Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia.

Autor: Bruce JK; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Burns GL; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Sinn Soh W; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Nair PM; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Sherwin S; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Fan K; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Dowling LR; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Goggins BJ; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Koloski N; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, and Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia., Potter M; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia., Bollipo S; Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia., Foster R; Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia., Gan LT; Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia., Veysey M; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia., Philpott DJ; Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Girardin SE; Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Holtmann G; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, and Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia., Kaiko GE; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Walker MM; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia., Talley NJ; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia., Keely S; School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. Electronic address: simon.keely@newcastle.edu.au.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2022 Mar; Vol. 101, pp. 335-345. Date of Electronic Publication: 2022 Jan 31.
DOI: 10.1016/j.bbi.2022.01.019
Abstrakt: Functional dyspepsia (FD) affects up to 15% of the population and is characterised by recurring upper gastrointestinal (GI) symptoms occurring in the absence of clinically identifiable pathology. Psychological stress is a key factor associated with the onset of FD and locally acting hypothalamic-pituitary-adrenal (HPA) axis hormones have been implicated in GI motility and barrier dysfunction. Recent pre-clinical work has identified mechanistic pathways linking corticotropin-releasing hormone (CRH) with the innate epithelial immune protein NLRP6, an inflammasome that has been shown to regulate GI mucus secretion. We recruited twelve FD patients and twelve healthy individuals to examine whether dysregulation of hypothalamic-pituitary adrenal (HPA) axis hormones and altered NLRP6 pathways were evident in the duodenal mucosa. Protein expression was assessed by immunoblot and immunohistochemistry in D2 duodenal biopsies. Plasma HPA axis hormones were assayed by ELISA and enteroid and colorectal cancer cell line cultures were used to verify function. FD patients exhibited reduced duodenal CRH-receptor 2, compared to non-GI disease controls, indicating a dysregulation of duodenal HPA signalling. The loss of CRH-receptor 2 correlated with reduced NLRP6 expression and autophagy function, processes critical for maintaining goblet cell homeostasis. In accordance, duodenal goblet cell numbers and mucin exocytosis was reduced in FD patients compared to controls. In vitro studies demonstrated that CRH could reduce NLRP6 in duodenal spheroids and promote mucus secretion in the HT29-MTX-E12 cell line. In conclusion, FD patients exhibit defects in the NLRP6-autophagy axis with decreased goblet cell function that may drive symptoms of disease. These features correlated with loss of CRH receptor 2 and may be driven by dysregulation of HPA signalling in the duodenum of FD patients.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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