Intestinal Transfer Research Articles

Silicon as a Functional Meat Ingredient Improves Jejunal and Hepatic Cholesterol Homeostasis in a Late-Stage Type 2 Diabetes Mellitus Rat Model.

Silicon included in a restructured meat (RM) matrix (Si-RM) as a functional ingredient has been demonstrated to be a potential bioactive antidiabetic compound. However, the jejunal and hepatic molecular mechanisms by which Si-RM exerts its cholesterol-lowering effects remain unclear. Male Wistar rats fed an RM included in a high-saturated-fat high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection were used as late-stage type 2 diabetes mellitus (T2DM) model. Si-RM was included into the HSFHCD as a functional food. An early-stage TD2M group fed a high-saturated-fat diet (HSFD) was taken as reference. Si-RM inhibited the hepatic and intestinal microsomal triglyceride transfer protein (MTP) reducing the apoB-containing lipoprotein assembly and cholesterol absorption. Upregulation of liver X receptor (LXRα/β) by Si-RM turned in a higher low-density lipoprotein receptor (LDLr) and ATP-binding cassette transporters (ABCG5/8, ABCA1) promoting jejunal cholesterol efflux and transintestinal cholesterol excretion (TICE), and facilitating partially reverse cholesterol transport (RCT). Si-RM decreased the jejunal absorptive area and improved mucosal barrier integrity. Consequently, plasma triglycerides and cholesterol levels decreased, as well as the formation of atherogenic lipoprotein particles. Si-RM mitigated the dyslipidemia associated with late-stage T2DM by Improving cholesterol homeostasis. Silicon could be used as an effective nutritional approach in diabetic dyslipidemia management.

Effect of P-glycoprotein and Cotreatment with Sofosbuvir on the Intestinal Permeation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate.

We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF. Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed. TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV(TDF) and TFV(TAF)-equivalents. However, TDF and TAF were absorbed more efficiently than TFV and TEM. SOF did not inhibit intestinal efflux of TDF and TAF or affect intestinal accumulation of TFV(TDF) and TFV(TAF)-equivalents but did significantly increase the proportion of absorbed TDF. TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV(TDF)-equivalents crossing the intestinal barrier. Our data thus suggest that reported increases in the TFV plasma concentrations in patients treated with SOF and TDF result either from a DDI between SOF and TDF that does not involve ABCB1 or from a DDI involving another drug used in combination therapy.

O11. Ceased intestinal macromolecular uptake and transfer by enteral exposure to lectin (phytohemagglutinin) in new-born piglets

O11. Ceased intestinal macromolecular uptake and transfer by enteral exposure to lectin (phytohemagglutinin) in new-born piglets

Correcting gender dysphoria –the anatomical changes with male to female gender reassignment surgery

ABSTRACT Introduction & Objectives Increased Global acceptance of transgender communities, gender-affirming genital reconstructive surgery is becoming more prominent. Formalised education and training however has not quite entered the curriculum of many surgical training programs yet it remains imperative we have an understanding of modified anatomy in out patients. We demonstrate anatomical reconstruction during the transition between male to female anatomy. Methods Patient consent was obtained to take a series of photographs during gender affirming surgery from male to female. Results Contemporary patients receive both spinal and general anaesthesia prior to positioning in standard lithotomy. A perineal incision of approximately 10cm in the midline raphae exposes the corpora and spongiosum. A simple bilateral orchidectomy was performed at the level of the external inguinal ring. A neovaginal cavity was created by firstly dividing the bulbospongiosus attachments to the perineal body and the space is both blunt and sharply dissected. Further dissection is carried out in the avascular perirectal fat plant anterior to the Denonvilliers fascia. During this dissection a 18-22Fr urethral sound is used to apply downward traction on the rectum. A sterile ultrasound sleeve is placed in the rectum to allow bimanual palpation to confirm intact rectal mucosa. A circumferential incision proximal to the glans is performed to aide degloving of the penis. Bucks fasica is left intact and distal penile skin will later be used to form the clitoral hood. The dorsal neurvascular bundle is raised off the corporal bodies but an attachment to the glans remains. A triangular section of dorsal glans is preserved and dissected off the tips of corpora. The penile tissue is then disassembled separating the corpus spongiosum from the corporal bodies. The corpora are amputated at the level of the pubis, remaining erectile tissue destroyed and oversewn for haemostasis. The Urethra is shortened to an appropriate length to allow the dorsal aspect to align between the neoclitoris and neomeatus. The ventral aspect is spatulated to expose the neomeatus. The penile skin flap is invaginated within the neovaginal space and the skin incised to expose the neoclitoris and neomeatus. The penile skin is then anastomosed to the neoclitoris and neomeatus The distal end of the penile skin flaps is oversewn to create a blind ending tube and thus creating the neovagina. Labia Majora are formed by excising excess scrotal skin to create an appropriate contour. This form of neovagina is compared to methods that involve intestinal and peritoneal lining transfer. Conclusions We have outline the stepwise transition of male to female anatomy with a conventional contemporary technique. Creation of a neovagina with penile inversion has become common practice in gender affirming surgery. However there are other means of creating genitalia with alternative tissues, which subspecialised practitioners should be aware. Disclosure Work supported by industry: no.

Immunoglobulin G Concentrations in Alpaca Colostrum during the First Four Days after Parturition.

Simple SummaryDuring the first days after parturition, mammalian milk (colostrum) is specifically formulated to nourish newborns. Immunoglobulins are a particularly important component for newborn New World camelids, as their immune system is almost totally dependent on the intestinal transfer of colostral immunoglobulins to acquire passive immunity. In this study, colostrum samples were collected from 20 alpaca mares in the first four days after parturition and analyzed for their immunoglobulin concentration. Sampling started on the day of parturition. The associations of immunoglobulins with other components were determined. The immunoglobulin G (IgG) concentrations decreased significantly within the first four days after parturition. The correlation coefficients between IgG content and the content of various minerals were significant but variable. The correlation between IgG content and fat and lactose content was negative but between IgG content and protein content was highly positive. This strong association could be used for a brief estimation of the IgG content of the colostrum based on the measured protein concentration. The results of the present study can be used for the development of colostrum replacers where motherless rearing is required.Colostrum provides the newborn with nutrients and immunoglobulins. Immunoglobulins and their intestinal transfer play a major role in the immune system of neonates since they are born agammaglobulinemic. In this study immunoglobulin G (IgG) content was determined in alpaca colostrum and the correlations of the IgG concentration by fat, protein, lactose and minerals were calculated. Colostrum samples were collected daily from 20 multiparous alpaca mares during the first four days after parturition. The IgG concentrations were determined by radial immunodiffusion using a Camelid IgG Test Kit. The IgG concentration decreased significantly from 26,319 mg/dL on day 1 to 3848.8 mg/dL on day 4. There were significant correlations between IgG concentration and the other components of the colostrum. While the correlations between IgG and fat (r = −0.69, p ≤ 0.001) and lactose (r = −0.64, p ≤ 0.001) were negative, the correlations with protein (r = 0.91, p ≤ 0.001), magnesium (r = 0.86, p ≤ 0.001) and cobalt (r = 0.87, p ≤ 0.001) were strongly positive. Due to the strong association, the colostrum protein concentration could be used for a brief estimation of the IgG content.

Acyl-CoA:diacylglycerol acyltransferase 1 inhibition in the small intestine increases plasma transaminase activity via the activation of protein kinase C pathway.

Acyl-CoAdiacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in the fat absorption step in enterocytes. We previously reported that the pharmacological inhibition of DGAT1 increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in corn oil-loaded rats without any sign of hepatotoxicity. In this study, we investigated this mechanism. We found that this elevation occurred only during the pharmacologically active period of a DGAT1 inhibitor and the magnitude did not depend on the volume of corn oil. In addition, this elevation was not accompanied by increases in ALT or AST mRNA levels in the small intestine and liver. To clarify a lipid component responsible for this elevation, rats were treated with free fatty acids instead of corn oil and no plasma ALT elevation was observed. Next, rats were pretreated with inhibitors of monoacylglycerol acyltransferase 2 and intestinal microsomal triglyceride transfer protein instead of the DGAT1 inhibitor, but no plasma ALT elevation was observed after corn oil loading. Since the results suggested a possible role of diacylglycerol (DAG), which activates protein kinase C (PKC), we measured PKC activity in the small intestine and found that the activity was increased by treatment with the DGAT1 inhibitor and corn oil. Moreover, rats pretreated with a PKC inhibitor in combination with the DGAT1 inhibitor showed suppression of plasma ALT elevation. Taken together, the present results suggest that DAG accumulation induced by pharmacological DGAT1 inhibition and resultant PKC activation in enterocytes are involved in the increase in plasma ALT and AST activity in rats.

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets.

Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC0-inf < 2). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

Evaluation of colostrum bioactive protein transfer and blood metabolic traits in neonatal lambs in the first 24 hours of life

Colostrum is a unique resource that contributes to the passive transfer of immunity and plays a central role in the health status of neonatal ruminants. However, digestion and absorption of colostral proteins in the gut remain incompletely understood. Therefore, this study aimed to investigate the effect of bovine colostrum feeding on blood metabolic traits and to quantify colostral bioactive proteins in the gastrointestinal digesta and blood to evaluate intestinal transfer in neonatal lambs in the first 24 h of life. Fifty-four newborn lambs were used in this study, including 27 lambs fed pooled bovine colostrum and slaughtered at 6 (C6h), 12 (C12h), or 24 h (C24h) after birth; 18 lambs not fed any colostrum or milk and slaughtered at birth (N0h) or 24 h (N24h) after birth; and 9 milk-fed lambs slaughtered at 24 h (M24h) after birth. Lambs receiving colostrum or milk were bottle-fed within the first 2 h to obtain intakes of 8% of body weight at birth. Samples of blood and digesta from the abomasum, jejunum, and ileum were collected after slaughter. Serum concentrations of glucose, insulin, total protein, and aspartate aminotransferase were higher in colostrum-fed lambs than in N0h lambs. Serum concentrations of insulin, total protein, insulin-like growth factor 1, and γ-glutamyl transpeptidase were higher in C24h lambs than in N24h or M24h lambs. Apparent efficiencies of IgG absorption in C6h, C12h, and C24h lambs were 14.4, 26.8, and 17.2%, respectively, whereas apparent efficiencies of lactoferrin (LF), α-lactalbumin (α-LA), and β-lactoglobulin (β-LG) absorption were very low in colostrum-fed lambs, with mean values of 0.06, 0.002, and 0.003%, respectively. Concentrations of IgG, LF, α-LA, and β-LG in the digesta of the abomasum, jejunum, and ileum rapidly decreased from C6h to C24h lambs, and the disappearance rates of IgG, LF, α-LA, and β-LG were higher in lambs from C6h to C12h (62.1, 75.7, 91.3, and 95.0% for IgG, LF, α-LA, and β-LG, respectively) than from C12h to C24h (34.6, 22.5, 7.5, and 2.2% for IgG, LF, α-LA, and β-LG, respectively). These results indicated that bovine colostrum feeding improved the metabolic and immunological status of lambs, and that ingested colostral IgG was prone to intact uptake into the blood, whereas almost all ingested LF, α-LA, and β-LG disappeared in the lumen of the gastrointestinal tract in a time-dependent manner. The findings provide novel information for exploring selective absorption of colostral compounds in the small intestine of lambs.

The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals.

The gut is an efficient barrier which protects against the passage of pathogenic microorganisms and potential harmful macromolecules into the body, in addition to its primary function of nutrient digestion and absorption. Contrary to the restricted macromolecular passage in adulthood, enhanced transfer takes place across the intestines during early life, due to the high endocytic capacity of the immature intestinal epithelial cells during the fetal and/or neonatal periods. The timing and extent of this enhanced endocytic capacity is dependent on animal species, with a prominent non-selective intestinal macromolecular transfer in newborn ungulates, e.g., pigs, during the first few days of life, and a selective transfer of mainly immunoglobulin G (IgG), mediated by the FcRn receptor, in suckling rodents, e.g., rats and mice. In primates, maternal IgG is transferred during fetal life via the placenta, and intestinal macromolecular transfer is largely restricted in human neonates. The period of intestinal macromolecular transmission provides passive immune protection through the transfer of IgG antibodies from an immune competent mother; and may even have extra-immune beneficial effects on organ maturation in the offspring. Moreover, intestinal transfer during the fetal/neonatal periods results in increased exposure to microbial and food antigens which are then presented to the underlying immune system, which is both naïve and immature. This likely stimulates the maturation of the immune system and shifts the response toward tolerance induction instead of activation or inflammation, as usually seen in adulthood. Ingestion of mother's milk and the dietary transition to complex food at weaning, as well as the transient changes in the gut microbiota during the neonatal period, are also involved in the resulting immune response. Any disturbances in timing and/or balance of these parallel processes, i.e., intestinal epithelial maturation, luminal microbial colonization and mucosal immune maturation due to, e.g., preterm birth, infection, antibiotic use or nutrient changes during the neonatal period, might affect the establishment of the immune system in the infant. This review will focus on how differing developmental processes in the intestinal epithelium affect the macromolecular passage in different species and the possible impact of such passage on the establishment of immunity during the critical perinatal period in young mammals.

Two-stage Reconstruction Using a Free Jejunum/Ileum Flap After Total Esophagectomy.

Reconstruction after esophagectomy is conventionally performed with a gastric conduit. However, in cases where a gastric conduit is unavailable, reconstructive procedures vary in terms of flap type, operative timing, and conduit route. Single-stage surgery is associated with a long operation time and high surgical stress, resulting in perioperative mortality. Recent advances in reconstructive microsurgery have made free intestinal flap transfer safe and reliable. Therefore, to overcome the shortcomings with previous methods, we performed 2-stage surgery involving free jejunum/ileum transfer for reconstruction after esophagectomy. From 2010 to 2018, 42 free jejunum/ileum flaps were transferred for reconstruction after esophagectomy in 41 patients. The diagnosis was esophageal cancer in 38 patients. All operations were performed in 2 stages. In most cases, total esophagectomy was performed in the first operation. The cervical stump of the esophagus was sutured to the cervical skin, creating an esophagostomy in the left neck. About 4 to 7 weeks after the first operation, the second operation was performed. The free jejunum/ileum flap was transferred through the subcutaneous route. Microvascular anastomosis was performed with the internal mammary artery and internal mammary vein, transverse cervical artery, internal and external jugular veins (internal jugular vein and EJV, respectively), and cephalic vein. The mean follow-up duration was 20 months. Free jejunum/ileum transfer was performed as the first operation in 4 cases and as the second operation in 38 cases. A free jejunal flap was used in 36 cases and free ileal flap was used in 6 cases. The recipient arteries were the internal mammary artery in 38 cases and transverse cervical artery in 4 cases. The recipient veins were the internal mammary vein in 15 cases, cephalic vein in 13 cases, EJV in 10 cases, and internal jugular vein in 10 cases. The flaps survived in all cases, except 1 case (41/42, 97.6%). The complications were anastomotic leakage of the flap in 9 cases, respiratory complications in 10 cases, and ileus in 2 cases. Perioperative mortality was not noted. Two-stage surgery using free jejunum/ileum flap transfer is a safe and reliable option for esophageal reconstruction in cases where gastric pull-up is unavailable.

Plasma triacylglycerol-reducing activity of ergosterol linolenate is associated with inhibition of intestinal lipid absorption

Abstract This study investigated the role of ergosterol linolenate in the alleviation of hyperlipidemia induced by a high-fat diet and further explored the expression of key genes involved in lipid absorption and metabolism in mice. Twenty-four male C57BL/6J mice were divided into three groups and fed one of three experimental diets: a high-fat diet (HF), or a HF diet with either ergosterol (ER) or ergosterol linolenate (EL), respectively, for 6 weeks. The results demonstrate that EL significantly reduced plasma triacylglycerol (TG) levels by 20%, weight gain by 50% and relative perirenal and epididymal fat by 23.6%. This was accompanied by a significant decrease in liver cholesterol, liver total fatty acids and fecal bile acids, accompanied by a marked increase in fecal total fatty acids. Ergosterol linolenate effectively counteracted steatosis induced by a high-fat diet. Ergosterol linolenate also altered the mRNA expression of key intestinal and hepatic genes involved in lipid absorption and metabolism. Of them, ergosterol linolenate significantly reduced the mRNA expression of intestinal microsomal triglyceride transfer protein (MTP), a key component in the formation of chylomicrons. Therefore, the plasma TG-reducing action of ergosterol linolenate can be largely attributed to reduced lipid absorption and increased fecal lipid excretion.

Influence of flowing fluid property through an elastic tube on various deformations along the tube length

The study of fluid flow characteristics in collapsible elastic tubes is useful to understand biofluid mechanics encountered in the human body. The research work presented here is aimed at thoroughly investigating the influence of both Newtonian and/or non-Newtonian fluids (low and high shear thinning) during steady flow through an elastic tube on various tube deformations, which enables understanding of the interaction between wall motion, fluid flow, and intestinal transmembrane mass transfer as a crucial contribution to a mechanistic understanding of bioaccessibility/bioavailability. It is observed that for a given steady volume flow rate, the tube is buckled from an elliptical shape to a line or area contacted two lobes as the critical external pressure is increased. The downstream transmural pressure is found to get more negative than that at the upstream as the outlet pressure decreased due to stronger tube collapse resulting in a reduced cross-sectional area. The experimental results depict that the tube cross-sectional area decreased by only about a factor of one for PEG (polyethylene glycol) and about a factor of six for both CMC (carboxymethyl cellulose) and PAA (polyacrylamide) from the undeformed one under an applied external pressure of 105 mbar. The corresponding maximum velocity increased by a factor of two during steady flow of shear-thinning fluids. The shear-thinning behavior of both CMC and PAA solutions is clearly observed at a constant flow rate of 17 ml/s as the tube cross-sectional area decreased due to an increase in compressive transmural pressure. In addition, the viscosity of PAA is drastically decreased due to its high shear-thinning behavior than that of the CMC under the same applied external pressure.

PB2043 UPPER AND LOWER GASTROINTESTINAL ENDOSCOPY FINDINGS IN PATIENTS WITH ISOLATED FERRITIN DEFICIENCY

Background:Iron deficiency without anemia is the most common nutritional disorder in children. Iron balancing is provided by intestinal absorption and iron transfer mechanisms. The most common causes of anemia are chronic blood loss from the gastrointestinal tract (peptic ulcer, hemorrhoids, parasites), inadequate dietary intake, gynecological problems (menorrhagia), decreased gastrointestinal mucosal absorption (celiac disease), Helicobacter pylori (Hp) infection and autoimmune gastritis. In the literature, there are not many studies about iron deficiency without decreasing hemoglobin (Hg) levels in the early period of iron deficiency.Aims:In our study, we aimed to evaluate the lower and upper endoscopic findings of patients with normal Hg levels and low ferritin levels.Methods:A total of 2391 patients aged between 0‐18 years and had normal Hg levels were included into the study performing upper and lower gastrointestinal system (GIS) endoscopy by the pediatric gastroenterology‐hepatology department between 2009 and 2018. The patients were divided into two groups as Hb level was normal, ferritin level below 15 mg / dl (group 1; n = 549) and Hb level was normal, ferritin level was above 15 mg / dl (group 2; n = 1143). In group 1, upper GIS endoscopy was performed to 520 patients, lower GIS endoscopy to 56 patients. In Group 2, upper GI endoscopy was performed to 1095 patients and lower GI endoscopy to 120 patients. All endoscopy results of the patients were evaluated and compared.Results:The most common complaint was abdominal pain in both groups (63%, 67.4%, respectively). And the most common endoscopic findings in both groups were reflux esophagitis in the esophagus (9.6%, 9.1%, respectively, p&gt;0.05), gastritis in the stomach (32.1%, 37.9%, respectively, p &gt; 0.05). Hp gastritis was the second most common endoscopic finding in group 1. When the both groups were compared, there was a significant difference between group for Hp gastritis (24%, 27.6%, respectively, p = 0.002). In duodenum findings, celiac disease was higher in group 1 and there was a significant statistically between group for celiac disease (6%, 2.1%, respectively, p = 0.000). In colonoscopic examination, lymphoid nodular hyperplasia and polyp were higher in group 1 and there were statistically significant between groups (14.3%, 5%, and 10.7%, 3.3% respectively, p = 0.03, 0.04).Summary/Conclusion:In the literature, generally the studies are about anemia and upper GIS findings. In our study, the patients with decreased ferritin and normal Hg levels and undergoing upper and lower GIS endoscopy were investigated. The risk of Hp gastritis and celiac disease was found to be increased in patients with ferritin deficiency without anemia (group 1). In addition, lymphoid noduler hyperplasia and polyps were also caused ferritin deficiency.

Glycation of the Major Milk Allergen β-Lactoglobulin Changes Its Allergenicity by Alterations in Cellular Uptake and Degradation.

ScopeDuring food processing, the Maillard reaction (МR) may occur, resulting in the formation of glycated proteins. Glycated proteins are of particular importance in food allergies because glycation may influence interactions with the immune system. This study compared native and extensively glycated milk allergen β‐lactoglobulin (BLG), in their interactions with cells crucially involved in allergy.Methods and resultsBLG was glycated in MR and characterized. Native and glycated BLG were tested in experiments of epithelial transport, uptake and degradation by DCs, T‐cell cytokine responses, and basophil cell degranulation using ELISA and flow cytometry. Glycation of BLG induced partial unfolding and reduced its intestinal epithelial transfer over a Caco‐2 monolayer. Uptake of glycated BLG by bone marrow–derived dendritic cells (BMDC) was increased, although both BLG forms entered BMDC via the same mechanism, receptor‐mediated endocytosis. Once inside the BMDC, glycated BLG was degraded faster, which might have led to observed lower cytokine production in BMDC/CD4+ T‐cells coculture. Finally, glycated BLG was less efficient in induction of degranulation of BLG‐specific IgE sensitized basophil cells.ConclusionsThis study suggests that glycation of BLG by MR significantly alters its fate in processes involved in immunogenicity and allergenicity, pointing out the importance of food processing in food allergy.

Dipeptidyl peptidase 4 inhibitor anagliptin ameliorates hypercholesterolemia in hypercholesterolemic mice through inhibition of intestinal cholesterol transport.

Aims/IntroductionRecent data showed that dipeptidyl peptidase 4 (DPP‐4) inhibitors exert a lipid‐lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non‐diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol‐lowering action.Materials and MethodsMale apolipoprotein E (ApoE)‐deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14C‐labeled cholesterol (14C‐Chol). In additional experiments, effects of exendin‐4 in mice and of anagliptin in DPP‐4‐deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice.ResultsThe serum total and non‐high‐density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE‐deficient mice. The cholesterol‐lowering effect was predominantly observed in the chylomicron fraction. The plasma 14C‐Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14C‐Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP‐4 activity, and exendin‐4 had no effect on the 14C‐Chol transport in ApoE‐deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport‐related microsomal triglyceride transfer protein, acyl‐coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin.ConclusionsThese findings suggest that anagliptin might exert a cholesterol‐lowering action through DPP‐4‐dependent and glucagon‐like peptide 1‐independent suppression of intestinal cholesterol transport.

Transepithelial transfer of phenanthrene, but not of benzo[a]pyrene, is inhibited by fatty acids in the proximal intestine of rainbow trout (Oncorhynchus mykiss)

The inclusion of vegetable oils in aquafeeds introduces contaminating polycyclic aromatic hydrocarbons (PAHs) in salmonids. Since lipophilic PAHs solubilize in micelles composed of lipids, bile salts and fatty acids, dietary lipid composition can alter intestinal transepithelial PAH transfer. We studied the uptake of two PAHs, viz. benzo[a]pyrene (BaP) and phenanthrene (PHE), in rainbow trout (Oncorhynchus mykiss) intestine. We also investigated the effects of two fatty acids, viz. fish oil-derived eicosapentaenoic acid (EPA, 20:5n-3) and vegetable oil-derived oleic acid (18:1n-9) on intestinal uptake. Radiolabeled PAHs were solubilized in micelles composed of tritiated EPA and oleic acid, respectively, and administrated to intestinal segments mounted in Ussing chambers.In the absence of micelles, PHE accumulation was two times higher than BaP in the mucosal and serosal layers of proximal and distal intestine. Administration of PHE in micelles composed of oleic acid resulted in a 50% lower accumulation of PHE in the mucosal layers of the proximal intestine compared to EPA-composed micelles. Accumulation of EPA and oleic acid in the proximal intestinal mucosa correlated negatively with the transepithelial transfer of these fatty acids across the proximal intestinal epithelium. Transepithelial PHE transfer across the proximal intestine was reduced by 30% in co-exposure with EPA-composed micelles compared to 80% with oleic acid micelles. BaP was not transferred across the intestine.We conclude that the lipid composition of an aquafeed is an important determinant of PAH bioavailability. Therefore, lipid composition should be an important consideration in choosing vegetable oils as alternatives for fish oil in aquafeeds.

Role of ABC transporters in trans-epithelial transport of vitamin K antagonists.

Vitamin K antagonists (VKAs) remain the oral anticoagulant of choice in venous thromboembolic disease. These drugs are characterized by a large inter-individual variability requiring frequent dose tailoring. Genetic polymorphisms for cytochrome CYP2C9 and VKORC1 explain some of the variability, especially in warfarin and acenocoumarol responses. The aim of this study was to assess, in cell models, the role of ABC transporters in the intestinal transfer of the main coumarin derivatives (warfarin, acenocoumarol) and indanedione derivatives (phenindione, fluindione). The results show a basal to apical polarized transport for fluindione, phenindione and acenocoumarol only. Experimental studies using specific inhibitors of transport protein demonstrate the implication of MRPs and BCRP proteins and to a lesser extent P-gp. Warfarin and acenocoumarol seem to be poor inhibitors of MRPs protein, whereas fluindione and phenindione have a slight or no effect. The regulation of the expression of ABC transporters by exposure to VKAs was also investigated in Caco-2 cells. The expression of mRNA P-gp, MRP1, MRP2 and BCRP was weakly or not modified after 24h of VKAs exposure. In conclusion, the intestinal transfer of indanedione derivatives and acenocoumarol could be influenced by transport proteins of the ABC superfamily. Coumarin derivatives are poor inhibitors of these proteins and AVKs have a slight effect on the mRNA ABC transporter expression level. Copyright © 2016 John Wiley & Sons, Ltd.

Monoacylglycerol-enriched oil increases EPA/DHA delivery to circulatory system in humans with induced lipid malabsorption conditions

It was hypothesized that under induced lipid malabsorption/maldigestion conditions, an enriched sn-1(3)-monoacylglycerol (MAG) oil may be a better carrier for n-3 long-chain PUFAs (LC-PUFAs) compared with triacylglycerol (TAG) from fish oil. This monocentric double blinded clinical trial examined the accretion of EPA (500 mg/day) and DHA (300 mg/day) when consumed as TAG or MAG, into the erythrocytes, plasma, and chylomicrons of 45 obese (BMI ≥30 kg/m2 and ≤40 kg/m2) volunteers who were and were not administered Orlistat, an inhibitor of pancreatic lipases. Intake of MAG-enriched oil resulted in higher accretion of LC-PUFAs than with TAG, the concentrations of EPA and DHA in erythrocytes being, respectively, 72 and 24% higher at 21 days (P < 0.001). In addition, MAG increased the plasma concentration of EPA by 56% (P < 0.001) as compared with TAG. In chylomicrons, MAG intake yielded higher levels of EPA with the area under the curve (0-10 h) of EPA being 55% greater (P = 0.012). In conclusion, in obese human subjects with Orlistat-induced lipid maldigestion/malabsorption conditions, LC-PUFA MAG oil increased LC-PUFA levels in erythrocytes, plasma, and chylomicrons to a greater extent than TAG. These results indicate that MAG oil might require minimal enzymatic digestion prior to intestinal uptake and transfer across the epithelial barrier.

Study on the uptake and deglycosylation of the masked forms of zearalenone in human intestinal Caco-2 cells

This study investigated for the first time the intestinal transfer of two modified forms of zearalenone (ZEN), zearalenone-14-glucoside (ZEN14Glc) and zearalenone-16-glucoside (ZEN16Glc), using polarized monolayers of Caco-2 cells. The cells were apically exposed to 40 μM of ZEN14Glc, ZEN16Glc and ZEN, separately. Results showed that, after apical administration, ZEN14Glc and ZEN16Glc can be detected in cellular extracts indicating uptake by intestinal cells. Moreover, the glucosylated forms were cleaved to release ZEN, with a different cleavage ability for the two conjugated isomers. In particular, ZEN16Glc seems to be less prone to deglycosylation compared to ZEN14Glc, probably on account of an increased steric hindrance. We could show that human cytosolic β-glucosidase is able to cleave ZEN14Glc liberating ZEN, but is unable to cleave ZEN16Glc.All metabolites could cross the cell membrane and be detected in the apical compartment, while ZEN was also found in the basolateral compartment together with the modified mycotoxin form.

Usefulness of the Clavien-Dindo Classification in Understanding the Limitations and Indications of Larynx-preserving Esophageal Reconstruction.

Background:The Clavien–Dindo (CD) classification is used to evaluate the severity of surgical complications. However, its usefulness in esophageal reconstruction has not been reported. To address this, this case series study used the CD classification to evaluate the complications after cervical esophageal reconstruction with free jejunum transfer or supercharged pedicled intestinal transfer.Methods:All consecutive patients who underwent esophageal cancer surgery with larynx-preserving free jejunum or pedicled ileocolic transfer in June 2012–December 2015 were identified. The postoperative complications were classified using the CD classification.Results:In total, 22 patients (20 men and 2 women; mean age, 63.3 years) underwent esophageal cancer reconstruction with larynx-preserving free jejunum transfer (n = 9) and supercharged pedicled intestinal transfer (n = 13). Seven patients underwent prophylactic tracheotomy. Four patients underwent emergent tracheotomy 1 or 5 days after surgery. The most frequent complication was recurrent nerve paralysis (RNP) (n = 8). Of these 8 RNP cases, 6 and 2 were classified as CD I and III complications, respectively. Pneumonia was the next most common complication (n = 7). Of these 7 pneumonia cases, 5 and 2 were classified as CD II and III, respectively. There were 2 cases of intestinal anastomosis leakage (CD II and III). On average, patients were able to start oral alimentation 15.1 (9–35) days after surgery.Conclusions:Our analysis with the CD classification suggested that vascularized free jejunum transfer or supercharge-drainage pedicled ileocolic transfer prevents postoperative intestinal anastomosis leakage and that prophylactic tracheotomy is especially indicated in cases with significant surgical damage in the cervical region.