[Note: Though the full text of this article is fee-based, two web-only Data Supplement files - "Materials" and "Methods" - may be accessed here. ]
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. [Immunocytes are different white blood cell types that participate in the body’s inflammatory & immune responses to protect against infection and repair injured tissues. Unlike red blood cells they have a nucleus.]
Design: Peripheral blood mononuclear cell supernatants [clear fluid at the top of blood sample after centrifuging] from 20 diarrhea 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 [nerve sensitivity to movement] 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.
[Cytokines act as molecular messengers between cells, usually regulating various inflammatory responses. Afferent neurons are nerve pathways that carry impulses from the stimulus receptor site/sense organ through the nervous system toward the brain. Efferent neurons communicate in the opposite direction.]
Results:
• D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. [Infliximab, aka Remicade, is an antibody that blocks the inflammation-promoting cytokine TNF-alpha and is used to treat (reduce inflammation in) autoimmune diseases such as Crohn’s disease and RA.]
• C-IBS supernatants did not, but occasionally elevated basal discharge [neuron activity].
• Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic [suppressing perception of pain] 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-1beta,
• IL-6,
• IL-10 and
• TNF-alpha.
TNF-alpha most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. [TRPA1 is one of the many types of ion channels located on cell membranes. It serves as a sensor/communicator. A TRPA1 antagonist would reduce TRPA1 sensitivity.]
IL-1beta elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels. [IL-1 beta induces pro-inflammatory COX-2 in the central nervous system, contributing to inflammatory pain hypersensitivity. Tetrodotoxin quells neuron activity.]
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.
Source: Gut, Jul 5, 2012. DOI:10.1136/gutjnl-2011-301856, by Hughes PA, Harrington AM, Castro J, Liebregts T, Adam B, Grasby DJ, Isaacs NJ, Maldeniya L, Martin CM, Persson J, Andrews JM, Holtmann G, Blackshaw AL, Brierley SM. Nerve-Gut Research Laboratory, Discipline of Medicine and Discipline of Physiology, Faculty of Health Sciences, The University of Adelaide; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital; and Department of Leukocyte Biology, Women's and Children's Health Research Institute, Women's and Children's Hospital, Adelaide, South Australia, Australia; Department of Bone Marrow Transplantation, University Hospital Essen, West German Cancer Centre, Germany; Neurogastroenterology Group, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK. [Email: patrick.hughes@adelaide.edu.au]
