Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?

Abstract

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder.

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

“…Little is known of the mechanisms underlying IBS and it has historically been viewed as a neurological motility disorder involving alterations in the brain-gut axis. However there is increasing evidence that the immune system is altered in these patients, and that these alterations contribute toward symptoms (Hughes et al, 2013b).…”

“…They also express putative nociceptive channels, including members of the Transient Receptor Potential (TRPV1, TRPA1) and Acid Sensing Ion Channel 6 (ASIC3) families, implying they act as intensity encoders and modulate the sensory processing of pain (Brierley et al, 2009;Brookes et al, 2013;Gebhart, 2000;Jones et al, 2005). Immune derived mediators are known to excite viscerosensory nerves and have previously been implicated in the heightened sensitivity to distension of the colo-rectum experienced by IBS patients (Hughes et al, 2009a;Hughes et al, 2013b). However, the generation and propagation of action potentials is a dynamic process that not only results from increased excitation, but also loss of inhibition.…”

“…These receptors are G i/o members of the G-protein coupled receptor family, with binding typically decreasing neuronal excitability via inhibition of adenylyl cyclase, activation of potassium channels and inhibition of calcium channels. Immune cells are known to secrete opioids, and T cell derived β-endorphin, a MOR preferring agonist, has previously been shown to be essential for setting the colo-rectal afferent activation threshold to distension in healthy mice (Hughes et al, 2013b;Stein et al, 2003;Verma-Gandhu 7 et al, 2006). However, little is known of how these studies translate to humans, and opioid secretion by immune cells is yet to be directly investigated in IBS.…”

Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

“…10 Indeed, MCs in patients with IBS have been shown to be in closer proximity to colonic nerve endings, including the SP-positive afferents and endings expressing transient receptor potential vanilloid type 1 (TRPV1), and correlated strongly with severity and frequency of pain. 31,32 MC degranulation increases excitability of vagal, splanchnic, and mesenteric afferents, contributing to nociceptive processes associated with visceral pain. 10,14 Supernatants from mucosal biopsies from IBS patients are more likely to activate intestinal nerves than those from healthy subjects.…”

“…10,14 Supernatants from mucosal biopsies from IBS patients are more likely to activate intestinal nerves than those from healthy subjects. 31,33 Histamine and proteases are the main sensitizing mediators to nerves, which increased in spontaneous release in IBS patients without consideration of different subtypes. 33 Histamine H1 and H2 receptors (H 1 R and H 2 R) may mediate the activation of visceral afferents and enteric neurons, while H 3 R mediate suppression of fast synaptic transmission.…”