M. Tom Clandinin

Dietary gangliosides enhance in vitro lipid uptake in weanling rats.

Background: The intestine adapts morphologically or functionally in response to environmental stimuli. Dietary lipids modify brush border membrane (BBM) permeability and nutrient transporter activities. Gangliosides (GANG) are glycolipids in human milk that are present only in low amounts in infant formula. Exogenous GANG are incorporated into cell membranes and increase their permeability. The objective of this study was to determine whether feeding a GANG-enriched diet alters in vitro intestinal lipid absorption. Methods: Weanling rats were fed either (1) GANG-enriched diet; (2) diet enriched with polyunsaturated long-chain fatty acids; or (3) isocaloric control diet for 2 weeks, after which in vitro intestinal lipid uptake was measured. Results: Feeding GANG did not alter weight gain or intestinal morphology. Enhanced uptake of stearic acid (18:0) in the ileum and stearic and linoleic acid (18:2) in the jejunum was not associated with a change in the abundance of the ileal lipid binding protein (ILBP), the intestinal fatty acid binding protein (I-FABP), or the liver fatty acid binding protein (L-FABP). Conclusion: We speculate that the enhanced uptake of long-chain fatty acids in weanling rats fed GANG may be caused by a modification in physical properties of the BBM.

REVIEW: Small Bowel Review: Normal Physiology, Part 1

In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practising gastroenterologist. Selected important clinical learning points include the following: (1) numerous peptides are being identified which stimulate the proliferation and functional response of the small intestine to disease or resection, and may in time find a clinical use; (2) under usual in vivo conditions, absorption of nutrients has little effect on the paracellular movement of water; (3) the permeability of the intestine is modified by the function of the tight junctions, and measuring intestinal permeability may be useful to reflect the presence of disease; (4) the release of serotonin is influenced by cholinergic, adrenergic, and nonadrenergic, noncholinergic mechanisms, and serotonin agonists and antagonists may play an important future role in the treatment of motility disorders; (5) the use of endothelin receptor antagonists may be useful for the treatment of intestinal anaphylaxis; (6) the alterations in intestinal pH and motility in patients with Crohns disease may influence the action of pH- or time-dependent release medications; and (7) patients with irritable bowel syndrome may also have abnormalities in gastric and small intestinal motility.

Dietary Gangliosides Enhance In Vitro Glucose Uptake in Weanling Rats

BACKGROUNDnThe intestine adapts to environmental stimuli, such as modifications in dietary lipids. Dietary lipids modify brush border membrane (BBM) permeability and nutrient transporter activities. Gangliosides (GANG) are glycolipids present in human milk, but they are present only in low amounts in infant formula. Exogenous GANG are incorporated into cell membranes and increase their permeability. This study was undertaken to determine if feeding a 0.2% GANG-enriched diet for 2 weeks alters in vitro intestinal sugar absorption in weanling rats compared with an isocaloric control diet or diet enriched with polyunsaturated long-chain fatty acids.nnnMETHODSnIn vitro uptake of 34-96 mm glucose and fructose and morphological measurements were assessed on intestinal tissue of weanling rats. Western blotting, immunohistochemistry, Northern blotting, and reverse transcription-polymerase chain reaction were performed to determine the mRNA and protein abundance of the sugar transporters SGLT-1, GLUT2 and GLUT5.nnnRESULTSnFeeding GANG did not alter the rates of animal weight gain or intestinal morphology. GANG did not affect fructose uptake. Depending on the concentration of glucose, GANG increased jejunal uptake of higher concentrations of glucose by approximately 20%-60%. There were no changes in GLUT5 or GLUT2 protein or mRNA abundance. Similarly, there were no changes in SGLT-1 mRNA and protein abundance, as determined by Northern and Western blotting. However, using immunohistochemistry, SGLT-1 was lower in GANG than in controls.nnnCONCLUSIONSnThe results of this study suggest that the enhanced uptake of glucose that results from feeding 0.2% GANG for 2 weeks to weanling rats may be regulated posttranslationally. Clearly any adjustment of the content of GANG in infant formula must be studied carefully.

A combination of dexamethasone and glucagon-like peptide-2 increase intestinal morphology and glucose uptake in suckling rats

Objectives: Glucagon-like peptide (GLP)-2 enhances nutrient uptake in adult animals. Glucocorticosteroids accelerate intestinal ontogeny and increase nutrient uptake in adult animals. We hypothesized that administering GLP-2 and dexamethasone (DEX) to suckling rats will enhance sugar uptake and that this effect persists into the postweaning period. Methods: Suckling rats were treated for 10 days with GLP-2 (0.1 μg/g/d, twice daily), DEX (0.128 μg/g/d, once daily), GLP-2 + Dex (same doses as above), or placebo. The rate of intestinal uptake of glucose and fructose in sucklings (19-21 days old) and weanlings (49 days old) was assessed using an in vitro ring technique. Results: DEX reduced body weight in weanlings, whereas GLP-2 + DEX prevented this effect. In sucklings, GLP-2 + DEX increased ileal villous height and jejunal and ileal villous width and crypt depth. In sucklings, GLP-2 + DEX increased the maximal transport rate (Vmax) for jejunal glucose uptake, whereas DEX reduced the ileal Vmax. In weanlings, GLP-2 + DEX increased jejunal villous height, whereas ileal villous width and crypt depth were reduced. DEX increased the ileal Vmax and apparent affinity constant for glucose in weanlings. Conclusions: The combination of these hormones may be useful in stimulating glucose uptake in the developing intestine, and giving DEX to sucklings may enhance glucose uptake in later life.

Increased catabolism and decreased unsaturation of ganglioside in patients with inflammatory bowel disease

AIMnTo investigate whether accelerated catabolism of ganglioside and decreased ganglioside content contribute to the etiology of pro-inflammatory intestinal disease.nnnMETHODSnIntestinal mucosa from terminal ileum or colon was obtained from patients with ulcerative colitis or inflammatory Crohns disease (n = 11) undergoing bowel resection and compared to control samples of normal intestine from patients with benign colon polyps (n = 6) and colorectal cancer (n = 12) in this observational case-control study. Gangliosides and phospholipids of intestinal mucosa were characterized by class and ceramide or fatty acid composition using liquid chromatography triple-quad mass spectrometry. Content and composition of ganglioside classes GM1, GM3, GD3, GD1a, GT1 and GT3 were compared among subject groups. Content and composition of phospholipid classes phosphatidylcholine (PC) and phosphatidylethanolamine were compared among subject groups. Unsaturation index of individual ganglioside and phospholipid classes was computed and compared among subject groups. Ganglioside catabolism enzymes beta-hexosaminidase A (HEXA) and sialidase-3 (NEU3) were measured in intestinal mucosa using western blot and compared among subject groups.nnnRESULTSnRelative GM3 ganglioside content was 2-fold higher (P < 0.05) in intestine from patients with inflammatory bowel disease (IBD) compared to control intestine. The quantity of GM3 and ratio of GM3/GD3 was also higher in IBD intestine than control tissue (P < 0.05). Control intestine exhibited 3-fold higher (P < 0.01) relative GD1a ganglioside content than IBD intestine. GD3 and GD1a species of ganglioside containing three unsaturated bonds were present in control intestine, but were not detected in IBD intestine. The relative content of PC containing more than two unsaturated bonds was 30% lower in IBD intestine than control intestine (P < 0.05). The relative content of HEXA in IBD intestine was increased 1.7-fold (P < 0.05) and NEU3 was increased 8.3-fold (P < 0.01) compared to normal intestine. Intestinal mucosa in IBD is characterized by increased GM3 content, decreased GD1a, and a reduction in polyunsaturated fatty acid constituents in GD3, GD1a and PC.nnnCONCLUSIONnThis study suggests a new paradigm by proposing that IBD occurs as a consequence of increased metabolism of specific gangliosides.

Maternal dexamethasone and GLP-2 have early effects on intestinal sugar transport in their suckling rat offspring.

Both glucagon-like peptide 2 (GLP-2) and glucocorticosteroids enhance intestinal uptake in mature animals. Maternal stimuli may cause intestinal adaptation in the offspring. We hypothesized that administering GLP-2, dexamethasone (DEX) or a combination of GLP-2+DEX to rat dams during pregnancy and lactation would enhance intestinal sugar uptake in their offspring. Rat dams were treated with GLP-2 (0.1 microg/g/day), DEX (0.128 microg/g/day), a combination of GLP-2+DEX or placebo. Glucose and fructose uptake was assessed in their suckling offspring using an in vitro intestinal ring uptake technique. The protein abundance of SGLT1, GLUT5, GLUT2, Na(+)K(+)-ATPase and selected signals was determined by immunohistochemistry; GLP-2 caused hypertrophy of the jejunal enterocytes and increased ileal villous height. Jejunal fructose uptake was reduced by GLP-2, DEX and GLP-2+DEX. V(max) for jejunal glucose uptake was reduced with DEX and GLP-2+DEX. These declines were not explained by alterations in transporter abundance. Decreases in Akt and mTOR abundance were associated with declines in transporter activity. We speculate that the intrinsic activity of the sugar transporters was modified via the P13K pathway. In conclusion, maternal GLP-2 and DEX reduced intestinal sugar uptake in their offspring. This may have nutritional implications for the offspring of mothers treated with GLP-2 or steroids.

Moving Beyond “Good Fat, Bad Fat”: The Complex Roles of Dietary Lipids in Cellular Function and Health

The International Life Science Institute North America and the American Society for Nutrition annual Functional Foods for Health Symposium was held 9 April 2011. Evidence that foods and their components offer health benefits beyond basic nutrition continues to captivate the interest of the scientific community, government agencies, and the general public. This paper is comprised of extended abstracts from the session and addresses issues related to emerging lipid nutrition science, including active roles of lipids in modulating physiological pathways. Identified pathways underlie the development of obesity, cognitive development, and inflammation, the latter of which is thought to relate to multiple disease processes. These data point to a new way of thinking about the role of lipids in health and disease.

Dexamethasone and GLP-2 Given to Lactating Rat Dams Influence Glucose Uptake in Suckling and Postweanling Offspring

BACKGROUNDnGlucagon-like peptide-2 (GLP-2) enhances intestinal absorption in adult animals. Glucocorticosteroids accelerate the ontogeny of the intestine and increase sugar uptake in adult animals. Modifying the maternal diet during lactation alters nutrient uptake in the offspring. The authors hypothesized that GLP-2 and dexamethasone, when administrated to lactating rat dams, enhance sugar uptake in the suckling and postweanling offspring.nnnMETHODSnRat dams were treated during lactation with GLP-2 (0.1 microg/g/day subcutaneously [SC], twice daily), dexamethasone (0.128 microg/g/day SC, once daily), GLP-2 + dexamethasone (same doses), or placebo. The suckling offspring were sacrificed at 19-21 days of age, and the postweanlings were sacrificed 4 weeks later. Intestinal glucose and fructose uptake was assessed using an in vitro ring technique.nnnRESULTSnGLP-2 and dexamethasone resulted in lower body weights, and dexamethasone caused intestinal atrophy in sucklings. The jejunal atrophy in sucklings given dexamethasone was prevented by GLP-2 + dexamethasone. In sucklings, the maximal transport rate and the Michaelis affinity constant for ileal glucose uptake were both increased by GLP-2 and GLP-2 + dexamethasone. In contrast, in postweanlings, the maximal transport rate for jejunal glucose uptake was reduced by dexamethasone and GLP-2, as was ileal fructose uptake.nnnCONCLUSIONSnTreating lactating rat dams with GLP-2 or dexamethasone enhances glucose uptake in sucklings, but the late effect is a reduction in glucose and fructose absorption in postweanlings. The nutritional significance of these findings remains to be established.

Lipid malabsorption persists after weaning in rats whose dams were given GLP-2 and dexamethasone

Glucagon-like peptide-2 (GLP-2) enhances intestinal growth and absorption in mature animals, and glucocorticosteroids (GC) increase the sugar and lipid uptake in adult animals. However, the role of GC and GLP-2 in the ontogeny of lipid absorption is unknown. We hypothesized that GLP-2 and the GC dexamethasone (DEX), when administrated to rat dams during pregnancy and lactation, would enhance lipid uptake in the off-spring. Rat dams were treated in the last 10 d of pregnancy and during lactation with GLP-2 [0.1 μg/g/d subcutaneous (sc)], DEX (0.128 μg/g/d sc), GLP-2+DEX, or a placebo. Sucklings were sacrificed at 19–21 d of age, and weanlings were sacrificed 4 wk later. Lipid uptake was assessed using an in vitro ring uptake method. Although DEX and GLP-2+DEX increased the jejunal mass, the jejunal lipid uptake was unchanged. In contrast, GLP-2, DEX, and GLP-2+DEX reduced the ileal lipid uptake in suckling and weanling rats. This reduction was not due to alterations in intestinal morphology or to changes in fatty acid-binding protein abundance, but it was partially explained by an increase in the effective resistance of the intestinal unstirred water layer. In sucklings, DEX dramatically reduced the jejunal lipid uptake to levels similar to those seen in weanlings, such that the normal ontogenic decline in lipid uptake was not observed. Giving dams GLP-2 or DEX during pregnancy and lactation reduced lipid uptake in the offspring, and this persisted for at least 1 mon. The impact this may have on the nutritional well-being of the animal in later life is unknown.

Effect of steroids on intestinal lipid uptake in rats is enhanced by a saturated fatty acid diet. Cell and molecular biology collaborative network in gastrointestinal physiology.

Glucocorticosteroids enhance sugar digestive and absorptive functions of the intestine, but their effect on lipid uptake is unknown. Modifications in dietary lipids alter the nutrient transport properties of the intestine. The influence of 4 weeks’ treatment with budesonide (BUD), prednisone (PRED), or control vehicle in weanling rats fed either an isocaloric semisynthetic saturated fatty acid diet (SFA) or a polyunsaturated fatty acid diet (PUFA), on the uptake of lipids was assessed using everted gut rings. PRED and BUD increased the uptake of several fatty acids, and this was higher when the animals were fed SFA rather than PUFA. Changes in expression of the mRNAs for L-FABP (liver fatty acid binding protein) and ILBP (ileal lipid binding protein) did not explain these alterations in lipid uptake. Dietary lipid signalling of this adaptive response may involve proglucagon, c-jun, TNF-α and IL-10, whereas steroid signalling may involve proglucagon. In summary, steroids increase the absorption of lipids by a process which can be enhanced by the substitution of saturated for polyunsaturated lipids in the diet, and which is not explained by alterations in the expression of the mRNAs of L-FABP or ILBP.