Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia.

Jörn Karhausen,Shin-Ichiro Hagiwara,Sreenivasan Paruthiyil,Pankaj J Pasricha,Aditi Bhargava,Esha Kaushal,Burcu Hasdemir

doi:10.1371/journal.pone.0203704

Jörn Karhausen, Shin-Ichiro Hagiwara + Show 5 more

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https://doi.org/10.1371/journal.pone.0203704

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Abstract

Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body’s stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.

Highlights

Functional dyspepsia (FD) is a clinical syndrome characterized by pain or burning in the epigastrium, early satiety, fullness during or after meal, or a combination of these symptoms that involve the upper gastrointestinal tract, such as the stomach and the duodenum [1, 2]
Low-grade inflammation and a dysregulated gut-brain axis are being recognized as important contributors to Functional gastrointestinal disorders (FGIDs) symptoms
In this study, using a previously described rat model of FD where 10-day old neonates were exposed to gastric irritation over a period of several days, we found that mass cell infiltrate increased in stomachs of IA-treated adult rats and associated with behavioral changes in adult rats

Summary

Introduction

Functional dyspepsia (FD) is a clinical syndrome characterized by pain or burning in the epigastrium, early satiety, fullness during or after meal, or a combination of these symptoms that involve the upper gastrointestinal tract, such as the stomach and the duodenum [1, 2]. CRF system in functional bowel diseases the Rome IV criteria, FD is subdivided into two distinct categories: post-prandial distress syndrome and epigastric pain syndrome. Post-prandial distress syndrome is defined as mealinduced dyspeptic symptoms, bothersome post-prandial fullness, and early satiety for at least 3 days per week. Epigastric pain syndrome is defined by symptoms that occur in between meals for at least one day per week [1, 4, 5]

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