Irritable bowel syndrome (IBS) is a chronic, recurring, and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain, distention, and changes in bowel habits. Although there are several drugs for IBS, effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed. Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS. With regards to therapies for restoring intestinal permeability, multiple studies with prebiotics and probiotics are ongoing, even if to date their efficacy has been limited. In parallel, much progress has been made in targeting low-grade inflammation, especially through the introduction of drugs such as mesalazine and rifaximin, even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs. This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS, most recently developed in preclinical as well as Phase 1 and Phase 2 clinical studies.
BackgroundInflammation and immune activation have repeatedly been suggested as pathogentic factors in irritable bowel syndrome (IBS). The driving force for immune activation in IBS remains unknown. The aim of our study was to find out if the obligate intracellular pathogen Chlamydia could be involved in the pathogenesis of IBS.MethodsWe studied 65 patients (61 females) with IBS and 42 (29 females) healthy controls in which IBS had been excluded. Full thickness biopsies from the jejunum and mucosa biopsies from the duodenum and the jejunum were stained with a monoclonal antibody to Chlamydia lipopolysaccharide (LPS) and species-specific monoclonal antibodies to C. trachomatis and C. pneumoniae. We used polyclonal antibodies to chromogranin A, CD68, CD11c, and CD117 to identify enteroendocrine cells, macrophages, dendritic, and mast cells, respectively.ResultsChlamydia LPS was present in 89% of patients with IBS, but in only 14% of healthy controls (p < 0.001) and 79% of LPS-positive biopsies were also positive for C. trachomatis major outer membrane protein (MOMP). Staining for C. pneumoniae was negative in both patients and controls. Chlamydia LPS was detected in enteroendocrine cells of the mucosa in 90% of positive biopsies and in subepithelial macrophages in 69% of biopsies. Biopsies taken at different time points in 19 patients revealed persistence of Chlamydia LPS up to 11 years. The odds ratio for the association of Chlamydia LPS with presence of IBS (43.1; 95% CI: 13.2-140.7) is much higher than any previously described pathogenetic marker in IBS.ConclusionsWe found C. trachomatis antigens in enteroendocrine cells and macrophages in the small bowel mucosa of patients with IBS. Further studies are required to clarify if the presence of such antigens has a role in the pathogenesis of IBS.
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