Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa

Herring, B. Paul; Hoggatt, April M.; Gupta, Anita; Griffith, S. L.; Nakeeb, Atilla; Choi, Jennifer; Idrees, Muhammad T.; Nowak, Thomas; Morris, David L.; Wo, John M.

doi:10.1111/nmo.13230

Cited by 24 publications

(37 citation statements)

References 49 publications

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“…In summary, we have shown that expression of mRNA encoding FOXF1 and FOXF2 is decreased in human subjects with gastroparesis and that loss of both these proteins from adult smooth muscle in mice is sufficient to impair liquid gastric emptying. These findings together with our previous studies showing FOXF regulation of SRF/myocardin transcriptional complexes and altered transcriptional activity of contractile protein genes in the stomach of patients with gastroparesis suggest that SRF containing transcriptional complexes may play a central role in pathological changes that lead to gastroparesis.…”

Section: Discussionsupporting

confidence: 78%

“…None of these 14 controls subjects had diabetes (normal HbA1c <1 month prior to surgery; Figure A). The clinical description of these patients was described previously . The second group included 11 patients undergoing bariatric weight loss surgery that had diabetes (Figure B).…”

Section: Resultsmentioning

confidence: 99%

“…The second group included 11 patients undergoing bariatric weight loss surgery that had diabetes (Figure B). We also analyzed samples from two groups of patients with gastroparesis one group with no diabetes (16 patients with idiopathic gastroparesis described previously, Figure A) and one group in which the patients also had diabetes (9 patients with diabetic gastroparesis, Figure B). This analysis revealed that FOXF1 and FOXF2 mRNA levels were significantly decreased in the patients with idiopathic gastroparesis (Figure A), and FOXF1 mRNA was also significantly decreased in the patients with diabetic gastroparesis (Figure B).…”

Section: Resultsmentioning

confidence: 99%

“…This study received IRB approval from the Indiana University Institutional Review Board (protocol #1309147354R004). Biopsies from the control group of human subjects were obtained from either non‐diabetic or diabetic individuals without gastroparesis symptoms that were undergoing bariatric weight loss surgery as described previously (normal HbA1c level <1 month prior to surgery in non‐diabetic group) . Control and gastroparesis subjects were age‐ and sex‐matched.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently challenged some of these findings using qRT‐PCR analysis of RNA isolated from the stomach muscularis of control and gastroparesis patients. We found that idiopathic gastroparesis is associated with decreased mRNA encoding smooth muscle cell contractile proteins and PDGFRα + without a change in mRNA encoding ICC markers . The altered expression of mRNA encoding contractile proteins was correlated with decreased expression of serum response factor (SRF), a transcription factor that is crucial for regulating the differentiation state of smooth muscle cells .…”

Section: Introductionmentioning

confidence: 90%

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Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice

Herring

Hoggatt

Gupta

et al. 2018

Neurogastroenterology Motil

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Background and Aims The transcription factors FOXF1 and FOXF2 have been implicated in the development of the gastrointestinal tract but their role in adults or in gastrointestinal diseases is poorly understood. We have recently shown that expression of serum response factor (SRF), a transcription factor whose activity is modulated by FOXF proteins, is decreased in the stomach muscularis of patients with gastroparesis. The aim of the current study was to determine whether FOXF expression is decreased in gastroparesis patients and whether loss of FOXF1 and/or FOXF2 from adult smooth muscle is sufficient to impair gastric emptying in mice. Methods Full‐thickness stomach biopsy samples were collected from control subjects and from patients with gastroparesis. mRNA was isolated from the muscularis externa, and FOXF mRNA expression levels were determined by quantitative reverse transcriptase (RT)‐PCR. Foxf1 and Foxf2 were knocked out together and separately from smooth muscle cells in adult mice, and the subsequent effect on liquid gastric emptying and contractile protein expression was determined. Key Results Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients. Knockout of Foxf1 and Foxf2 together, but not alone, from mouse smooth muscle resulted in delayed liquid gastric emptying. Foxf1/2 double knockout mice had decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis. Conclusions and Inferences Our findings suggest that decreased expression of FOXF1 and FOXF2 may be contributing to the impaired gastric emptying seen in gastroparesis patients.

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

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Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice

Herring

Hoggatt

Gupta

et al. 2018

Neurogastroenterology Motil

Self Cite

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Stretchable Device for Simultaneous Measurements of Contractility and Electrophysiology of Neuromuscular Tissue in the Gastrointestinal Tract

Oldroyd,

Meng

et al. 2024

Advanced Materials

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Devices interfacing with biological tissues can provide valuable insights into function, disease, and metabolism through electrical and mechanical signals. However, certain neuromuscular tissues, like those in the gastrointestinal tract, undergo significant strains of up to 40%. Conventional inextensible devices cannot capture the dynamic responses in these tissues. This study introduces electrodes made from poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and polydimethylsiloxane (PDMS) that enable simultaneous monitoring of electrical and mechanical responses of gut tissue. The soft PDMS layers conform to tissue surfaces during gastrointestinal movement. Dopants, including Capstone™ FS‐30 and polyethylene glycol, are explored to enhance the conductivity, electrical sensitivity to strain, and stability of the PEDOT:PSS. The devices are fabricated using shadow masks and solution‐processing techniques, providing a faster and simpler process than traditional clean‐room based lithography. Tested on ex vivo mouse colon and human stomach, the device recorded voltage changes of up to 300 μV during contraction and distension consistent with muscle activity, while simultaneously recording resistance changes of up to 150% due to mechanical strain. These devices detect and respond to chemical stimulants and blockers, and can induce contractions through electrical stimulation. They hold great potential for studying and treating complex disorders like irritable bowel syndrome and gastroparesis.This article is protected by copyright. All rights reserved

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United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis

et al. 2021

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Background: Gastroparesis is a condition characterized by epigastric symptoms and delayed gastric emptying (GE) rate in the absence of any mechanical obstruction.The condition is challenging in clinical practice by the lack of guidance concerning diagnosis and management of gastroparesis.Methods: A Delphi consensus was undertaken by 40 experts from 19 European countries who conducted a literature summary and voting process on 89 statements. Quality of evidence was evaluated using grading of recommendations assessment, development, and evaluation criteria. Consensus (defined as ≥80% agreement) was reached for 25 statements. Results:The European consensus defined gastroparesis as the presence of symptoms associated with delayed GE in the absence of mechanical obstruction. Nausea and vomiting were identified as cardinal symptoms, with often coexisting postprandial distress syndrome symptoms of dyspepsia. The true epidemiology of gastroparesis is not known in detail, but diabetes, gastric surgery, certain neurological and connective tissue diseases, and the use of certain drugs recognized as risk factors. While the panel agreed that severely impaired gastric motor function is present in these patients, there was no consensus on underlying pathophysiology.The panel agreed that an upper endoscopy and a GE test are required for diagnosis.Only dietary therapy, dopamine-2 antagonists and 5-HT 4 receptor agonists were considered appropriate therapies, in addition to nutritional support in case of severe weight loss. No consensus was reached on the use of proton pump inhibitors, other classes of antiemetics or prokinetics, neuromodulators, complimentary, psychological, or more invasive therapies. Finally, there was consensus that gastroparesis adversely impacts on quality of life and healthcare costs and that the long-term prognosis of gastroparesis depends on the cause.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa

Abstract: Our findings suggest that idiopathic gastroparesis is associated with altered smooth muscle cell contractile protein expression and loss of PDGFRα cells without a significant change in ICCs.

Cited by 24 publications

References 49 publications

Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice

Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice

Stretchable Device for Simultaneous Measurements of Contractility and Electrophysiology of Neuromuscular Tissue in the Gastrointestinal Tract

United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis

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