Defensins in IBS
Even more confusing in the discussion of the role of innate immunity in gastrointestinal health and disease is the fact that IBS, which is characterized as a functional disorder, also displays signs of at least low-grade inflammation. IBS is a highly prevalent disorder of the GI tract that afflicts 10–20% of the population with a variable combination of abdominal pain or discomfort in combination with altered bowel habits including bloating, constipation and diarrhea. Accepted responsible mechanisms include psychosocial factors, abnormal gastrointestinal motility and disturbed visceral sensory perception, but without a known releasing cause, any animal model, or any reliable biomarkers the precise pathophysiology of IBS is still unclear. Being categorized as a functional disorder according to the defining Rome criteria, macroscopic and histological inflammation of the gut are thus important exclusion criteria for IBS. However, at least in a subset of IBS patients the disorder follows an episode of gastrointestinal infection (i.e., bacteriologically confirmed gastroenteritis)[67–71] and it was recently debated that similar pathogenic factors may be present also in non-postinfectious IBS and functional dyspepsia.
Although only a fraction of patients with infection develop IBS, there are several points supporting a pathogenic role for inflammation in this type: a relatively greater mucosal cellularity indicating a subcolitic inflammatory process, increased 1β mRNA in rectal biopsies, increased counts of intraepithelial lymphocytes and enteroendocrine cells, elevated CD3+ and CD8+ lymphocytes, and increased numbers of enterochromaffin cells, mast cells and lamina propria T lymphocytes. According to Gwee an episode of infectious diarrhea may produce changes in the gastrointestinal physiology that predispose to the development of IBS symptoms including diarrhea and pain, and when psychological factors exist in association with more severe inflammatory and physiological disturbances a manifestation of IBS is likely.
The idea that IBS could be an inflammatory disorder has not been limited to postinfectious IBS, but has also been extended to other forms such as diarrhea-predominant IBS. In a previous trial almost 90% of a group of IBS patients showed evidence of immune activation (higher numbers of CD25+ cells) regardless of the type of onset. CD25+ cells are regulatory T cells that are considered important in the prevention of autoimmunity, as well in controlling inflammatory responses in the gut. Thus an autogenous or exogenous antigen challenge in these patients with the CD25+ cells preventing the progression to a more florid inflammatory response can be considered here. In another study involving diarrhea-predominant IBS patients, intraepithelial CD3+ lymphocytes as well as mast cell numbers were increased in jejunal biopsies. In addition, this group of D-IBS patients had markedly higher jejunal fluid tryptase concentrations compared with healthy controls. Furthermore, low grade infiltration of lymphocytes in the myenteric plexus has been found. Intestinal immune activation in IBS is supported by Ohman et al. showing an augmented cell-mediated intestinal immune response. Furthermore, data by Elsenbruch et al. suggest that peripheral immune function might be altered in IBS as IBS patients failed to show the postprandial decrease in the in vitro TNF-α production observed in controls.
Another recent study of peripheral blood mononuclear cell (PBMC) proinflammatory cytokine production (TNF-α, IL-1β and IL-6) demonstrated that IBS patients compared with healthy controls display an enhanced proinflammatory cytokine release (increased basal and E. coli LPS-induced production of TNF-α), which might be associated with symptoms and anxiety. Since the production of cytokines is under genetic control, the role of genetics by evaluating the genotypes for various pro- and counter-inflammatory cytokines was studied, reporting lower frequency in IBS patients of genotypes promoting production of IL-10, which is a counter-inflammatory cytokine. Furthermore, an increased frequency of genotypes that promoted the production of the proinflammatory cytokine TNF-α was reported in IBS patients.
A study on human defensins and proinflammatory cytokines of our own group provides further evidence of a proinflammatory response in IBS patients. Since HBD-2 has been reported to be expressed in active intestinal inflammation in UC, we compared fecal HBD-2 levels measured by ELISA in healthy controls, patients with UC and IBS. For the fecal inflammation markers lactoferrin and calprotectin no significant difference between our group of IBS patients and the group of controls was detected. But interestingly, as in mucosal specimens, HBD-2 levels were significantly elevated in a similar extent in feces of both patients with active UC as well as IBS compared with healthy controls. And in these patients – all of whom had diarrhea and were not treated with probiotics – HBD-2 peptides were demonstrated in colonic epithelial enterocytes. Although there were no endoscopic or histologic signs of inflammation in IBS patients, their elevated HBD-2 levels may thus indicate an activation of the mucosal innate defense in IBS towards low-grade mucosal inflammation activity. However, these data are based on a rather small sample size (a total of 100), which did not allow for further subgroup analyses (e.g., diarrhea-predominant vs constipation-predominant IBS) it strengthens the re-evaluation of IBS according to disease category.
However, since both proinflammatory as well as protective microorganisms may stimulate the expression of HBD-2, the role of HD in IBS remains unclear. Despite promising results the role of inducible HBD levels accompanied by research concerning genetic susceptibility is still ambiguous in the field of gastroenterology, since the precise mechanisms of induction are incompletely understood. Also the functional significance remains to be established. Nevertheless, due to the growing evidence it is still probable that our understanding of the pathogenesis of IBD and maybe even IBS will shift from disturbed acquired immunity and psychosomatic causes to a model including more biomarkers, animal models, psychoneuroimmunologic aspects and more effective treatments. Innate immunity has the potential to clarify many undiscovered aspects in the pathogenesis of IBD and even IBS.
Expert Rev Clin Immunol. 2011;7(6):779-787. © 2011 Expert Reviews Ltd.
Cite this: The Role of Human Defensins in Gastrointestinal Diseases - Medscape - Nov 01, 2011.