The diverse nature of intestinal alkaline phosphatase (IAP) functions has remained elusive, and it is only recently that four additional major functions of IAP have been revealed. The present review analyzes the earlier literature on the dietary factors modulating IAP activity in light of these new findings. IAP regulates lipid absorption across the apical membrane of enterocytes, participates in the regulation of bicarbonate secretion and of duodenal surface pH, limits bacterial transepithelial passage, and finally controls bacterial endotoxin-induced inflammation by dephosphorylation, thus detoxifying intestinal lipopolysaccharide. Many dietary components, including fat, protein, and carbohydrate, modulate IAP expression or activity and may be combined to sustain a high level of IAP activity. In conclusion, IAP has a pivotal role in intestinal homeostasis and its activity could be increased through the diet. This is especially true in pathological situations (e.g., inflammatory bowel diseases) in which the involvement of commensal bacteria is suspected and when intestinal AP is too low to detoxify a sufficient amount of bacterial lipopolysaccharide.

Intestinal alkaline phosphatase: multiple biological roles in maintenance of intestinal homeostasis and modulation by diet

Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co-housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today’s health epidemics.

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A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia.

The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease

Relationship between intestinal brush border enzymatic activity and growth rate in tilapias fed diets containing 30% or 48% protein

To better understand the mode of action of ω3 fatty acids in cell membranes, human foreskin fibroblasts were grown in serum-free medium supplemented with 50 μM oleic acid linoleic acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), and the effects on membrane composition, fluorescence polarization and enzyme activities were followed. The cells were enriched with EPA and DHA up to 7 and 13% of total lipids, respectively, of which >95% was associated with phospholipids. In addition, the concentration of 22∶5n−3 increased with both EPA and DHA to 7.5, and 2.1% of the total fatty acids, respectively. When compared to controls (oleic acid), cells treated with DHA showed a decrease in cholesterol, phospholipids, arachidonic acid (AA) and free cholesterol/phospholipid ratio (P<0.05). In the presence of EPA, only decreases in AA and cholesterol were significant (P<0.05). Membrane fluidity, assessed by fluorescence anisotropy, was increased 16% in cells enriched with DHA (P<0.05), but showed no change with EPA or linoleic acid. There was an increase in membrane-associated 5′-nucleotidase (+27%) and adenylate cyclase (+19%) activities (P<0.05), in DHA-enriched, but not in EPA-enriched cells, when compared with oleate controls. The studies show that incorporation of DHA, but not EPA, into cell membranes of fibroblasts alters membrane biophysical characteristics and function. We suggest that these two major n−3 fatty acids of fish oils have differential effects on cell membranes, and this may be related to the known differences in their physiological effects.

Differential effects of eicosapentaenoic acid and docosahexaenoic acid on human skin fibroblasts

Rats were fed either a fat-free diet supplemented with 10% menhaden oil or a control diet for four months. Intestinal brush border membranes were isolated; phospholipid fatty acid analysis revealed that the membranes from the fish-oil fed animals had higher levels of palmitoleic (C16:1) and eicosapentaenoic (C20:5) acids and lesser levels of stearic (C18:0) linoleic (C18:2) acids compared with controls. The membranes from the fish-oil fed animals had increased levels of alkaline phosphatase activity compared with controls but disaccharidase levels were equivalent in the two groups. Rocket immunoelectrophoresis studies revealed that the increase in alkaline phosphatase activity was due to an increase in the specific activity of the enzyme rather than an increase in the amount of enzyme. Membrane fluidity was assessed by fluorescence anisotropy using diphenylhexatriene and 12-anthroyl stearate as fluorescent probes. The anisotropy of both probes was similar in the two membranes. These studies indicate that fish-oil supplementation alters the fatty acid composition of the intestinal brush border membrane and increases alkaline phosphatase activity without affecting membrane fluidity. Thus the effects of changes in membrane lipid composition on alkaline phosphatase activity appear to result from changes in the local lipid environment of the enzyme rather than from changes in the biophysical characteristics of the membrane.

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W Pickett

Papers

Effects of dietary fish oil supplementation on membrane fluidity and enzyme activity in rat small intestine