title: Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients.
abstract: Alterations in the neuro-immune axis contribute toward viscerosensory nerve sensitivity and symptoms in Irritable Bowel Syndrome (IBS). Inhibitory factors secreted from immune cells inhibit colo-rectal afferents in health, and loss of this inhibition may lead to hypersensitivity and symptoms. We aimed to determine the immune cell type(s) responsible for opioid secretion in humans and whether this is altered in patients with IBS. The β-endorphin content of specific immune cell lineages in peripheral blood and colonic mucosal biopsies were compared between healthy subjects (HS) and IBS patients. Peripheral blood mononuclear cell (PBMC) supernatants from HS and IBS patients were applied to colo-rectal sensory afferent endings in mice with post-inflammatory chronic visceral hypersensitivity (CVH). β-Endorphin was identified predominantly in monocyte/macrophages relative to T or B cells in human PBMC and colonic lamina propria. Monocyte derived β-endorphin levels and colonic macrophage numbers were lower in IBS patients than healthy subjects. PBMC supernatants from healthy subjects had greater inhibitory effects on colo-rectal afferent mechanosensitivity than those from IBS patients. The inhibitory effects of PBMC supernatants were more prominent in CVH mice compared to healthy mice due to an increase in μ-opioid receptor expression in dorsal root ganglia neurons in CVH mice. Monocyte/macrophages are the predominant immune cell type responsible for β-endorphin secretion in humans. IBS patients have lower monocyte derived β-endorphin levels than healthy subjects, causing less inhibition of colonic afferent endings. Consequently, altered immune function contributes toward visceral hypersensitivity in IBS.
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; Leukocyte Biology Laboratory, Women's and Children's Health Research Institute, North Adelaide, SA 5006, Australia. Electronic address: Patrick.hughes@adelaide.edu.au.
authors: Patrick A
authors: PA
authors: Hughes
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Melissa
authors: M
authors: Moretta
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Amanda
authors: A
authors: Lim
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Dallas J
authors: DJ
authors: Grasby
authors: Leukocyte Biology Laboratory, Women's and Children's Health Research Institute, North Adelaide, SA 5006, Australia.
authors: Daniel
authors: D
authors: Bird
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Stuart M
authors: SM
authors: Brierley
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Tobias
authors: T
authors: Liebregts
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Birgit
authors: B
authors: Adam
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: L Ashley
authors: LA
authors: Blackshaw
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Gerald
authors: G
authors: Holtmann
authors: Department of Gastroenterology, Flinders Medical Centre, Flinders University, Bedford Park, SA 5042, Australia.
authors: Peter
authors: P
authors: Bampton
authors: Adelaide Proteomics Centre, School of Molecular Biomedical Science, The University of Adelaide, Adelaide, SA 5005, Australia.
authors: Peter
authors: P
authors: Hoffmann
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: Jane M
authors: JM
authors: Andrews
authors: Leukocyte Biology Laboratory, Women's and Children's Health Research Institute, North Adelaide, SA 5006, Australia; Discipline of Paediatrics, Faculty of Health Sciences, University of Adelaide, SA 5005, Australia.
authors: Heddy
authors: H
authors: Zola
authors: Leukocyte Biology Laboratory, Women's and Children's Health Research Institute, North Adelaide, SA 5006, Australia; Discipline of Paediatrics, Faculty of Health Sciences, University of Adelaide, SA 5005, Australia; SA Pathology, Adelaide, SA 5000, Australia.
authors: Doreen
authors: D
authors: Krumbiegel
mesh_terms: D000328:Adult; D000818:Animals; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D043183:Irritable Bowel Syndrome / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000276:immunology* / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism*
chemical_list: D001615:beta-Endorphin
keywords: Irritable Bowel Syndrome; Macrophage; Monocyte; Neuro-immune; Opioid; Visceral pain