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...

IAP is involved in the maintenance of normal gut microbial homeostasis and may have therapeutic potential against dysbiosis and pathogenic infections.

The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.