The research group in http://en.vhir.org/portal1/grup-equip.asp?s=recerca&contentid=187018 Physiology and Pathophysiology of the Digestive Tract of Vall d'Hebron Research Institute (VHIR) has carried out a study to identify the molecular pathways involved in intestinal epithelial barrier dysfunction and explain the female predisposition to suffer from Irritable Bowel Syndrome with predominance of diarrhoea (IBS-D). The study Decreased TESK1-mediated cofilin 1 phosphorylation in the jejunum of IBS-D patients may explain increased female predisposition to epithelial dysfunction, directed by doctors María Vicario and Javier Santos, principal investigators of this group has been published in the journal https://www.nature.com/articles/s41598-018-20540-9 Scientific Reports.Although the true origin of the micro-inflammation observed in the intestinal mucosa of IBS patients is still unknown, a possible pathophysiological link to these findings would be the alteration of the epithelial barrier function. Greater understanding of the mechanisms modulating epithelial mucosal integrity and its association with the female sex may have important preventive, diagnostic and therapeutic implications for IBS. However, we still lack sensitive biological markers for precisely diagnosing these patients. This same group already demonstrated in 2012 that IBS-D presents a set of specific alterations in structural genes of the intestinal epithelium associated with the symptomatology of the disease. In the new study, they show that the jejunum of patients with IBS-D have a distinct proteomic profile compared to healthy controls. As an extension of their previous research, the integrative analysis of gene and protein expression profiles performed now confirms the disruption of intestinal epithelial barrier function as a central molecular mechanism in the disease. "Using a specific biological data analysis software, what we have done is to compare the results of both studies, the transcriptome and the proteome, which has allowed us to identify one of the molecular mechanisms responsible for altering the intestinal epithelial barrier function: the protein cofilin 1, which is involved in the modulation of the cell actin cytoskeleton", explains Dr. Vicario. The study found that healthy subjects have increased phosphorylated cofilin 1, which is the inactive form of this protein, so the actin cytoskeleton is not altered. However, in IBS-D patients we observed the opposite, they have a greater proportion of the non-phosphorylated form which triggers actin depolymerization and the consequent loss of epithelial barrier integrity. At the same time, one of the proteins responsible for the phosphorylation of cofilin 1, the protein kinase TESK1, is also decreased in patients with IBS-D. Although TESK1 has been previously described as a mechanism involved in the reorganization of actin filaments, this study is the first to show alterations of this protein in a human disease, which makes it a firm biomarker candidate for IBS-D.In addition, researchers have observed that the molecular mechanism controlling the stability of the cytoskeleton of intestinal epithelium is more active in women than in men. "We have observed that there is a correlation between the expression of proteins of this pathway of actin cytoskeleton destabilization with severity of major clinical symptoms, only in women," says Dr. Santos. These findings represent the identification of a molecular mechanism involved in bowel dysfunction never described before in these patients that, in addition, helps to explain the female predisposition to the disease."Although the number of subjects participating in the study is rather discrete, the patients are clinically well characterized. In addition, the study is very consistent because with two different omic techniques we have come to the same conclusion," continues Dr. Santos. "It is important to note that the data obtained from biopsies in this study are consistent with the signalling pathways associated with the proteomic profile identified by other groups in urine samples from IBS patients, which confirms the consistency of our observations and clearly points to the potential of our study in identifying biomarkers of this disease," concludes Dr. Vicario.This study shows that the mechanisms that regulate the stability of the intestinal epithelium are deficient in women with irritable bowel syndrome. Discovery of altered epithelial proteins in this patients provides potential candidate molecules for validation as biomarkers in IBS-D.