Alterations in Intestinal Permeability: The Role of the "Leaky Gut" in Health and Disease

Abstract

All species, including horses, suffer from alterations that increase intestinal permeability. These alterations, also known as "leaky gut," may lead to severe disease as the normal intestinal barrier becomes compromised and can no longer protect against harmful luminal contents including microbial toxins and pathogens. Leaky gut results from a variety of conditions including physical stressors, decreased blood flow to the intestine, inflammatory disease, and pathogenic infections, among others. Several testing methods exist to diagnose these alterations in both a clinical and research setting. To date, most research has focused on regulation of the host immune response due to the wide variety of factors that can potentially influence the intestinal barrier. This article serves to review the normal intestinal barrier, measurement of barrier permeability, pathogenesis and main causes of altered permeability, and highlight potential alternative therapies of leaky gut in horses while relating what has been studied in other species. Conditions resulting in barrier dysfunction and leaky gut can be a major cause of decreased performance and also death in horses. A better understanding of the intestinal barrier in disease and ways to optimize the function of this barrier is vital to the long-term health and maintenance of these animals.

Keywords: Barrier function; Decreased performance; Horse; Intestinal permeability; Leaky gut.

Fig. 1.

Altered intestinal permeability (leaky gut) in horses. Specific causes of leaky gut in horses range from alterations in the microbiota, acute and chronic inflammatory disease, and both mechanical and functional intestinal obstructions. These conditions alter permeability in several ways including disruption of normal blood flow to the intestine, increased production of proinflammatory cytokines, and disruption of the normal cell junctions, among others. Sequelae to leaky gut may include weight loss and poor performance in mild cases and SIRS, MODS, or death in severe cases. IBD, inflammatory bowel diseases; MODS, multiple organ dysfunction syndrome; SI, small intestinal; SIRS, systemic inflammatory response syndrome.

Fig. 2.

Components of the mucosal barrier in health and disease. The normal intestinal barrier is made up of a single layer of epithelial cells, with normal cell death (apoptosis) and turnover every 5–7 days. Undifferentiated stem cells are located at the crypt base and interspersed between post-mitotic Paneth cells. When intestinal permeability is altered, the junctions between the cells are disrupted and luminal contents can enter the surrounding tissues as well as systemic circulation. As a result, cells may undergo increased apoptosis and decreased barrier function.

Fig. 3.

Detailed diagram of the intercellular junctions between intestinal epithelial cells. The intercellular junctions of intestinal epithelial cells are composed of several complexes including TJs, AJs, and desmosomes. The AJs and TJs together form the AJC. TJs are located at the apical end of the epithelial cells and are made up of multiple transmembrane proteins including occludins, claudins and JAM. Scaffolding proteins such as ZO in turn anchor the membrane proteins to the actin cytoskeleton. Simply, permeability is regulated at the TJ through actin and myosin contractility. Cell to cell contact at the AJ is mediated by adhesion molecule complexes made up of protein families including the cadherins and catenins. AJs, along with desmosomes, provide strong connective bonds between epithelial cells. AJ, adherens junction; AJC, apical junctional complex; JAM, junctional adhesion molecules; TJs, tight junctions; ZO, zonula occludens.

Fig. 4.

Normal versus impaired barrier function. The role of the intestinal epithelium is to provide a physical barrier against luminal contents such as bacteria. There are several important components of the barrier including tight junctions, adherens junctions, and desmosomes. Potentially harmful molecules cannot normally penetrate the barrier; however, when the barrier becomes compromised at any contact point, the passage of noxious molecules can occur and result in both an inflammatory and immune response. Disruption of the intestinal barrier may result in the development of local and systemic disease.