Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice

Cipriani, Gianluca; Gibbons, Simon J.; Miller, Katie E.; Yang, Daniel S.; Terhaar, Matthew L.; Eisenman, Seth T.; Ördög, Tamás; Linden, David R.; Gajdos, Gabriela B.; Szurszewski, Joseph H.; Farrugia, Gianrico

doi:10.1053/j.gastro.2018.02.027

Cited by 68 publications

(76 citation statements)

References 36 publications

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“…One notable result is that inflammation, as measured by the cytokines IL‐6 and TNF‐α, appears to markedly improve with long‐term electrical stimulation of the GI tract. This is similar to what has recently been reported in an animal model of gastroparesis …”

Section: Discussionsupporting

confidence: 92%

“…This is similar to what has recently been reported in an animal model of gastroparesis. 18 Autonomic NS-traditional vs HRV. Both measures of autonomic function showed abnormalities.…”

Section: Anatomic-mucosal Neuronal Density Vs Full-thickness Biopsymentioning

confidence: 99%

“…An animal model has recently been published using high-resolution recordings on the mucosal surface. 18,19 Currently, low-resolution approaches can be used serosally in humans, often at the time of gastric stimulator insertion, and with the delivery of energy through proximal to distal electrodes.…”

Section: Anatomic-mucosal Neuronal Density Vs Full-thickness Biopsymentioning

confidence: 99%

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Gastroparesis syndromes: Response to electrical stimulation

Abell

Kedar

Stocker

et al. 2019

Neurogastroenterology Motil

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Background and Aims Factors underlying gastroparesis are not well defined, nor is the mechanism of action of gastric electrical stimulation (GES). We hypothesized that GES acts via several mechanisms related to underlying disordered pathophysiology. Methods We studied 43 consecutive eligible patients with gastroparetic symptoms, previously evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal; and also categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. We then studied 41 patients who underwent temporary GES for 5‐7 days. Thirty‐six of those patients were implanted and 30 were followed up at 6 months after permanent GES. Results In previous but separately reported work, patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status and all patients demonstrated abnormalities in each of the five areas studied. After GES, patients showed early and late effects of electrical stimulation with changes noted in multiple areas, categorized by improvement status. Conclusion Patients with symptoms of gastroparesis have multiple abnormalities, including systemic inflammation and disordered hormonal status. GES affects many of these abnormalities. We conclude electrical stimulation improves symptoms and physiology with (a) an early and sustained anti‐emetic effect; (b) an early and durable gastric prokinetic effect in delayed emptying patients; (c) an early anti‐arrhythmic effect that continues over time; (d) a late autonomic effect; (e) a late hormonal effect; (f) an early anti‐inflammatory effect that persists; and (g) an early and sustained improvement in health‐related quality of life. This study is registered with Clinicaltrials.gov under study # NCT03178370 (https://clinicaltrials.gov/ct2/show/NCT03178370).

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Section: Discussionsupporting

confidence: 92%

“…This is similar to what has recently been reported in an animal model of gastroparesis. 18 Autonomic NS-traditional vs HRV. Both measures of autonomic function showed abnormalities.…”

Section: Anatomic-mucosal Neuronal Density Vs Full-thickness Biopsymentioning

confidence: 99%

Section: Anatomic-mucosal Neuronal Density Vs Full-thickness Biopsymentioning

confidence: 99%

See 1 more Smart Citation

Gastroparesis syndromes: Response to electrical stimulation

Abell

Kedar

Stocker

et al. 2019

Neurogastroenterology Motil

View full text Add to dashboard Cite

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“…In the clinical setting, measurement of gastric emptying uses a [ 13 C] or [ 99m Tc]-DTPA-labeled egg white meal with breath testing or scintigraphy readouts, respectively (45). [ 13 C] breath testing following an egg white meal is also used in mice, with time to empty half of the stomach contents generally between 60 and 90 min (38,46). These methods using a solid meal are relevant to emptying of solids from stomach and do not assess the emptying of liquids, which is more relevant to the standard OGTT.…”

Section: Discussionmentioning

confidence: 99%

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A

Çil¹,

Anderson²,

Yen³

et al. 2019

FASEB j.

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Interstitial cells of Cajal, which express the calcium‐activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2‐bromodifluoroacetylamino‐5,6,7,8‐tetrahydro‐4H‐cyclohepta[b]thiophene‐3‐carboxylic acid o‐tolylamide (TMinh‐23) with 30 nM half‐maximal inhibitory concentration. Here, we tested the efficacy of TMinh‐23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TMinh‐23 strongly inhibited spontaneous and carbachol‐stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TMinh‐23 for at least 4 h following a single oral or intraperitoneal dose at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of phenol red or independently by [99mTc]‐diethylenetriamine pentaacetic acid scintigraphy, was reduced by TMinh‐23 by ∼60% at 20 min. Interestingly, there was little effect of TMinh‐23 on baseline whole‐gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TMinh‐23 administration significantly reduced the elevation in blood sugar in mice following an oral but not intraperitoneal glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as dumping syndrome, and potentially for improving glucose tolerance in diabetes mellitus/metabolic syndrome and enhancing satiety in obesity.—Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A. FASEB J. 33, 11247–11257 (2019). http://www.fasebj.org

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“…Both intrinsic and extrinsic enteric neuropathies have been shown to delay gastric emptying . In diabetic animals with gastroparesis, loss of CD206+ heme oxygenase‐1‐expressing M2 macrophages exhibits increased oxidative stress and loss of ICC number and function, leading to delayed emptying . While the loss of gastric enteric neurons may play a role in delayed gastric emptying, further investigation into potential treatment options has been limited by the lack of a tractable experimental model system.…”

Section: Introductionmentioning

confidence: 99%

Hypoganglionosis in the gastric antrum causes delayed gastric emptying

Baker

Ahmed

Cheng

et al. 2019

Neurogastroenterology Motil

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Background Enteric nervous system (ENS) abnormalities have been implicated in delayed gastric emptying but studies exploring potential treatment options are limited by the lack of an experimental animal model. We examined the ENS abnormalities in the mouse stomach associated with aging, developed a novel model of gastroparesis, and established a new approach to measure gastric emptying. Methods A modified gastric emptying assay was developed, validated in nNOS −/− mice, and tested in mice at multiple ages. Age‐related changes in ENS structure were analyzed by immunohistochemistry. Gastric aganglionosis was generated in Wnt1‐iDTR mice using focal administration of diphtheria toxin (DT) into the anterior antral wall. Key Results Older mice (>5 months) exhibit hypoganglionosis in the gastric antrum and a decreased proportion of nNOS neurons as compared to younger mice (age 5‐7 weeks). This was associated with a significant age‐dependent decrease in liquid and solid gastric emptying. A novel model of gastric antrum hypoganglionosis was established using neural crest‐specific expression of diphtheria toxin receptor. In this model, a significant reduction in liquid and solid gastric emptying is observed. Conclusions & Inferences Older mice exhibit delayed gastric emptying associated with hypoganglionosis and a reduction in nNOS‐expressing neurons in the antrum. The causal relationship between antral hypoganglionosis and delayed gastric emptying was verified using a novel experimental model of ENS ablation. This study provides new information regarding the pathogenesis of delayed gastric emptying and provides a robust model system to study this disease and develop novel treatments.

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Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice

Abstract: In studies of Csf1op/op and wild-type mice with diabetes, we found delayed gastric emptying to be associated with increased production of inflammatory factors, and reduced production of anti-inflammatory factors, by macrophages, leading to loss of ICC.

Cited by 68 publications

References 36 publications

Gastroparesis syndromes: Response to electrical stimulation

Gastroparesis syndromes: Response to electrical stimulation

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A

Hypoganglionosis in the gastric antrum causes delayed gastric emptying

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