Sensory neuro-immune interactions differ between Irritable Bowel Syndrome subtypes
- Patrick A Hughes1,2,
- Andrea M Harrington1,
- Joel Castro1,
- Tobias Liebregts1,3,
- Birgit Adam1,3,
- Dallas J Grasby1,
- Nicole J Isaacs1,
- Lochana Maldeniya1,
- Chris M Martin1,
- Jenny Persson1,
- Jane M Andrews1,
- Gerald Holtmann1,
- L Ashley Blackshaw1,4,
- Stuart M Brierley1,5
- 1Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide and Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia 5000
- 2Department of Leukocyte, Biology, Women's and Children's Health Research Institute, Women's and Children's Hospital, Adelaide, South Australia, Australia
- 3Department of Bone Marrow Transplantation, University Hospital Essen, West German Cancer Centre, Germany
- 4Neurogastroenterology Group, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- 5Discipline of Physiology, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Correspondence to Dr Patrick A Hughes, Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, South Australia 5000, Australia;
Contributors PAH, LAB and SMB contributed to study concept and design; PAH, AMH, JC, TL, BA, LM, CMM, JP and SMB contributed toward acquisition of data; PAH, AMH, TL, BA, DG, NI, JMA, GJH, LAB and SMB contributed to analysis and interpretation of data and statistical analysis; PAH, AMH, TL, LAB and SMB drafted the manuscript; PAH, LAB and SMB obtained the funding.
- Revised 6 June 2012
- Accepted 7 June 2012
- Published Online First 5 July 2012
Objective The gut is a major site of contact between immune and sensory systems and evidence suggests that patients with irritable bowel syndrome (IBS) have immune dysfunction. Here we show how this dysfunction differs between major IBS subgroups and how immunocytes communicate with sensory nerves.
Design Peripheral blood mononuclear cell supernatants from 20 diarrhoea predominant IBS (D-IBS) patients, 15 constipation predominant IBS (C-IBS) patients and 36 healthy subjects were applied to mouse colonic sensory nerves and effects on mechanosensitivity assessed. Cytokine/chemokine concentration in the supernatants was assessed by proteomic analysis and correlated with abdominal symptoms, and expression of cytokine receptors evaluated in colonic dorsal root ganglia neurons. We then determined the effects of specific cytokines on colonic afferents.
Results D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. C-IBS supernatants did not, but occasionally elevated basal discharge. Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic mechanism. Several cytokines were elevated in IBS supernatants, and levels correlated with pain frequency and intensity in patients. Visceral afferents expressed receptors for four cytokines: IL-1β, IL-6, IL-10 and TNF-α. TNF-α most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. IL-1β elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels.
Conclusions Distinct patterns of immune dysfunction and interaction with sensory pathways occur in different patient groups and through different intracellular pathways. Our results indicate IBS patient subgroups would benefit from selective targeting of the immune system.
- Irritable bowel syndrome
- sensory neurons
- gastro-oesophageal reflux disease
- Helicobacter Pylori—epidemiology
- functional dyspepsia
- functional bowel disorder
- visceral hypersensitivity
- nerve—gut interactions
- visceral nociception
- lower oesophageal sphincter
- real time PCR
- 2,4,6-trinitrobenzene sulphonic acid
Correction notice This article has been corrected since it was published Online First. The author name Ashley L Blackshaw has been amended to read L Ashley Blackshaw. The author affiliations have also been amended.
Funding This work was supported by NHMRC Australia project grant # 626960, NHMRC Principle Research Fellowship (LAB) and NHMRC Australian Biomedical Fellowships (PAH and SMB).
Competing interests None.
Ethics approval Ethics approval was provided by the Royal Adelaide Hospital and University of Adelaide.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This manuscript contains all data from this study.