Published in:
01-10-2021 | Type 2 Diabetes | EDITORIAL
Which Comes First: Increased Intestinal Paracellular Permeability or Subepithelial Inflammation?
Author:
Yasutada Akiba
Published in:
Digestive Diseases and Sciences
|
Issue 10/2021
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Excerpt
The intestinal barrier is the sum of multiple mechanisms, including those that regulate transepithelial electrical resistance, the transepithelial movement of small molecules, macromolecules, and particles, mucus secretion, and the bidirectional transport of water and ions. A key component of the intestinal barrier is paracellular permeability to solutes that traverse intercellular tight junctions [
1]. Increased intestinal paracellular permeability is linked to the metabolic syndrome, obesity, diabetes, and fatty liver, in which chronic low-grade inflammation of adipose tissue, the pancreatic islets, and the liver is associated with measurable elevations of circulating lipopolysaccharides (LPS), termed metabolic endotoxemia, associated with enhanced LPS entry from the intestinal lumen into the circulation possibly via increased intestinal paracellular permeability [
2]. Intestinal paracellular permeability is primarily regulated by intrinsic tight junction (TJ) proteins, including zonula occludens-1 (ZO-1), the occludins, and the claudins [
3]. Changes in the expression of TJ proteins and their structure are well studied and correlate with paracellular permeability to molecular size markers such as FITC-dextran, polyethylene glycol, and carbohydrates and polyols such as mannitol and lactulose [
4]. Although there is an extensive literature documenting associations among TJ protein abundance and structure, epithelial barrier function, and numerous disease states, a cause-and-effect relationship among these factors and the time course of barrier dysfunction changes have not been fully evaluated. Furthermore, there is often confusion regarding the contributions of individual intestinal segments toward the regulation of overall gut permeability. For instance, it is not known which specific intestinal segment is responsible for the paracellular absorption of macromolecular solutes, and if paracellular permeability changes precede or follow the development of metabolic syndrome. High-fat diet-induced elevation in circulating lipopolysaccharides (LPS) levels are explained by increased paracellular permeability, but in which intestinal segment? Although the density of Gram-negative microbes and thus LPS concentrations in the cecum or colon can be a millionfold or more greater than in the jejunum, it appears that in some instances such as in coprophagic rodents, the proximal small intestinal lumen also has high luminal LPS levels [
5], suggesting that segmental differences should be examined in order to determine the segments responsible for absorption of specific substances. …