric neuronal degeneration. We observed higher levels of cleaved caspase-1, a marker of pyroptosis, in myenteric ganglia of overweight and obese human subjects compared with normal-weight subjects. Western diet-fed (WD-fed) mice exhibited increased myenteric neuronal pyroptosis, delayed colonic transit, and impaired electric field stimulation-induced colonic relaxation responses. WD increased TLR4 expression and cleaved caspase-1 in myenteric nitrergic neurons. Overactivation of nitrergic neuronal NF-κB signaling resulted in increased pyroptosis and delayed colonic motility. In caspase-11-deficient mice, WD did not induce nitrergic myenteric neuronal pyroptosis and colonic dysmotility. To understand the contributions of saturated fatty acids and bacterial products to the steps leading to enteric neurodegeneration, we performed in vitro experiments using mouse enteric neurons. Palmitate and lipopolysaccharide (LPS) increased nitrergic, but not cholinergic, enteric neuronal pyroptosis. LPS gained entry to the cytosol in the presence of palmitate, activating caspase-11 and gasdermin D, leading to pyroptosis. These results support a role of the caspase-11-mediated pyroptotic pathway in WD-induced myenteric nitrergic neuronal degeneration and colonic dysmotility, providing important therapeutic targets for enteric neuropathy.

Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans.

BACKGROUND AND AIMS: Mucoid structures that coat the epithelium play an essential role in keeping the intestinal microbiota at a safe distance from host cells. Encroachment of bacteria into the normally almost-sterile inner mucus layer has been observed in inflammatory bowel disease and in mouse models of colitis. Moreover, such microbiota encroachment has also been observed in mouse models of metabolic syndrome, which are associated low-grade intestinal inflammation. Hence, we investigated if microbiota encroachment might correlate with indices of metabolic syndrome in humans. METHODS: Confocal microscopy was used to measure bacterial-epithelial distance of the closest bacteria per high-powered field in colonic biopsies of all willing participants undergoing cancer screening colonoscopies. RESULTS: We observed that, among all subjects, bacterial-epithelial distance was inversely correlated with body mass index, fasting glucose levels, and hemoglobin A1C. However, this correlation was driven by dysglycemic subjects, irrespective of body mass index, whereas the difference in bacterial-epithelial distance between obese and nonobese subjects was eliminated by removal of dysglycemic subjects. CONCLUSIONS: We conclude that microbiota encroachment is a feature of insulin resistance-associated dysglycemia in humans.

Three-Dimensional Anorectal Manometry Enhances Diagnostic Gain by Detecting Sphincter Defects and Puborectalis Pressure.

BACKGROUND: Constipation and fecal incontinence (FI) are common and are often evaluated with anorectal manometry. Three-dimensional high-resolution anorectal manometry (HRAM) is a promising technology; however, implementation has been limited by lack of metrics and unclear clinical utility. AIM: To investigate the diagnostic utility of 3D HRAM compared to 2D HRAM. METHODS: Three-dimensional HRAM studies performed from April 2012 to October 2013 were identified and re-interpreted by two blinded investigators examining 3D function. Disagreements were resolved by a third investigator. Puborectalis (PR) visualization, focal defects, and dyssynergy were reported. Differences between groups were analyzed with Fisher's exact test. Discordance was analyzed with McNemar Chi-square test. RESULTS: Two hundred and twenty-one 3D HRAM studies were identified. Mean age and BMI were 52.2 ± 17.4 and 27.1 ± 7.5 years (81% female, 74% white). Most common indications for 3D HRAM were constipation (65%) and FI (28%). PR function was visualized in 81% (rest), 97% (squeeze), and 73% (strain). PR was visualized less often at rest in FI than constipation (68 vs. 85%, p = 0.007). Defects were identified twice as often in FI than constipation (19 vs. 10%, p = 0.113). Twenty-nine defects (86% anterior) were visualized on 3D HRAM. Inter-reader agreement was moderate for PR function (κ = 0.471), but fair for focal defects (κ = 0.304). CONCLUSIONS: PR function and focal defects can be visualized on 3D-HRAM with added diagnostic benefit compared to 2D. Fair inter-reader agreement for focal defects highlights the need for quantitative metrics.

Comprehensive analysis of efficacy and safety of peroral endoscopic myotomy performed by a gastroenterologist in the endoscopy unit: a single-center experience.

BACKGROUND AND AIMS: The safety and efficacy of peroral endoscopic myotomy (POEM) when performed by gastroenterologists in the endoscopy unit are currently unknown. The aims of this study were to assess (1) the safety and efficacy of POEM in which all procedures were performed by 1 gastroenterologist in the endoscopy unit, and (2) the predictors of adverse events and nonresponse. METHODS: All consecutive patients who underwent POEM at 1 tertiary center were included. Clinical response was defined by a decrease in the Eckardt score to 3 or lower. Adverse events were graded according to the American Society for Gastrointestinal Endoscopy lexicon's severity grading system. RESULTS: A total of 60 consecutive patients underwent POEM in the endoscopy suite with a mean procedure length of 99 minutes. The mean length of submucosal tunnel was 14 cm and the mean myotomy length was 11 cm. The median length of hospital stay was 1 day. Among 52 patients with a mean follow-up period of 118 days (range 30-750), clinical response was observed in 48 patients (92.3%). There was a significant decrease in Eckardt score after POEM (8 vs 1.19, P < .0001). The mean lower esophageal sphincter pressure decreased significantly after POEM (29 mm Hg vs 11 mm Hg, P < .0001). A total of 10 adverse events occurred in 10 patients (16.7%): 7 rated as mild, 3 as moderate, and none as severe. Procedure length was the only predictor of adverse events (P = .01). pH impedance testing was completed in 25 patients, and 22 (88%) had abnormal acid exposure, but positive symptom correlation was present in only 6 patients. All patients with symptomatic reflux were successfully treated with proton pump inhibitors. CONCLUSIONS: POEM can be effectively and safely performed by experienced gastroenterologists at a tertiary care endoscopy unit. Adverse events are infrequent, and most can be managed intraprocedurally. Post-POEM reflux is frequent but can be successfully managed medically.

Comprehensive radionuclide esophagogastrointestinal transit study: methodology, reference values, and initial clinical experience.

UNLABELLED: A radionuclide methodology and reference values have been developed for a single gastrointestinal transit study including esophageal transit, liquid and solid gastric emptying, and small- and large-bowel transit, using (111)In-diethylenetriaminepentaacetic acid (DTPA) with the standardized (99m)Tc-labeled solid meal. METHODS: Eighteen healthy subjects and 18 patients were investigated. The esophageal transit study was performed with 3.7 MBq (0.1 mCi) of (111)In-DTPA in 15 mL of water. A liquid-only 30-min gastric-emptying study followed, with ingestion of 3.7 MBq (0.1 mCi) of (111)In-DTPA in 300 mL of water. Then, a simultaneous solid-liquid emptying study was acquired after ingestion of a solid (99m)Tc-sulfur colloid-labeled meal and 7.4 MBq (0.2 mCi) of (111)In-DTPA in 120 mL of water. Images were acquired intermittently for 4 h. Additional (111)In images were acquired at 5 and 6 h to measure small-bowel transit, and at 24, 48, and 72 h for large-bowel transit. RESULTS: Reference values were determined for esophageal transit (transit time, percentage emptying at 10 s), liquid-only gastric emptying (emptying half-time), liquid and solid emptying in a dual-phase solid-liquid study (emptying half-time and percentage emptying at 1, 2, 3, and 4 h), small-bowel transit index (percentage transit to ileocecal valve at 6 h), and colonic transit (geometric center and percentage colonic emptying) at 24, 48, and 72 h. Results from the first 18 patients found abnormal transit in 72% (13/18); clinical management changed in 61% (11/18). CONCLUSION: We have developed a radionuclide methodology and derived reference values for a comprehensive gastrointestinal transit study using (111)In-DTPA with the standardized (99m)Tc-labeled solid meal. Our initial clinical experience suggests clinical value.

Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and beta-cell proliferation in the developing mouse pancreas.

Glial cell line-derived neurotrophic factor (GDNF) is a factor produced by glial cells that is required for the development of the enteric nervous system. In transgenic mice that overexpress GDNF in the pancreas, GDNF has been shown to enhance beta-cell mass and improve glucose control, but the transcriptional and cellular processes involved are not known. In this study we examined the influence of GDNF on the expression of neurogenin3 (Ngn3) and other transcription factors implicated in early beta-cell development, as well as on beta-cell proliferation during embryonic and early postnatal mouse pancreas development. Embryonic day 15.5 (E15.5) mouse pancreatic tissue when exposed to GDNF for 24 h showed higher Ngn3, pancreatic and duodenal homeobox gene 1 (Pdx1), neuroD1/beta(2), paired homeobox gene 4 (Pax4), and insulin mRNA expression than tissue exposed to vehicle only. Transgenic expression of GDNF in mouse pancreata was associated with increased numbers of Ngn3-expressing pancreatic cells and higher beta-cell mass at embryonic day 18 (E18), as well as higher beta-cell proliferation and Pdx1 expression in beta-cells at E18 and postnatal day 1. In the HIT-T15 beta-cell line, GDNF enhanced the expression of Pax6. This response was, however, blocked in the presence of Pdx1 small interfering RNA (siRNA). Chromatin immunoprecipitation studies using the HIT-T15 beta-cell line demonstrated that GDNF can influence Pdx1 gene expression by enhancing the binding of Sox9 and neuroD1/beta(2) to the Pdx1 promoter. Our data provide evidence of a mechanism by which GDNF influences beta-cell development. GDNF could be a potential therapeutic target for the treatment and prevention of diabetes.