Intestinal Permeability, Irritable Bowel Syndrome with Constipation, and the Role of Sodium-Hydrogen Exchanger Isoform 3 (NHE3)

Abstract

Brian E Lacy,1 David Rosenbaum,2 Susan Edelstein,2 Kenji Kozuka,2 Laura A Williams,2 David C Kunkel3 1Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA; 2Ardelyx, Inc, Waltham, MA, USA; 3Division of Gastroenterology, University of California San Diego, La Jolla, CA, USACorrespondence: Brian E Lacy, Division of Gastroenterology and Hepatology, Mayo Clinic, Davis Building, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, Tel [phone], Fax [phone], Email [email protected]: Increased intestinal permeability has been identified as one of the many pathophysiological factors associated with the development of irritable bowel syndrome (IBS), a common disorder of gut–brain interaction. The layer of epithelial cells that lines the intestine is permeable to a limited degree, and the amount of paracellular permeability is tightly controlled to enable the absorption of ions, nutrients, and water from the lumen. Increased intestinal permeability to macromolecules can be triggered by a variety of insults, including infections, toxins from food poisoning, or allergens, which in turn cause an inflammatory response and are associated with abdominal pain in patients with IBS. This review article discusses increased intestinal permeability in IBS, focusing on IBS with constipation (IBS-C) through the lens of a patient case with a reported prior diagnosis of “leaky gut syndrome” upon initial contact with a gastrointestinal specialist. We review advantages and disadvantages of several methods of measuring intestinal permeability in patients and discuss when measuring intestinal permeability is appropriate in the therapeutic journey of patients with IBS-C. Furthermore, we discuss a possible mechanism of restoring the intestinal barrier to its healthy state through altering intracellular pH by inhibiting sodium-hydrogen exchanger isoform 3 (NHE3). Tenapanor is a minimally absorbed, small-molecule inhibitor of NHE3 that has been approved by the US Food and Drug Administration for the treatment of IBS-C in adults. Preclinical studies showed that tenapanor may restore the intestinal barrier in IBS-C by affecting the conformation of tight junction proteins via NHE3 inhibition to block the paracellular transport of macromolecules from the intestinal lumen. Testing for increased permeability in patients with IBS-C who experience abdominal pain may help inform the choice of therapeutics and alter patients’ misconceptions about “leaky gut syndrome”.Keywords: tenapanor, abdominal pain, leaky gut, gut permeability, IBS-C, tight junction protein, transepithelial resistance

Keywords

• tenapanor
• abdominal pain
• leaky gut
• gut permeability
• ibs-c
• tight junction protein
• transepithelial resistance.