Interplay between intestinal alkaline phosphatase, diet, gut microbes and immunity

Abstract

Intestinal alkaline phosphatase (IAP) plays an essential role in intestinal homeostasis and health through interactions with the resident microbiota, diet and the gut. IAP's role in the intestine is to dephosphorylate toxic microbial ligands such as lipopolysaccharides, unmethylated cytosine-guanosine dinucleotides and flagellin as well as extracellular nucleotides such as uridine diphosphate. IAP's ability to detoxify these ligands is essential in protecting the host from sepsis during acute inflammation and chronic inflammatory conditions such as inflammatory bowel disease. Also important in these complications is IAP's ability to regulate the microbial ecosystem by forming a complex relationship between microbiota, diet and the intestinal mucosal surface. Evidence reveals that diet alters IAP expression and activity and this in turn can influence the gut microbiota and homeostasis. IAP's ability to maintain a healthy gastrointestinal tract has accelerated research on its potential use as a therapeutic agent against a multitude of diseases. Exogenous IAP has been shown to have beneficial effects when administered during ulcerative colitis, coronary bypass surgery and sepsis. There are currently a handful of human clinical trials underway investigating the effects of exogenous IAP during sepsis, rheumatoid arthritis and heart surgery. In light of these findings IAP has been marked as a novel agent to help treat a variety of other inflammatory and infectious diseases. The purpose of this review is to highlight the essential characteristics of IAP in protection and maintenance of intestinal homeostasis while addressing the intricate interplay between IAP, diet, microbiota and the intestinal epithelium.

Keywords: Diet; Infection; Inflammation; Inflammatory disease; Intestinal alkaline phosphatase; Intestinal microbiota; Lipopolysaccharides.

Figure 1

Intestinal alkaline phosphatase regulates gut homeostasis. Intestinal alkaline phosphatase (IAP) secreted by the enterocytes plays a vital role in various physiological functions in and around the intestine. Though mainly membrane-bound, IAP can be found both in the lumen and blood. High concentration of IAP molecules are present in protein-rich lumenal vesicles on the lumenal and apical side of the epithelium. IAP dephosphorylates both lumenal and circulating lipopolysaccharides (LPS) derived from the cell wall of gram negative bacteria effectively eliminating their toxic constituent. Preliminary work from our lab and others have shown IAP expressed on infiltrated immunocytes in the lamina propria. IAP is also crucial in preventing the transmigration of bacteria across the epithelium layer, preventing downstream activation of immunocytes and the subsequent inflammatory responses. Through its complex relationship with food, commensal bacteria and immune cells, IAP plays an essential role in gut homeostasis.