Mucosal RNA and protein expression as the next frontier in IBS: abnormal function despite morphologically intact small intestinal mucosa

Abstract

Irritable bowel syndrome (IBS) is one of the commonest gastrointestinal disorders. Although long-time considered a pure functional disorder, intense research in past years has rendered a very complex and varied array of observations indicating the presence of structural and molecular abnormalities underlying characteristic motor and sensitive changes and clinical manifestations. Analysis of gene and protein expression in the intestinal mucosa has shed light on the molecular mechanisms implicated in IBS physiopathology. This analysis uncovers constitutive and inductive genetic and epigenetic marks in the small and large intestine that highlight the role of epithelial barrier, immune activation, and mucosal processing of foods and toxins and several new molecular pathways in the origin of IBS. The incorporation of innovative high-throughput techniques into IBS research is beginning to provide new insights into highly structured and interconnected molecular mechanisms modulating gene and protein expression at tissue level. Integration and correlation of these molecular mechanisms with clinical and environmental data applying systems biology/medicine and data mining tools emerge as crucial steps that will allow us to get meaningful and more definitive comprehension of IBS-detailed development and show the real mechanisms and causality of the disease and the way to identify more specific diagnostic biomarkers and effective treatments.

Comparative expression profiling in the intestine of patients with Giardia‐induced postinfectious functional gastrointestinal disorders

“…Barrier dysfunction is based on disassembly of the apical junctions and increased paracellular permeability. In line with this, genes and proteins belonging to apical junctional complex structures, including tight and adherens junctions, have been consistently reported to be deregulated in IBS in the small and large intestinal mucosa 16 . Indeed, we could confirm OCLN to be downregulated with disturbed subcellular localization in PI‐FGID.…”

“…Relevant to our study, among others, stress‐related genes such as NR3C1, CRHR1 , and BDNF were hyper‐methylated 70 . Whether the altered methylation marks described in blood samples of IBS patients correlate with the ones in intestinal tissue remains unclear 16 . Whether in turn the increased expression of the stress and epigenetics‐relevant genes found in our study might impact genetic signaling pathways in the gut of our PI‐FGID patients will have to be determined in future studies.…”

“…Cytokines that are released from lymphocytes and macrophages including interleukins (IL‐4 and IL‐12), tumor necrosis factor TNF‐alpha, and interferon (IFN‐gamma), as well as mast cell tryptase increase epithelial permeability. In contrast, IL‐10 and transforming growth factor TGF‐β act protective against tight junction disruption 16 . The genes found to be dysregulated in our PI‐IBS study correlate with this: TGFB1 and the TGF‐β‐related transcription factor zinc finger E‐box‐binding homeobox 2 ( ZEB2 ) were found to be upregulated in the lamina propria of our PI‐IBS samples.…”

“…A few studies performed comparative expression profiling, consistently pointing to impairment of intestinal epithelial barrier function in IBS based on differential expression of tight junction genes 16 . This is in line with recent epigenetic and genetic findings supported by current models of IBS pathogenesis, suggesting disturbed intestinal barrier function in addition to immune response and neuronal signal transduction 7 …”

Overexpression of corticotropin-releasing factor in intestinal mucosal eosinophils is associated with clinical severity in Diarrhea-Predominant Irritable Bowel Syndrome

“…The importance of our findings needs to be related to the increasing recognition of the small bowel in the generation of symptoms in IBS, which can be ascribed to the distinctive anatomical structure and function of the small intestine, compared with the colon. The small bowel is equipped with a vast and versatile lamina propriaassociated immune system; with a unique epithelial-associated hormone and neurotransmitter machinery; with a slow trending motor activity; with a particular morphological and ultrastructural composition of luminal tips and intercellular junctions that determine intestinal permeability, secretion, and absorption; with a differential gas and biliary metabolism; with a less deeper and fragile mucus layer; with a scarce but predominantly aerobic microbiota in its upper segments; and with an intricate pain processing system 68 . Therefore, in this context, our findings support and should stimulate future research focused on the role of neuro-immune interactions happening in the small bowel, as compared to the colon, in the pathogenesis of IBS.…”