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.

Intestinal alkaline phosphatase at the crossroad of intestinal health and disease – a putative role in type 1 diabetes

“…IAP enzyme activity affects gut health and lipid metabolism by mechanisms including intestinal tolerance to commensal bacteria, intestinal barrier integrity and the regulation of fatty acid absorption [4,20]. High-fat fed IAP-knockout mice develop the metabolic syndrome, which was prevented by oral IAP supplementation [4]. Oral IAP supplementation also prevents the metabolic syndrome in high-fat diet fed wild-type mice [9].…”

“…Oral IAP supplementation also prevents the metabolic syndrome in high-fat diet fed wild-type mice [9]. Exogenous bovine IAP administration has shown promising therapeutic effects in heart surgery as well as in the treatment for sepsis and rheumatoid arthritis [4].…”

“…IAPknockout mice exhibit increased fat absorption and obesity, suggesting that IAP is an important regulator of intestinal lipid transport [3]. IAP reduces luminal ATP concentrations and dephosphorylates bacterial endotoxins, thereby promoting intestinal bacterial growth and tolerance to commensal microbiota [4]. In healthy human controls, IAP accounts for~80% of the total faecal AP activity [5].…”

“…In animal models of intestinal damage, oral administration of IAP reduced gut epithelial damage and inflammation [8]. In IAP-knockout mice, the development of MetS was prevented by oral IAP supplementation [4,9]. In humans, treatment with bovine IAP mitigated adverse symptoms of sepsis and showed beneficial renoprotective effects [4].…”

Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes

“…Intestinal alkaline phosphatase (IAP or Akp3) plays an essential role in intestinal homeostasis through a relationship with food, gut microbiota and immune cells, and may regulate intestinal lipid metabolism (reviewed in [230]). IAP dephosphorylates the endotoxin, lipopolysaccharide, which is derived from gram negative bacteria in both the intestinal lumen and circulation.…”