Publications by authors named "Pankaj Pasricha"

228 Publications

Effect of Domperidone Therapy on Gastroparesis Symptoms: Results of a Dynamic Cohort Study by NIDDK Gastroparesis Consortium.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Division of Gastroenterology, Texas Tech University Health Sciences Center, El Paso, TX.

Background: The use of domperidone (DOM), for gastroparesis (GP) remains controversial and limited. We aimed to present outcomes of DOM therapy for treatment of patients participating in the multicenter NIDDK Gastroparesis Clinical Research Consortium (GPCRC) Registries (GpR).

Methods: The GpCRC cohort consisted of GP (75%) and GP-like symptoms patients but with normal gastric emptying (25%). The DOM group initiated therapy during the 96 weeks of enrollment in GpR1 and 2. Patients who had previously taken or were on DOM therapy at enrollment were excluded from this analysis. The control group did not use domperidone (non-DOM group) before or after enrollment. The following outcome measures were identified: change from baseline in Gastroparesis Cardinal Symptom Index (GCSI) total score, with 3 subscales, plus GERD and PAGI-QOL scores.

Results: Overall, of 748 patients, 181 (24%) were in the DOM, while 567 were in non-DOM group. 63% of participants had idiopathic GP. At baseline DOM compared to non-DOM patients were significantly younger, had lower BMI, non-Hispanic ethnicity, a higher annual household income, lower narcotic utilization, lower supplemental and complimentary medication use, more likely to have delayed GET, as well as worse nausea and fullness scores. Compared to non-DOM, DOM patients experienced moderate, but significantly more improvement in GP outcome measures: GCSI total score (p=0.003), nausea (p=0.003), and fullness subscales (p=0.005), upper abdominal pain score (p=0.04), GERD score (p=0.05) and PAGI-QOL (p=0.05).

Conclusions: Utilizing the method of pragmatic modeling to evaluate long-term treatment of GP in a large GpCRC database, domperidone treatment resulted in moderately but significantly improved GP.
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http://dx.doi.org/10.1016/j.cgh.2021.05.063DOI Listing
June 2021

Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model.

JCI Insight 2021 Mar 22;6(6). Epub 2021 Mar 22.

Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity - in response to gastric distention - was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a "bottom-up" pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.
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http://dx.doi.org/10.1172/jci.insight.144046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026195PMC
March 2021

Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features.

Gastroenterology 2021 May 3;160(6):2006-2017. Epub 2021 Feb 3.

Temple University, Philadelphia, Pennsylvania.

Background: The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis.

Methods: Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models.

Results: Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206 macrophages in both groups compared with obese controls.

Conclusions: A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. CLINICALTRIALS.

Gov Identifier: NCT00398801, NCT01696747.
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http://dx.doi.org/10.1053/j.gastro.2021.01.230DOI Listing
May 2021

Factors that contribute to the impairment of quality of life in gastroparesis.

Neurogastroenterol Motil 2021 Jan 25:e14087. Epub 2021 Jan 25.

Johns Hopkins University, Baltimore, MD, USA.

Background: Understanding factors that impair quality of life (QOL) in gastroparesis is important for clinical management.

Aims: (a) Determine QOL in patients with gastroparesis; (b) Determine factors that impair QOL.

Methods: Gastroparetic patientsAQ6 underwent history and questionnaires assessing symptoms (PAGI-SYM and Rome III), QOL (SF-36v2 and PAGI-QOL), depression (Beck Depression Inventory [BDI]), and anxiety (State Trait Anxiety InventoryAQ7).

Key Results: 715 gastroparesis patients (256 diabetic (DG), 459 idiopathic (IG)) were evaluated. SF-36 physical component (PC) score averaged 33.3 ± 10.5; 41% had impaired score <30. SF-36 PC scores were similar between diabetic and idiopathic gastroparesis. Impaired SF-36 PC associated with increased nausea/vomiting and upper abdominal pain subscores, acute onset of symptoms, higher number of comorbidities, use of narcotic pain medications, and irritable bowel syndrome (IBS). SF-36 mental component (MC) score averaged 38.9 ± 13.0; 26% had impaired score <30. Poor SF-36 MC associated with diabetic etiology, higher Beck depression inventory, and state anxiety scores. PAGI-QOL score averaged 2.6 ± 1.1; 50% had a score of <2.6. Low PAGI-QOL associated with higher fullness, bloating, and upper abdominal pain subscores, more depression and Trait anxiety, smoking cigarettes, need for nutritional support, progressively worsening symptoms and periodic exacerbations.

Conclusions & Inferences: Multiple measures show poor QOL present in gastroparesis. Several areas impacted on reduced QOL: (a) Symptoms of nausea, vomiting, and abdominal pain, as well as IBS; (b) Etiology and acute onset and progressively worsening symptoms; (c) Comorbidities and psychological factors such as anxiety and depression; (d) Patient-related factors such as smoking. Targeting the modifiable factors may improve patient outcomes in gastroparesis.
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http://dx.doi.org/10.1111/nmo.14087DOI Listing
January 2021

Decoding the Enteric Nervous System: The Beginning of Our Understanding of Enteric Neuromuscular Disorders?

Gastroenterology 2021 Feb 18;160(3):651-652. Epub 2020 Dec 18.

Center for Neurogastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.12.018DOI Listing
February 2021

Constipation in Patients With Symptoms of Gastroparesis: Analysis of Symptoms and Gastrointestinal Transit.

Clin Gastroenterol Hepatol 2020 Oct 28. Epub 2020 Oct 28.

Johns Hopkins University, Baltimore, Maryland.

Background & Aims: Constipation can be an important symptom in some patients with gastroparesis. The aims were to: 1) Determine prevalence of constipation and delayed colonic transit in patients with symptoms of gastroparesis; 2) Correlate severity of constipation to severity of symptoms of gastroparesis; and 3) Relate severity of constipation to GI transit delays assessed by gastric emptying scintigraphy (GES) and wireless motility capsule (WMC).

Methods: Patients with symptoms of gastroparesis underwent gastric emptying scintigraphy (GES), wireless motility capsule (WMC) assessing gastric emptying, small bowel transit, and colonic transit, and questionnaires assessing symptoms using a modified Patient Assessment of Upper GI Symptoms [PAGI-SYM] and Rome III functional GI disorder questionnaire.

Results: Of 338 patients with symptoms of gastroparesis, 242 (71.5%) had delayed gastric emptying by scintigraphy; 298 (88.2%) also met criteria for functional dyspepsia. Severity of constipation was severe/very severe in 34% patients, moderate in 24%, and none/very mild/mild in 42%. Increasing severity of constipation was associated with increasing symptoms of gastroparesis and presence of irritable bowel syndrome (IBS). Severity of constipation was not associated with gastric retention on GES or WMC. Delayed colonic transit was present in 108 patients (32% of patients). Increasing severity of constipation was associated with increasing small bowel transit time, colonic transit time, and whole gut transit time.

Conclusions: Severe/very severe constipation and delayed colon transit occurs in a third of patients with symptoms of gastroparesis. The severity of constipation is associated with severity of gastroparesis symptoms, presence of IBS, small bowel and colon transit delay, but not delay in gastric emptying. ClinicalTrials.gov Identifier: NCT01696747.
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http://dx.doi.org/10.1016/j.cgh.2020.10.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079462PMC
October 2020

The relationship between gastrointestinal transit, Medsger GI severity, and UCLA GIT 2.0 symptoms in patients with systemic sclerosis.

Arthritis Care Res (Hoboken) 2020 Oct 16. Epub 2020 Oct 16.

Johns Hopkins University, Division of Rheumatology, Baltimore, United States.

Objective: Scleroderma (SSc)-associated gastrointestinal (GI) complications are attributed to a variety of factors including diet, microbiota dysbiosis, or GI transit abnormalities. We examined the contribution of abnormal GI transit to SSc Medsger GI severity scores and/or UCLA GIT 2.0 symptoms.

Methods: Patients with SSc and GI symptoms (n=71) and healthy controls (n=18) underwent whole gut transit (WGT) scintigraphy to assess transit from the esophagus to the colon. The presence of delayed transit and percent emptying in each GI region were measured. We compared the WGT measurements between categories of the Medsger GI severity score (0-4) and across UCLA GIT 2.0 domains and total score (0-3).

Results: Eighty-percent of patients had >1 abnormal region of the gut on WGT scintigraphy. All patients requiring total parenteral nutrition had delayed small bowel transit, compared to only ~11% of patients in other Medsger GI severity groups (p=<0.01). Severe colonic transit delays were more likely in patients with Medsger GI scores of 3 (pseudo-obstruction and/or malabsorption) compared to other Medsger GI groups (p=0.02). Seventy-percent of these patients had ≤30% colonic emptying at 72 hours. Modest associations were noted between GERD symptoms and delayed esophageal (r=-0.31,p=0.05) and gastric emptying (r=-0.32,p=0.05).

Conclusion: These data are important in providing evidence that SSc bowel disease affects transit of GI content and that delay in transit accounts in part for both bowel symptoms and Medsger GI severity. Prospective studies examining the benefit of early therapeutic intervention targeting GI transit abnormalities in patients at high-risk for severe GI complications are needed.
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http://dx.doi.org/10.1002/acr.24488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050123PMC
October 2020

Body weight in patients with idiopathic gastroparesis.

Neurogastroenterol Motil 2021 02 15;33(2):e13974. Epub 2020 Sep 15.

Johns Hopkins University, Baltimore, MD, USA.

Background: The classic clinical picture of gastroparesis is a symptomatic patient losing weight. In addition, a number of patients with delayed gastric emptying are obese and/or gaining weight. Our aim was to investigate the factors impacting body weight in patients with idiopathic gastroparesis.

Methods: In patients with idiopathic gastroparesis, detailed history and weight were acquired at enrollment and after 48 weeks. Questionnaires assessed symptoms, food intake, physical activity, and quality of life. Patients underwent laboratory testing, gastric emptying scintigraphy, and water load testing.

Results: Of 138 patients with idiopathic gastroparesis, 10% were underweight (BMI < 18.5), 39% were normal weight (BMI 18.5-25), 20% were overweight with BMI 25 to 30 kg/m , and 29% were obese with BMI > 30 kg/m . Body weight at enrollment was positively associated with oral caloric consumption (P < .001), following a gastroparesis diet (P = .04), nutrition consultation (P = .001), upper abdominal pain (P = .01); and negatively associated with energy expenditure (P = .05), alcohol use (P = .003) and severity of bloating (P < .001). When followed over 48 weeks, 53% patients stayed stable (within 5% of baseline weight), 30% gained, and 17% lost weight. Weight gain over 48 weeks was positively associated with oral caloric consumption (P = .003) and constipation severity (P = .005) at enrollment, and negatively associated with lower abdominal pain severity (P = .007) at enrollment, and associated with improvement in inability to finish meal score (P < .001) at 48 weeks.

Conclusions: In this series of patients with idiopathic gastroparesis, 10% were underweight whereas 29% were obese. Over 48 weeks, 30% of patients increased their body weight ≥ 5%. Diet, activity, and symptoms are important factors associated with body weight in patients with idiopathic gastroparesis.
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http://dx.doi.org/10.1111/nmo.13974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180181PMC
February 2021

Gastric Biopsies in Gastroparesis: Insights into Gastric Neuromuscular Disorders to Aid Treatment.

Gastroenterol Clin North Am 2020 09 14;49(3):557-570. Epub 2020 Jun 14.

Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA; Division of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA. Electronic address:

The cellular and molecular understanding of human gastroparesis has markedly improved due to studies on full-thickness gastric biopsies. A decrease in the number of interstitial cells of Cajal (ICC) and functional changes in ICC constitutes the hallmark cellular feature of gastroparesis. More recently, in animal models, macrophages have also been identified to play a central role in development of delayed gastric emptying. Activation of macrophages leads to loss of ICC. In human gastroparesis, loss of anti-inflammatory macrophages in gastric muscle has been shown. Deeper molecular characterization using transcriptomics and proteomics has identified macrophage-based immune dysregulation in human gastroparesis.
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http://dx.doi.org/10.1016/j.gtc.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387746PMC
September 2020

Cholinergic-induced anion secretion in murine jejunal enteroids involves synergy between muscarinic and nicotinic pathways.

Am J Physiol Cell Physiol 2020 08 17;319(2):C321-C330. Epub 2020 Jun 17.

Department of Cellular and Molecular Physiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Acetylcholine induces robust electrogenic anion secretion in mammalian intestine and it has long been hypothesized that it mediates the epithelial response through the M and, to a lesser extent, the M muscarinic receptors in the mouse. However, nicotinic receptors have recently been identified in intestinal enterocytes by quantitative real-time (qRT)-PCR/RNAseq, although any direct influence on intestinal transport has not been identified. We tested the hypothesis that cholinergic-induced anion secretion in the intestine is a result of both muscarinic and nicotinic pathways that are intrinsic to the intestinal epithelia. We developed a method to generate mouse jejunal enteroid monolayers which were used to measure active electrogenic anion secretion by the Ussing chamber/voltage-clamp technique. Here, we show that the cholinergic agonist carbachol (CCh) and the muscarinic agonist bethanechol (BCh) stimulate short-lived, concentration-dependent anion secretion in the epithelial cell-only enteroid monolayers. The muscarinic antagonist atropine completely inhibited CCh- and BCh-induced secretion, while the nicotinic antagonist hexamethonium reduced the CCh response by ~45%. While nicotine alone did not alter anion secretion, it increased the BCh-induced increase in short-circuit current in a concentration-dependent manner; this synergy was prevented by pretreatment with hexamethonium. In addition to being sensitive to hexamethonium, monolayers express both classes of cholinergic receptor by qRT-PCR, including 13 of 16 nicotinic receptor subunits. Our findings indicate that an interaction between muscarinic and nicotinic agonists synergistically stimulates anion secretion in mouse jejunal epithelial cells and identify a role for epithelial nicotinic receptors in anion secretion.
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http://dx.doi.org/10.1152/ajpcell.00179.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500216PMC
August 2020

Experience with Esophagogastrointestinal Transit Scintigraphy in the Initial 229 Patients: Multiple Regions of Dysmotility Are Common.

J Nucl Med 2021 01 1;62(1):115-122. Epub 2020 Jun 1.

Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The purpose of this investigation was to review our experience with our comprehensive esophagogastrointestinal transit study in the first 229 patients. This scintigraphic study analyzes the motility of the entire gut, from the esophagus through the rectosigmoid colon. Data were reviewed for our first 2 y of experience with this examination (184 women and 45 men aged 20-79 y [mean ± SD, 44 ± 16 y]). Patients were referred with symptoms suggestive of a motility disorder. They first swallowed In-diethylenetriaminepentaacetic acid in water for the esophageal-swallow study and then 300 mL for a 30-min In water-only study, followed by 120 mL of In water simultaneously with the solid standardized Tc egg-substitute meal. Images and quantification were obtained for esophageal transit, water-only gastric emptying, water-with-solid gastric emptying, small-bowel transit, and colonic transit. Of the 229 patient studies, 45 (20%) were normal. The remaining 184 (80%) had at least 1 region of dysmotility, for a total of 336 regions of abnormal motility. A single region of dysmotility was seen in 92 patients (50%), 2 regions in 50 (27%), 3 regions in 26 (14%), 4 regions in 12 (7%), and 5 regions in 4 (2%). There was a poor correlation between the results of the water-only study and water with the solid meal. Three different patterns of delayed colonic transit were seen. Patient symptoms were often not predictive of the scintigraphic findings. This study highlights the frequent occurrence of dysmotility in more than 1 region of the gastrointestinal tract in patients with a suspected motility disorder and the frequent concurrence of both upper- and lower-tract dysmotility in the same patients. It provides information to referring physicians regarding which motility disorders may be causing the patient symptoms, why the patient is or is not responding to the present therapy, and if and what additional workup and therapy may be needed.
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http://dx.doi.org/10.2967/jnumed.120.243527DOI Listing
January 2021

Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice.

Gastroenterology 2020 07 29;159(1):200-213.e8. Epub 2020 Mar 29.

Center for Neurogastroenterology and Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background & Aims: The enteric nervous system (ENS) exists in close proximity to luminal bacteria. Intestinal microbes regulate ENS development, but little is known about their effects on adult enteric neurons. We investigated whether intestinal bacteria or their products affect the adult ENS via toll-like receptors (TLRs) in mice.

Methods: We performed studies with conventional C57/BL6, germ-free C57/BL6, Nestin-creER:tdTomato, Nestin-GFP, and ChAT-cre:tdTomato. Mice were given drinking water with ampicillin or without (controls). Germ-free mice were given drinking water with TLR2 agonist or without (controls). Some mice were given a blocking antibody against TLR2 or a TLR4 inhibitor. We performed whole gut transit, bead latency, and geometric center studies. Feces were collected and analyzed by 16S ribosomal RNA gene sequencing. Longitudinal muscle myenteric plexus (LMMP) tissues were collected, analyzed by immunohistochemistry, and levels of nitric oxide were measured. Cells were isolated from colonic LMMP of Nestin-creER:tdTomato mice and incubated with agonists of TLR2 (receptor for gram-positive bacteria), TLR4 (receptor for gram-negative bacteria), or distilled water (control) and analyzed by flow cytometry.

Results: Stool from mice given ampicillin had altered composition of gut microbiota with reduced abundance of gram-positive bacteria and increased abundance of gram-negative bacteria, compared with mice given only water. Mice given ampicillin had reduced colon motility compared with mice given only water, and their colonic LMMP had reduced numbers of nitrergic neurons, reduced neuronal nitric oxide synthase production, and reduced colonic neurogenesis. Numbers of colonic myenteric neurons increased after mice were switched from ampicillin to plain water, with increased markers of neurogenesis. Nestin-positive enteric neural precursor cells expressed TLR2 and TLR4. In cells isolated from the colonic LMMP, incubation with the TLR2 agonist increased the percentage of neurons originating from enteric neural precursor cells to approximately 10%, compared with approximately 0.01% in cells incubated with the TLR4 agonist or distilled water. Mice given an antibody against TLR2 had prolonged whole gut transit times; their colonic LMMP had reduced total neurons and a smaller proportion of nitrergic neurons per ganglion, and reduced markers of neurogenesis compared with mice given saline. Colonic LMMP of mice given the TLR4 inhibitor did not have reduced markers of neurogenesis. Colonic LMMP of germ-free mice given TLR2 agonist had increased neuronal numbers compared with control germ-free mice.

Conclusions: In the adult mouse colon, TLR2 promotes colonic neurogenesis, regulated by intestinal bacteria. Our findings indicate that colonic microbiota help maintain the adult ENS via a specific signaling pathway. Pharmacologic and probiotic approaches directed towards specific TLR2 signaling processes might be developed for treatment of colonic motility disorders related to use of antibiotics or other factors.
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http://dx.doi.org/10.1053/j.gastro.2020.03.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387157PMC
July 2020

Ameliorating effects of sacral neuromodulation on gastric and small intestinal dysmotility mediated via a sacral afferent-vagal efferent pathway.

Neurogastroenterol Motil 2020 07 19;32(7):e13837. Epub 2020 Mar 19.

Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background/aims: In a recent study of sacral nerve stimulation (SNS) for colonic inflammation, a possible spinal-vagal pathway was implicated. The aim of this study was to provide evidence for such a pathway by investigating the effects of SNS on dysmotility of the stomach and duodenum that are not directly innervated by the sacral efferents.

Methods: Twenty-seven rats were chronically implanted with wire electrodes for SNS and gastrointestinal slow waves. SNS was performed in several acute sessions to investigate its effects on gastric/duodenal slow waves and emptying/transit impaired by glucagon and rectal distention (RD).

Results: (a) SNS increased the percentage of normal gastric slow waves impaired by glucagon (from 53.9% to 77.0%, P < .0001) and RD (from 64% to 78%, P = .037). This improvement was abolished by atropine. (b) Similar effects were observed with SNS on duodenal slow waves, which was also blocked by atropine. (c) SNS normalized delayed gastric emptying induced by glucagon (control: 61.3%, glucagon: 44.3%, glucagon + SNS: 65.8%) and RD (control: 61.3%, RD: 46.7%, RD + SNS: 64.3%). It also normalized small intestinal transit delayed by RD (P = .001, RD + SNS vs RD; P = .9, RD + SNS vs control). (4) Both glucagon and RD induced an increase in the sympathovagal ratio (P = .007, glucagon vs baseline; P < .001, RD vs baseline) and SNS decreased the ratio (P = .006, glucagon + SNS vs glucagon; P = .04, RD + SNS vs RD).

Conclusions: Neuromodulation of the sacral nerve improves gastric and small intestinal pacemaking activity and transit impaired by glucagon and RD by normalizing the sympathovagal balance via a retrograde neural pathway from the sacral nerve to vagal efferents.
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http://dx.doi.org/10.1111/nmo.13837DOI Listing
July 2020

Ingestible Sensors and Sensing Systems for Minimally Invasive Diagnosis and Monitoring: The Next Frontier in Minimally Invasive Screening.

ACS Sens 2020 04 20;5(4):891-910. Epub 2020 Mar 20.

Institute for Systems Research, University of Maryland, College Park, Maryland 20742, United States.

Ingestible electronic systems that are capable of embedded sensing, particularly within the gastrointestinal (GI) tract and its accessory organs, have the potential to screen for diseases that are difficult if not impossible to detect at an early stage using other means. Furthermore, these devices have the potential to (1) reduce labor and facility costs for a variety of procedures, (2) promote research for discovering new biomarker targets for associated pathologies, (3) promote the development of autonomous or semiautonomous diagnostic aids for consumers, and (4) provide a foundation for epithelially targeted therapeutic interventions. These technological advances have the potential to make disease surveillance and treatment far more effective for a variety of conditions, allowing patients to lead longer and more productive lives. This review will examine the conventional techniques, as well as ingestible sensors and sensing systems that are currently under development for use in disease screening and diagnosis for GI disorders. Design considerations, fabrication, and applications will be discussed.
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http://dx.doi.org/10.1021/acssensors.9b02263DOI Listing
April 2020

Novel and effective disposable device that provides 2-way protection to the duodenoscope from microbial contamination.

Gastrointest Endosc 2020 07 6;92(1):199-208. Epub 2020 Mar 6.

Accelerate Diagnostics Inc, Tucson, Arizona, USA.

Background And Aims: Duodenoscope contamination is associated with notable patient morbidity and mortality and can occur despite high-level disinfection protocols, requiring a solution that protects against contamination of the endoscope in the first place.

Methods: We assessed a newly cleared, single-use device to seal the distal end of duodenoscopes while preserving optics and other endoscope functionality and tested its ability to protect against contamination using dye immersion tests and microbial inoculation.

Results: Dye immersion tests revealed a complete seal with no leakage. Rigorous microbial challenge tests showed the device can both protect against contamination of the endoscope by external microbes ("outside-in" protection) and shield instruments from contact with pre-existing microbial biofilm on or around the elevator that may have survived reprocessing ("inside-out" protection). Optical and mechanical performance of the endoscope was not compromised by the addition of the device.

Conclusions: The results show that this disposable device provides 2-way protection to the duodenoscope from microbial contamination, without the potential for disrupting current equipment, technique, and workflow.
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http://dx.doi.org/10.1016/j.gie.2020.03.001DOI Listing
July 2020

A novel method of sacral nerve stimulation for colonic inflammation.

Neurogastroenterol Motil 2020 06 1;32(6):e13825. Epub 2020 Mar 1.

Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, Johns Hopkins Medicine, Baltimore, Maryland.

Background: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms.

Methods: Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with the parameters set at 5 Hz, 10 seconds on, 90 seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5 Hz intermittent stimulation vs 14 Hz-210 μs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed.

Key Results: Both SNS-1h and SNS-3h significantly ameliorated intestinal inflammation; SNS-1h was superior to SNS-3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5 Hz intermittent stimulation but not the 14 Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. CONCLUSION & INFERENCES: Bipolar stimulation for 1 hour daily using intermittent 5 Hz parameters is most effective in improving colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function.
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http://dx.doi.org/10.1111/nmo.13825DOI Listing
June 2020

Autonomic function in gastroparesis and chronic unexplained nausea and vomiting: Relationship with etiology, gastric emptying, and symptom severity.

Neurogastroenterol Motil 2020 08 15;32(8):e13810. Epub 2020 Feb 15.

University of Louisville, Louisville, Kentucky.

Background: Autonomic dysfunction can be present in patients with idiopathic and diabetic gastroparesis. The role of autonomic dysfunction relating to gastric emptying and upper gastrointestinal symptoms in patients with gastroparesis and chronic unexplained nausea and vomiting (CUNV) remains unclear. The aim of our study is to evaluate autonomic function in patients with gastroparesis and CUNV with respect to etiology, gastric emptying and symptom severity.

Methods: We studied 242 patients with chronic gastroparetic symptoms recruited at eight centers. All patients had a gastric emptying scintigraphy within 6 months of the study. Symptom severity was assessed using the gastroparesis cardinal symptom index. Autonomic function testing was performed at baseline enrollment using the ANX 3.0 autonomic monitoring system which measures heart rate variability and respiratory activity measurements.

Key Results: Low sympathetic response to challenge (Valsalva or standing) was the most common abnormality seen impacting 89% diabetic and 74% idiopathic patients. Diabetics compared to idiopathics, exhibited greater global hypofunction with sympathetic (OR = 4.7, 95% CI 2.2-10.3; P < .001) and parasympathetic (OR = 7.2, 95% CI 3.4-15.0; P < .001) dysfunction. Patients with delayed gastric emptying were more likely to have paradoxic parasympathetic excessive during sympathetic challenge [(Valsalva or standing) 40% vs. 26%, P = .05]. Patients with more severe symptoms exhibited greater parasympathetic dysfunction compared to those with mild-moderate symptoms: resting sympathovagal balance [LFa/RFa 1.8 (1.0-3.1) vs. 1.2 (0.6-2.3), P = .006)] and standing parasympathetic activity [0.4 (0.1-0.8) vs. 0.6 (0.2-1.7); P = .03].

Conclusions: Autonomic dysfunction was common in patients with gastroparesis and CUNV. Parasympathetic dysfunction was associated with delayed gastric emptying and more severe upper gastrointestinal symptoms. Conversely, sympathetic hypofunction was associated with milder symptoms.

Inferences: Gastroparesis and CUNV may be a manifestation of GI autonomic dysfunction or imbalance, such that sympathetic dysfunction occurs early on in the manifestation of chronic upper GI symptoms, while parasympathetic dysfunction results in more severe symptoms and delayed gastric emptying.
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http://dx.doi.org/10.1111/nmo.13810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377964PMC
August 2020

Effects of High-Fiber Diets and Macronutrient Substitution on Bloating: Findings From the OmniHeart Trial.

Clin Transl Gastroenterol 2020 01;11(1):e00122

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objectives: To examine the effects of high-fiber, isocaloric, macronutrient substitutions on bloating.

Methods: The OmniHeart study is a randomized 3-period crossover feeding trial conducted from April 2003 to June 2005. Participants were provided 3 isocaloric versions of high-fiber (∼30 g per 2,100 kcal) diet, each different in carbohydrate, protein, and unsaturated fat composition. Each feeding period lasted for 6 weeks with a 2- to 4-week washout period between diets. Participants reported the presence and severity of bloating at baseline (participants were eating their own diet) and at the end of each feeding period.

Results: One hundred sixty-four participants were included in the analysis (mean age: 53.1 years; 45% women; 55% black). The prevalence of bloating at baseline and at the end of the carbohydrate-rich, protein-rich, and unsaturated fat-rich diet period was 18%, 24%, 33%, and 30%, respectively. Compared with baseline, the relative risk of bloating for the carbohydrate-rich, protein-rich, and unsaturated fat-rich high-fiber diet was 1.34 (95% confidence interval [CI]: 0.93, 1.92), 1.78 (95% CI: 1.32, 2.40), and 1.63 (95% CI: 1.17, 2.26), respectively. The protein-rich diet increased the risk of bloating more than the carbohydrate-rich diet (relative risk = 1.40; 95% CI: 1.03, 1.88). Bloating did not significantly vary between protein-rich vs unsaturated fat-rich or unsaturated fat-rich vs carbohydrate-rich diets. Black participants compared with non-black participants had a higher risk of bloating after all 3 versions of the high-fiber OmniHeart diet (P-value for interaction = 0.012).

Discussion: Substitution of protein with carbohydrate may be an effective strategy to decrease bloating among individuals experiencing gastrointestinal bloating from a high-fiber diet.
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http://dx.doi.org/10.14309/ctg.0000000000000122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056053PMC
January 2020

Marijuana Use in Patients with Symptoms of Gastroparesis: Prevalence, Patient Characteristics, and Perceived Benefit.

Dig Dis Sci 2020 08 22;65(8):2311-2320. Epub 2019 Nov 22.

NIH Gastroparesis Clinical Research Consortium, Bethesda, MD, USA.

Background: Marijuana may be used by some patients with gastroparesis (Gp) for its potential antiemetic, orexigenic, and pain-relieving effects.

Aims: The aim of this study was to describe the use of marijuana by patients for symptoms of Gp, assessing prevalence of use, patient characteristics, and patients' perceived benefit on their symptoms of Gp.

Methods: Patients with symptoms of Gp underwent history and physical examination, gastric emptying scintigraphy, and questionnaires assessing symptoms. Patients were asked about the current use of medications and alternative medications including marijuana.

Results: Fifty-nine of 506 (11.7%) patients with symptoms of Gp reported current marijuana use, being similar among patients with delayed and normal gastric emptying and similar in idiopathic and diabetic patients. Patients using marijuana were younger, more often current tobacco smokers, less likely to be a college graduate, married or have income > $50,000. Patients using marijuana had higher nausea/vomiting subscore (2.7 vs 2.1; p = 0.002), higher upper abdominal pain subscore (3.5 vs 2.9; p = 0.003), more likely to be using promethazine (37 vs 25%; p = 0.05) and dronabinol (17 vs 3%; p < 0.0001). Of patients using marijuana, 51% had been using it for more than 2 years, 47% were using this once or more per day, and 81% of marijuana users rated their benefit from marijuana as better or much better.

Conclusions: A subset of patients (12%) with symptoms of Gp use marijuana. Patients with severe nausea and abdominal pain were more likely to use marijuana and perceive it to be beneficial for their symptoms.

Trial Registration: ClinicalTrials.gov Identifier: NCT01696747.
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http://dx.doi.org/10.1007/s10620-019-05963-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242137PMC
August 2020

Intestinal IgA Regulates Expression of a Fructan Polysaccharide Utilization Locus in Colonizing Gut Commensal Bacteroides thetaiotaomicron.

mBio 2019 11 5;10(6). Epub 2019 Nov 5.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Gut-derived immunoglobulin A (IgA) is the most abundant antibody secreted in the gut that shapes gut microbiota composition and functionality. However, most of the microbial antigens targeted by gut IgA remain unknown, and the functional effects of IgA targeting these antigens are currently understudied. This study provides a framework for identifying and characterizing gut microbiota antigens targeted by gut IgA. We developed a small intestinal culture assay to harvest lamina propria IgA from gnotobiotic mice, with the aim of identifying antigenic targets in a model human gut commensal, VPI-5482. Colonization by induced a microbe-specific IgA response that was reactive against diverse antigens, including capsular polysaccharides, lipopolysaccharides, and proteins. IgA against microbial protein antigens targeted membrane and secreted proteins with diverse functionalities, including an IgA specific against proteins of the polysaccharide utilization locus (PUL) that are necessary for utilization of fructan, which is an important dietary polysaccharide. Further analyses demonstrated that the presence of dietary fructan increased the production of fructan PUL-specific IgA, which then downregulated the expression of fructan PUL in , both and Since the expression of fructan PUL has been associated with the ability of to colonize the gut in the presence of dietary fructans, our work suggests a novel role for gut IgA in regulating microbial colonization by modulating their metabolism. Given the significant impact that gut microbes have on our health, it is essential to identify key host and environmental factors that shape this diverse community. While many studies have highlighted the impact of diet on gut microbiota, little is known about how the host regulates this critical diet-microbiota interaction. In our present study, we discovered that gut IgA targeted a protein complex involved in the utilization of an important dietary polysaccharide: fructan. While the presence of dietary fructans was previously thought to allow unrestricted growth of fructan-utilizing bacteria, our work shows that gut IgA, by targeting proteins responsible for fructan utilization, provides the host with tools that can restrict the microbial utilization of such polysaccharides, thereby controlling their growth.
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http://dx.doi.org/10.1128/mBio.02324-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831775PMC
November 2019

Delayed Gastric Emptying Associates With Diabetic Complications in Diabetic Patients With Symptoms of Gastroparesis.

Am J Gastroenterol 2019 11;114(11):1778-1794

Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Objectives: Diabetic gastroparesis (Gp) occurs more often in type 1 diabetes mellitus (T1DM) than in type 2 diabetes mellitus (T2DM). Other diabetic end-organ complications include peripheral neuropathy, nephropathy, and retinopathy (together termed triopathy). This study determines the prevalence of diabetic complications (retinopathy, nephropathy, and peripheral neuropathy) in diabetic patients with symptoms of Gp, assessing the differences between T1DM and T2DM and delayed and normal gastric emptying (GE).

Methods: Diabetic patients with symptoms of Gp underwent history and physical examination, GE scintigraphy, electrogastrography with water load, autonomic function testing, and questionnaires assessing symptoms and peripheral neuropathy.

Results: One hundred thirty-three diabetic patients with symptoms of Gp were studied: 59 with T1DM and 74 with T2DM and 103 with delayed GE and 30 without delayed GE. The presence of retinopathy (37% vs 24%; P = 0.13), nephropathy (19% vs 11%; P = 0.22), and peripheral neuropathy (53% vs 39%; P = 0.16) was not significantly higher in T1DM than in T2DM; however, triopathies (all 3 complications together) were seen in 10% of T1DM and 3% of T2DM (P = 0.04). Diabetic patients with delayed GE had increased prevalence of retinopathy (36% vs 10%; P = 0.006) and number of diabetic complications (1.0 vs 0.5; P = 0.009); however, 39% of diabetic patients with delayed GE did not have any diabetic complications.

Discussion: In diabetic patients with symptoms of Gp, delayed GE was associated with the presence of retinopathy and the total number of diabetic complications. Only 10% of patients with T1DM and 3% of those with T2DM had triopathy of complications, and 39% of diabetic patients with Gp did not have any diabetic complications. Thus, the presence of diabetic complications should raise awareness for Gp in either T1DM or T2DM; however, diabetic Gp frequently occurs without other diabetic complications.
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http://dx.doi.org/10.14309/ajg.0000000000000410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832848PMC
November 2019

Pyloric interventions for gastroparesis: Does a "flippant" approach help us select the right patients?

Gastrointest Endosc 2019 11;90(5):761-762

Department of Medicine and Neurosciences, Center for Neurogastroenterology, Amos Food Body and Mind Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1016/j.gie.2019.06.034DOI Listing
November 2019

Effectiveness of gastric electrical stimulation in gastroparesis: Results from a large prospectively collected database of national gastroparesis registries.

Neurogastroenterol Motil 2019 12 4;31(12):e13714. Epub 2019 Oct 4.

Johns Hopkins University, Baltimore, Maryland.

Background: Gastric electrical stimulation (GES) for treating gastroparesis symptoms is controversial.

Methods: We studied 319 idiopathic or diabetic gastroparesis symptom patients from the Gastroparesis Clinical Research Consortium (GpCRC) observational studies: 238 without GES and 81 with GES. We assessed the effects of GES using change in GCSI total score and nausea/vomiting subscales between baseline and 48 weeks. We used propensity score methods to control for imbalances in patient characteristics between comparison groups.

Key Results: GES patients were clinically worse (40% severe vs. 18% for non-GES; P < .001); worse PAGI-QOL (2.2. vs. 2.6; P = .003); and worse GCSI total scores (3.5 vs. 2.8; P < .001). We observed improvements in 48-week GCSI total scores for GES vs. non-GES: improvement by ≥ 1-point (RR = 1.63; 95% CI = (1.14, 2.33); P = .01) and change from enrollment (difference = -0.5 (-0.8, -0.3); P < .001). When adjusting for patient characteristics, symptom scores were smaller and not statistically significant: improvement by ≥ 1-point (RR = 1.29 (0.88, 1.90); P = .20) and change from the enrollment (difference = -0.3 (-0.6, 0.0); P = .07). Of the individual items, the nausea improved by ≥ 1 point (RR = 1.31 (1.03, 1.67); P = .04). Patients with GCSI score ≥ 3.0 tended to improve more than those with score < 3.0. (Adjusted P = 0.02).

Conclusions And Inferences: This multicenter study of gastroparesis patients found significant improvements in gastroparesis symptoms among GES patients. Accounting for imbalances in patient characteristics, only nausea remained significant. Patients with greater symptoms at baseline improved more after GES. A much larger sample of patients is needed to fully evaluate symptomatic responses and to identify patients likely to respond to GES.
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http://dx.doi.org/10.1111/nmo.13714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863164PMC
December 2019

Satiety testing in diabetic gastroparesis: Effects of insulin pump therapy with continuous glucose monitoring on upper gastrointestinal symptoms and gastric myoelectrical activity.

Neurogastroenterol Motil 2020 01 1;32(1):e13720. Epub 2019 Oct 1.

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Background: Symptoms induced by caloric or non-caloric satiety test meals and gastric myoelectrical activity (GMA) have not been studied in patients with diabetic gastroparesis (DGP) before and after intense glucose management.

Aims: We determined the effects of continuous subcutaneous insulin infusion (CSII) with continuous glucose monitoring (CGM) on GI symptoms, volume consumed, and GMA induced by the caloric meal satiety test (CMST) and water load satiety test (WLST) in DGP.

Methods: Forty-five patients with DGP underwent CMST and WLST at baseline and 24 weeks after CSII with CGM. Subjects ingested the test meals until they were completely full. Visual analog scales were used to quantify pre- and postmeal symptoms, and GMA was recorded with cutaneous electrodes and analyzed visually and by computer. KEY RESULTS: At baseline and 24-week visits, nausea, bloating, abdominal discomfort, and fullness were immediately increased after CMST and WLST (Ps < 0.01). The meal volumes ingested were significantly less than normal controls at both visits in almost one-third of the subjects. After the CMST, the percentage 3 cycle per minute GMA increased and bradygastria decreased compared with WLST (Ps < 0.05). After treatment for 24 weeks meal volumes ingested, postmeal symptoms and GMA were no different than baseline. CONCLUSIONS AND INFERENCES: (a) Satiety test meals elicited symptoms of nausea, bloating, and abdominal discomfort; (b) CMST stimulated more symptoms and changes in GMA than WLST; and (c) CSII with CGM for 24 weeks did not improve symptoms, volumes ingested, or GMA elicited by the two satiety test meals in these patients with diabetic GP. Satiety tests in diabetic gastropresis are useful to study acute postprandial symptoms and GMA, but these measures were not improved by intensive insulin therapy.
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http://dx.doi.org/10.1111/nmo.13720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382784PMC
January 2020

Lymphatic vessel remodeling and invasion in pancreatic cancer progression.

EBioMedicine 2019 Sep 5;47:98-113. Epub 2019 Sep 5.

Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Background: The lymphatic system is involved in metastasis in pancreatic cancer progression. In cancer staging, lymphatic spread has been used to assess the invasiveness of tumor cells. However, from the endothelium's perspective, the analysis downplays the peri-lesional activities of lymphatic vessels. This unintended bias is largely due to the lack of 3-dimensional (3-D) tissue information to depict the lesion microstructure and vasculature in a global and integrated fashion.

Methods: We targeted the pancreas as the model organ to investigate lymphatic vessel remodeling in cancer lesion progression. Transparent pancreases were prepared by tissue clearing to facilitate deep-tissue, tile-scanning microscopy for 3-D lymphatic network imaging.

Findings: In human pancreatic ductal adenocarcinoma, we identify the close association between the pancreatic intraepithelial neoplasia (PanIN) lesions and the lymphatic network. In mouse models of PanIN (elastase-CreER;LSL-Kras and elastase-CreER;LSL-Kras;p53), the 3-D image data reveal the peri-lesional lymphangiogenesis, endothelial invagination, formation of the bridge/valve-like luminal tubules, vasodilation, and luminal invasion. In the orthotopic mouse model of pancreatic cancer, we identify the localized, graft-induced lymphangiogenesis and the peri- and intra-tumoral lymphatic vessel invasion.

Interpretation: The integrated view of duct lesions and vascular remodeling suggests an active role, rather than a passive target, of lymphatic vessels in the metastasis of pancreatic cancer. Our 3-D image data provide insights into the pancreatic cancer microenvironment and establish the technical and morphological foundation for systematic detection and 3-D analysis of lymphatic vessel invasion. FUND: Taiwan Academia Sinica (AS-107-TP-L15 and AS-105-TP-B15), Ministry of Science and Technology (MOST 106-2321-B-001-048, 106-0210-01-15-02, 106-2321-B-002-034, and 106-2314-B-007-004-MY2), and Taiwan National Health Research Institutes (NHRI EX107-10524EI).
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http://dx.doi.org/10.1016/j.ebiom.2019.08.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796580PMC
September 2019

Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis.

Am J Physiol Gastrointest Liver Physiol 2019 11 4;317(5):G716-G726. Epub 2019 Sep 4.

Enteric NeuroScience Program, Mayo Clinic, Rochester, Minnesota.

Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10; IG FDR = 6.3 × 10]. In DG, properdin expression correlated with GCSI bloating ( = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-ζ type, and complement C2 correlated with 4 h gastric retention ( = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis. This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.
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http://dx.doi.org/10.1152/ajpgi.00115.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879892PMC
November 2019

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease.

Neuron 2019 08 26;103(4):627-641.e7. Epub 2019 Jun 26.

Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address:

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).
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http://dx.doi.org/10.1016/j.neuron.2019.05.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706297PMC
August 2019

Enteric Neuromodulation for the Gut and Beyond.

Cold Spring Harb Perspect Med 2020 01 2;10(1). Epub 2020 Jan 2.

Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205.

The small intestine is the longest organ in the human body, spanning a length of ∼5 m and compartmentalized into three distinct regions with specific roles in maintenance of comprehensive homeostasis. Along its length exists as a unique and independent system-called the enteric nervous system (ENS)-which coordinates the multitude of functions continuously around the clock. Yet, with so many vital roles played, the functions, relationships, and roles of the small intestine and ENS remain largely elusive. This fundamental hole in the physiology of the small intestine and ENS introduces a substantial number of challenges when attempting to create bioelectronic approaches for treatment of various disorders originating in the small intestine. Here, we review existing therapeutic options for modulating the small intestine, discuss fundamental gaps that must be addressed, and highlight novel methods and approaches to consider for development of bioelectronic approaches aiming to modulate the small intestine.
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http://dx.doi.org/10.1101/cshperspect.a034355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938660PMC
January 2020

Abdominal Pain in Patients with Gastroparesis: Associations with Gastroparesis Symptoms, Etiology of Gastroparesis, Gastric Emptying, Somatization, and Quality of Life.

Dig Dis Sci 2019 08 9;64(8):2242-2255. Epub 2019 Mar 9.

Johns Hopkins University, Baltimore, MD, USA.

Abdominal pain can be an important symptom in some patients with gastroparesis (Gp).

Aims: (1) To describe characteristics of abdominal pain in Gp; (2) describe Gp patients reporting abdominal pain.

Methods: Patients with idiopathic gastroparesis (IG) and diabetic gastroparesis (DG) were studied with gastric emptying scintigraphy, water load test, wireless motility capsule, and questionnaires assessing symptoms [Patient Assessment of Upper GI Symptoms (PAGI-SYM) including Gastroparesis Cardinal Symptom Index (GCSI)], quality of life (PAGI-QOL, SF-36), psychological state [Beck Depression Inventory (BDI), State-Trait Anxiety Index (STAI), PHQ-15 somatization scale].

Results: In total, 346 Gp patients included 212 IG and 134 DG. Ninety percentage of Gp patients reported abdominal pain (89% DG and 91% IG). Pain was primarily in upper or central midline abdomen, described as cramping or sickening. Upper abdominal pain was severe or very severe on PAGI-SYM by 116/346 (34%) patients, more often by females than by males, but similarly in IG and DG. Increased upper abdominal pain severity was associated with increased severity of the nine GCSI symptoms, depression on BDI, anxiety on STAI, somatization on PHQ-15, the use of opiate medications, decreased SF-36 physical component, and PAGI-QOL, but not related to severity of delayed gastric emptying or water load ingestion. Using logistic regression, severe/very severe upper abdominal pain associated with increased GCSI scores, opiate medication use, and PHQ-15 somatic symptom scores.

Conclusions: Abdominal pain is common in patients with Gp, both IG and DG. Severe/very severe upper abdominal pain occurred in 34% of Gp patients and associated with other Gp symptoms, somatization, and opiate medication use. ClinicalTrials.gov Identifier: NCT01696747.
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http://dx.doi.org/10.1007/s10620-019-05522-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656584PMC
August 2019

Endoscopic full-thickness muscle biopsy for rectal tissue sampling in patients with severe gut motility disorders: an initial experience (with video).

Gastrointest Endosc 2019 06 9;89(6):1242-1247.e1. Epub 2019 Jan 9.

Division of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background And Aims: Diagnosis of GI neuromuscular diseases is mostly on the basis of symptomatology and is often unreliable. Pathologic analysis of affected tissue (eg, the myenteric plexus and muscle) is a potentially valuable method for both diagnosis and advancement of our knowledge about the biologic basis for these syndromes. However, until now access to the deeper layers of the GI tract has been limited, generally requiring invasive surgical techniques.

Methods: We report a "close-then-resect" endoscopic full-thickness biopsy sampling (EFTB) technique using an over-the-scope clip and telescope for rectal muscle biopsy sampling in patients with suspected severe neuromuscular gut disorders. The main outcome measures were technical success and adverse events.

Results: Thirteen patients (11 women; mean age 27 ± 5.4 years) with diffusely delayed colonic transit underwent EFTB. The mean (± standard deviation) procedure time was 30 ± 5.2 minutes. The mean size of the resected specimen was 18 ± 3.5 mm. Histologic full-thickness tissue samples were achieved for all patients. Postprocedural adverse events were reported in 2 patients, and both were graded as mild (1 self-limited bleeding and 1 with rectal pain). Hematoxylin and eosin staining of tissue samples confirmed adequate cross-sectional imaging of muscularis propria in all patients with excellent demonstration of the myenteric plexus and both layers of muscle. Two patients demonstrated a decrease in interstitial cells of Cajal as demonstrated by CD117 staining. No cases demonstrated appreciable inflammation involving myenteric ganglia.

Conclusions: Diagnostic EFTB with modified over-the-scope clip for the close-then-resect method appears to be a safe and effective technique to obtain adequate full-thickness rectal specimens, allowing for both quantitative and qualitative analysis for the diagnosis of neuromuscular GI dysmotility.
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http://dx.doi.org/10.1016/j.gie.2019.01.001DOI Listing
June 2019