Human Intestinal Barrier Function in Health and Disease

Abstract

The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed.

Figure 1

Schematic figure of the intestinal barrier and affecting factors. The intestinal barrier is composed of several layers providing protection against microbial invasion. The intestinal lumen contains anti-microbial peptides (AMPs), secreted immunoglobulin A (IgA), and commensal bacteria, which inhibit the colonization of pathogens by competitive inhibition and by production of, e.g., butyrate, which has barrier-protective properties. A mucus layer covers the intestinal surface providing a physical barrier. The epithelial layer consists of a single layer of epithelial cells that are sealed by tight junction proteins such as occludin, claudin, and zonulin-1 preventing paracellular passage. This layer also harbors intraepithelial lymphocytes, M cells (overlying Peyer's patches and lymphoid follicles), mucus-producing Goblet cells and bacteriocin-producing Paneth cells (not shown). The lamina propria contains a large amount of immune cells, both of the innate immune system (e.g., macrophages, dendritic cells, mast cells) and the adaptive immune system (e.g., T cells, IgA producing plasma cells). In addition, cells of the central and enteric nervous system innervate in the lamina propria (not shown). Factors affecting the intestinal barrier function include pathogenic bacteria such as enteropathogenic E. coli, high-fat diet, lipopolysaccharides (LPS), drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs), as well as various food allergens and the gluten component gliadin.

Figure 2

Epithelial barrier dysfunction and inflammation in inflammatory bowel disease (IBD). Genetically encoded variation in the epithelial barrier function may allow microbes to cross the barrier and trigger a T-cell response (1). The cytokines produced by activated T cells and macrophages loosen tight junctions allowing more antigens to cross (2). Finally, degradation of the basement membrane causes the epithelial cells to be shed and massive penetration of microbes into the gut wall occurs (3).