Grape seed Proanthocyanidins target the Enteroendocrine system in cafeteria‐diet‐fed rats

Scope The effects on the enteroendocrine system of three different grape seed proanthocyanidin extract (GSPE) treatments are analyzed in rats on a cafeteria diet for 17 weeks. Methods and results GSPE is administered in a corrective manner (15 last days of the cafeteria diet) at two doses, 100 and 500 mg GSPE per kg bw. A third, longer treatment in which GSPE (500 mg kg–1 bw) is administered daily every other week during the 17 weeks of the cafeteria diet is also tested. Most GSPE treatments lead to ghrelin accumulation in the stomach, limited CCK secretion in the duodenum, and increased GLP‐1 and PYY mRNA in colon. GSPE also increases cecal hypertrophy and reduces butyrate content. When the treatment is administered daily every other week during 17 weeks, there is also an increase in colon size. These effects are accompanied by a reduced food intake at the end of the experiment when GSPE is administered at 500 mg GSPE kg–1 during the last 15 days, but not on the other treatments, despite an observed reduction in body weight in the longer treatment. Conclusion GSPE modulates the enteroendocrine system in models in which it also reduces food intake or body weight.info:eu-repo/semantics/acceptedVersio

Grape seed proanthocyanidins as modulators of the inflammatory response and barrier function in the intestine

La disfunció intestinal es basa en un estat proinflamatori en l'intestí i en una funció de barrera defectuosa, característiques comunes de diverses malalties cròniques intestinals, però també associades amb patologies metabòliques relacionades amb la dieta, com és l’obesitat. En aquest sentit, les proantocianidines són compostos bioactius naturals de la família dels flavonoides que han mostrat posseir propietats antiinflamatòries i que podrien tenir efectes significatius en l’entorn intestinal, influint en la fisiologia i la bioquímica de l'intestí. En aquest marc, la present tesi va ser dissenyada per aclarir el possible paper de les proantocianidines en la modulació de la resposta inflamatòria intestinal i la funció de barrera en diferents models animals complementaris de disfunció intestinal. Per assolir aquest objectiu global, primer vam examinar l'impacte d'una dieta obesogènica en l'estat de salut intestinal al llarg del temps i posteriorment vam analitzar l'efecte protector d'un extracte de proantocianidines de la llavor de raïm, comparant l'eficàcia de les diferents dosis i dels temps d'administració a l’hora de protegir de la disfunció intestinal. En segon lloc, vam analitzar el paper del mateix extracte de proantocianidines en un model animal d’inflamació intestinal aguda i d’alteració de la permeabilitat intestinal induïda per injecció amb lipopolisacàrids. En resum, la present tesi va revelar que l'obesitat induïda per la dieta i l'exposició aguda a lipopolisacàrids desencadenen un grau similar d’inflamació intestinal i deteriorament de l'estat funcional de la barrera, i més important, que l'administració oral de les proantocianidines millora la inflamació intestinal i la funció de barrera.La disfunción intestinal se basa en un estado proinflamatorio en el intestino y en una función de barrera defectuosa, características comunes de diversas enfermedades crónicas intestinales, pero también asociadas con patologías metabólicas relacionadas con la dieta, como es la obesidad. En este sentido, las proantocianidinas son compuestos bioactivos naturales de la familia de los flavonoides que han mostrado poseer propiedades antiinflamatorias y que podrían tener efectos significativos en el entorno intestinal, influyendo así en la fisiología y la bioquímica del intestino. En este marco, la presente tesis fue diseñada para aclarar el posible papel de las proantocianidinas en la modulación de la respuesta inflamatoria intestinal y la función de barrera en diferentes modelos animales complementarios de disfunción intestinal. Para alcanzar este objetivo global, primero examinamos el impacto de una dieta obesogénica en el estado de salud intestinal a lo largo del tiempo y posteriormente analizamos el efecto protector de un extracto de proantocianidinas de la semilla de la uva, comparando la eficacia de las diferentes dosis y los tiempos de administración a la hora de proteger de la disfunción intestinal. En segundo lugar, analizamos el papel del mismo extracto de proantocianidinas en un modelo animal de inflamación intestinal aguda y de alteración de la permeabilidad intestinal inducida por inyección con lipopolisacáridos. En resumen, la presente tesis reveló que la obesidad inducida por la dieta y la exposición aguda a lipopolisacáridos desencadenan un grado similar de inflamación intestinal y deterioro del estado funcional de la barrera, y más importante, que la administración oral de las proantocianidinas mejora la inflamación intestinal y la función de barrera.Intestinal dysfunction is based on a pro-inflammatory state in the intestine and on a defective barrier function, both considered common features of intestinal chronic diseases. However, intestinal dysfunction has also been associated with obesity and other metabolic diet-related pathologies. In this regard, proanthocyanidins are natural bioactive compounds from the flavonoid family with anti-inflammatory properties that might have significant effects on the intestinal environment, the physiology and the biochemistry of the intestine. In this framework, the present thesis was designed to elucidate the role of proanthocyanidins in the modulation of the intestinal inflammatory response and barrier function in complementary animal models of intestinal dysfunction To accomplish this global objective, firstly we examined the impact of an obesogenic diet on intestinal health status over time to then analyse the protective effect of a grape seed proanthocyanidin extract and compare the effectiveness of different doses and times of administration to protect against intestinal dysfunction. Secondly, the role of the same extract of proanthocyanidins was analysed in an animal model of acute intestinal inflammation and impaired intestinal permeability induced by lipopolysaccharides injection. To sum up, the present thesis revealed that diet induced obesity or acute lipopolysaccharide exposition trigger similar degree of intestinal inflammation and impaired barrier function state, and more importantly, that the oral administration of proanthocyanidins improves intestinal inflammation and barrier function

Grape seed proanthocyanidins as modulators of the inflammatory response and barrier function in the intestine

La disfunció intestinal es basa en un estat proinflamatori en l'intestí i en una funció de barrera defectuosa, característiques comunes de diverses malalties cròniques intestinals, però també associades amb patologies metabòliques relacionades amb la dieta, com és l’obesitat. En aquest sentit, les proantocianidines són compostos bioactius naturals de la família dels flavonoides que han mostrat posseir propietats antiinflamatòries i que podrien tenir efectes significatius en l’entorn intestinal, influint en la fisiologia i la bioquímica de l'intestí. En aquest marc, la present tesi va ser dissenyada per aclarir el possible paper de les proantocianidines en la modulació de la resposta inflamatòria intestinal i la funció de barrera en diferents models animals complementaris de disfunció intestinal. Per assolir aquest objectiu global, primer vam examinar l'impacte d'una dieta obesogènica en l'estat de salut intestinal al llarg del temps i posteriorment vam analitzar l'efecte protector d'un extracte de proantocianidines de la llavor de raïm, comparant l'eficàcia de les diferents dosis i dels temps d'administració a l’hora de protegir de la disfunció intestinal. En segon lloc, vam analitzar el paper del mateix extracte de proantocianidines en un model animal d’inflamació intestinal aguda i d’alteració de la permeabilitat intestinal induïda per injecció amb lipopolisacàrids. En resum, la present tesi va revelar que l'obesitat induïda per la dieta i l'exposició aguda a lipopolisacàrids desencadenen un grau similar d’inflamació intestinal i deteriorament de l'estat funcional de la barrera, i més important, que l'administració oral de les proantocianidines millora la inflamació intestinal i la funció de barrera.La disfunción intestinal se basa en un estado proinflamatorio en el intestino y en una función de barrera defectuosa, características comunes de diversas enfermedades crónicas intestinales, pero también asociadas con patologías metabólicas relacionadas con la dieta, como es la obesidad. En este sentido, las proantocianidinas son compuestos bioactivos naturales de la familia de los flavonoides que han mostrado poseer propiedades antiinflamatorias y que podrían tener efectos significativos en el entorno intestinal, influyendo así en la fisiología y la bioquímica del intestino. En este marco, la presente tesis fue diseñada para aclarar el posible papel de las proantocianidinas en la modulación de la respuesta inflamatoria intestinal y la función de barrera en diferentes modelos animales complementarios de disfunción intestinal. Para alcanzar este objetivo global, primero examinamos el impacto de una dieta obesogénica en el estado de salud intestinal a lo largo del tiempo y posteriormente analizamos el efecto protector de un extracto de proantocianidinas de la semilla de la uva, comparando la eficacia de las diferentes dosis y los tiempos de administración a la hora de proteger de la disfunción intestinal. En segundo lugar, analizamos el papel del mismo extracto de proantocianidinas en un modelo animal de inflamación intestinal aguda y de alteración de la permeabilidad intestinal inducida por inyección con lipopolisacáridos. En resumen, la presente tesis reveló que la obesidad inducida por la dieta y la exposición aguda a lipopolisacáridos desencadenan un grado similar de inflamación intestinal y deterioro del estado funcional de la barrera, y más importante, que la administración oral de las proantocianidinas mejora la inflamación intestinal y la función de barrera.Intestinal dysfunction is based on a pro-inflammatory state in the intestine and on a defective barrier function, both considered common features of intestinal chronic diseases. However, intestinal dysfunction has also been associated with obesity and other metabolic diet-related pathologies. In this regard, proanthocyanidins are natural bioactive compounds from the flavonoid family with anti-inflammatory properties that might have significant effects on the intestinal environment, the physiology and the biochemistry of the intestine. In this framework, the present thesis was designed to elucidate the role of proanthocyanidins in the modulation of the intestinal inflammatory response and barrier function in complementary animal models of intestinal dysfunction To accomplish this global objective, firstly we examined the impact of an obesogenic diet on intestinal health status over time to then analyse the protective effect of a grape seed proanthocyanidin extract and compare the effectiveness of different doses and times of administration to protect against intestinal dysfunction. Secondly, the role of the same extract of proanthocyanidins was analysed in an animal model of acute intestinal inflammation and impaired intestinal permeability induced by lipopolysaccharides injection. To sum up, the present thesis revealed that diet induced obesity or acute lipopolysaccharide exposition trigger similar degree of intestinal inflammation and impaired barrier function state, and more importantly, that the oral administration of proanthocyanidins improves intestinal inflammation and barrier function

TetraSOD^®, a Unique Marine Microalgae Ingredient, Promotes an Antioxidant and Anti-Inflammatory Status in a Metabolic Syndrome-Induced Model in Rats

Increased oxidative stress has been linked to the pathogenic process of obesity and can trigger inflammation, which is often linked with the risk factors that make up metabolic syndrome (MetS), including obesity, insulin resistance, dyslipidaemia and hypertension. TetraSOD®, a natural marine vegan ingredient derived from the microalgae Tetraselmis chuii that is high in the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) has recently demonstrated in vitro increased activity of these key antioxidant enzymes. In the present study, the potential bioactive effects of three dietary dosages of TetraSOD® in enhancing antioxidant and anti-inflammatory mechanisms to combat the metabolic disturbances that compose MetS were assessed in rats given a cafeteria (CAF) diet. Chronic supplementation with 0.17, 1.7, and 17 mg kg−1 day−1 of TetraSOD® for 8 weeks ameliorated the abnormalities associated with MetS, including oxidative stress and inflammation, promoting endogenous antioxidant defence mechanisms in the liver (GPx and GSH), modulating oxidative stress and inflammatory markers in plasma (NOx, oxLDL and IL-10), and regulating genes involved in antioxidant, anti-inflammatory and immunomodulatory pathways in the liver, mesenteric white adipose tissue (MWAT), thymus, and spleen. Overall, TetraSOD® appears to be a potential therapeutic option for the management of MetS

Effects of an Intermittent Grape-Seed Proanthocyanidin (GSPE) Treatment on a Cafeteria Diet Obesogenic Challenge in Rats

Obesity is highly associated with the pathologies included in the concept of the Metabolic Syndrome. Grape-seed proanthocyanins (GSPE) have showed very positive effects against all these metabolic disruptions; however, there is, as yet, no consensus about their effectiveness against an obesogenic challenge, such as a cafeteria diet. We determined the effectiveness of a dose of 500 mg GSPE/kg b.w. (body weight) against the obesogenic effects of a 17-week cafeteria diet, administered as a sub-chronic treatment, 10–15 days before, intermittently and at the end of the diet, in Wistar rats. Body weight, adiposity, indirect calorimetry and plasma parameters were analyzed. GSPE pre-treatment showed a long-lasting effect on body weight and adiposity that was maintained for seven weeks after the last dose. A corrective treatment was administered for the last two weeks of the cafeteria diet intervention; however, it did not effectively correct any of the parameters assessed. The most effective treatment was an intermittent GSPE dosage, administered every second week during the cafeteria diet. This limited body weight gain, adiposity and most lipotoxic effects. Our results support the administration of this GSPE dose, keeping an intermittent interval between dosages longer than every second week, to improve obesogenic disruptions produced by a cafeteria diet

Grape-Seed Proanthocyanidins are Able to Reverse Intestinal Dysfunction and Metabolic Endotoxemia Induced by a Cafeteria Diet in Wistar Rats

We evaluated the effectiveness of pharmacological doses of grape-seed proanthocyanidin extract (GSPE) in reversing intestinal barrier alterations and local inflammation in female Wistar rats fed a long-term obesogenic diet. Animals were fed a 17-week cafeteria diet (CAF diet), supplemented with daily GSPE doses (100 or 500 mg kg−1 body weight) during the final two weeks. CAF diet enhanced the intestinal permeation of an orally administered marker (ovalbumin, OVA) and increased the plasma levels of tumor necrosis factor-α (TNF-α) and lipopolysaccharides (LPS) in 2−3-fold. Ex vivo Ussing chamber assays showed a 55−70% reduction in transepithelial electrical resistance (TEER) and increased the TNF-α secretions in both small and large intestinal sections with a 25-fold increment in the ileum. Ileal tissues also presented a 4-fold increase of myeloperoxidase (MPO) activity. Both GSPE-treatments were able to restitute TEER values in the ileum and colon and to reduce plasma LPS to basal levels without a dose-dependent effect. However, effects on the OVA permeation and TNF-α secretion were dose and section-specific. GSPE also reduced ileal MPO activity and upregulated claudin 1 gene expression. This study provides evidence of the efficacy of GSPE-supplementation ameliorating diet-induced intestinal dysfunction and metabolic endotoxemia when administered at the end of a long-term obesogenic diet

Proanthocyanidins Limit Adipose Accrual Induced by a Cafeteria Diet, Several Weeks after the End of the Treatment

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle

Long-Lasting Effects of GSPE on Ileal GLP-1R Gene Expression Are Associated with a Hypomethylation of the GLP-1R Promoter in Female Wistar Rats

Flavonoids have been shown to modulate GLP-1 in obesity. GLP-1 induces some of its effects through the intestinal GLP-1 receptor (GLP-1R), though no data exist on how flavonoids affect this receptor. Here, we examine how a dose of grape seed proanthocyanidin extract (GSPE) with anti-obesity activity affects intestinal GLP-1R and analyze whether epigenetics play a role in the long-lasting effects of GSPE. We found that 10-day GSPE administration prior to the cafeteria diet upregulated GLP-1R mRNA in the ileum 17 weeks after the GSPE treatment. This was associated with a hypomethylation of the GLP-1R promoter near the region where the SP1 transcription factor binds. In the colon, the cafeteria diet upregulated GLP-1R without showing any GSPE effect. In conclusion, we have identified long-lasting GSPE effects on GLP-1R gene expression in the ileum that are partly mediated by hypomethylation at the gene promoter and may affect the SP1 binding factor