Intestinal alkaline phosphatase prevents metabolic syndrome in mice

Abstract

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet-induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.etabolic syndrome is a complex syndrome composed of a cluster of disorders that includes obesity, glucose intolerance, insulin resistance, abnormal lipid profile (dyslipidemia), fatty liver, and hypertension (1, 2). Metabolic syndrome leads to type 2 diabetes, atherosclerosis, and nonalcoholic fatty liver disease (1, 2). Approximately 35-39% of the US population suffers from the syndrome (3). This epidemic of metabolic syndrome has devastating consequences in terms of mortality, morbidity, and total healthcare expenditures (4).Recently, "metabolic endotoxemia" has been proposed to be central to the pathogenesis of metabolic syndrome. The Gramnegative bacterial cell wall component lipopolysaccharide (LPS) is known as endotoxin, and metabolic endotoxemia is defined as a two-to threefold persistent increase in circulating endotoxin concentrations above the normal levels (5). Metabolic endotoxemia leads to low-grade systemic inflammation as evidenced by increased serum levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, and IL-6 (5). It is well recognized that chronic inflammation causes damage to pancreatic beta cells (6), hepatocytes (7), and vascular endothelial cells (8), and dysfunction of these cells is thought to contribute to metabolic syndrome.A high-fat diet (HFD) has been shown to cause metabolic endotoxemia in animals and humans (5, 9), but the underlying molecular mechanisms remain incompletely understood. Ghoshal et al. (10) demonstrated that intestinal epithelial cells (enterocytes) internalize LPS from the apical surface, which is then transported to the Golgi apparatus where it complexes with chylomicrons, the lipoproteins that transport the absorbed longchain fatty acids in enterocytes. The chylomicron-LPS complex is then secreted into mesenteric lymph and makes its way into the systemic circulation. Excess chylomicron formation during highfat feeding leads to prolonged chylomicronemia (complexed with LPS) that ultimately induces systemic inflammation. Also, it has been shown that an HFD causes local intestinal inflammation (11). Systemic and local inf...

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

“…In the present study we provide evidence that the brush-border enzyme IAP promotes the growth of commensal bacteria. IAP exerts a number of beneficial effects on the gut, including the maintenance of local gut immunity (8), enhancing barrier function, reducing excessive inflammation, and inhibiting metabolic endotoxemia (4,12,14,21,26). The present study delineates another key beneficial impact of the IAP enzyme, promoting the growth of the commensal flora.…”

“…Furthermore, IAP has been found to act as a gut mucosal defense factor and its expression is influenced by exposure to bacteria (4,14,25). IAP is also involved in the maintenance of normal gut barrier function (12,21).…”

“…Pharmacologically, IAP has been found to be an effective therapy against various human as well as animal disease models including IBD, necrotizing enterocolitis, gram-negative sepsis, C. difficile, and S. typhimurium infections, and metabolic syndrome (1,21,34,44,56,58,61). Clinical trials using bovine IAP against colitis have shown that IAP has no or minimal side effects (34).…”

Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa

“…26 IAP, expressed by intestinal epithelial cells, dephosphorylates the bioactive lipid A portion of the endotoxin molecule and renders it less stimulatory, significantly reducing the systemic toxicity of microbiota-derived endotoxin and promoting mucosal wound healing. 29,30 The finding that IAP could not be detected at the mucosa of mucin (Muc) 2-deficient mice suggests that IAP also needs to bind to the intestinal mucus layer after being secreted by the epithelial cells. 27 Finally, SIgA within the enteric mucus layer provides high affinity protection against enteric pathogens and toxins but additionally provides low affinity binding to commensal bacteria and thereby reinforces the antimicrobial and anti-inflammatory barrier.…”

Dietary Refinement And The Upper Gut Microbiota: The Starting Point For Obesity And Non-Communicable Diseases?

“…An "aggressive microbiota" (showing increased encroachment through the mucus layer) found in TLR5-/-or emulsifier-fed mice produced overweight and colitis, which could be transferred by microbial transplant to germ-free controls (41). Similar increases in body weight were produced by selective knock-outs of brush border alkaline phosphatase, an enzyme on the intestinal lining that breaks down microbial products (42). These effects could be reversed by the addition of the missing enzyme to food.…”