Beneficial Effects of Proanthocyanidins on Intestinal Permeability and Its Relationship with Inflammation

The intestinal barrier is constantly exposed to potentially harmful environmental factors including food components and bacterial endotoxins. When the intestinal barrier function and immune homeostasis are compromised, inflammatory conditions may be developed and impact overall health. Evidence from experimental animal and cell-culture studies suggests that exposure of intestinal mucosa to proanthocyanidin-rich plant products may contribute to maintain the barrier function and to ameliorate the inflammation present in prevalent pathologies such as diet-induced obesity and inflammatory bowel disease. In this review, we aim to update the current knowledge on the bioactivity of PACs in experimental models of altered intestinal permeability and in humans, emphasizing the beneficial effects of grape-seed proanthocyanidin extracts in intestinal health and giving insights into the subjacent biochemical and molecular mechanism

Modulation of food intake by differential TAS2R stimulation in rat

Metabolic surgery modulates the enterohormone profile, which leads, among other effects, to changes in food intake. Bitter taste receptors (TAS2Rs) have been identified in the gastrointestinal tract and specific stimulation of these has been linked to the control of ghrelin secretion. We hypothesize that optimal stimulation of TAS2Rs could help to modulate enteroendocrine secretions and thus regulate food intake. To determine this, we have assayed the response to specific agonists for hTAS2R5, hTAS2R14 and hTAS2R39 on enteroendocrine secretions from intestinal segments and food intake in rats. We found that hTAS2R5 agonists stimulate glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), and reduce food intake. hTAS2R14 agonists induce GLP1, while hTASR39 agonists tend to increase peptide YY (PYY) but fail to reduce food intake. The effect of simultaneously activating several receptors is heterogeneous depending on the relative affinity of the agonists for each receptor. Although detailed mechanisms are not clear, bitter compounds can stimulate differentially enteroendocrine secretions that modulate food intake in rats

Impact of Proanthocyanidins on Intestinal Dysfunction Induced by Nutritional or Chemical Agents

El tracte intestinal és un lloc d'interacció amb microorganismes i factors ambientals potencialment nocius. En aquest sentit, un alt consum de components majoritaris de la dieta occidental com la fructosa i els greixos saturats s'ha associat amb la disfunció intestinal (disrupció de la funció de barrera i inflamació) i l'entrada d'endotoxines bacterianes amb efecte proinflamatori en la circulació. Addicionalment, una alta concentració d'endotoxina en plasma (endotoxemia metabòlica) es vincula amb la síndrome metabòlica. Així, l'intestí està emergint com un blanc terapèutic per a la prevenció i tractament de malalties. Les proantocianidines (PACs) són compostos fenòlics naturals amb potent efecte antiinflamatori en la mucosa intestinal d'acord amb evidència preclínica. Per tant, l'administració de PACs és prometedora com a estratègia terapèutica complementària, però la seva eficàcia s'ha de confirmar en humans. El principal objectiu de la present tesi doctoral va ser avaluar l'impacte d'un extracte de PACs de la pinyol de raïm (GSPE) en models preclínics de disfunció intestinal i explorar la seva efectivitat en l'humà. Trobem que una dieta estil occidental (dieta de cafeteria) indueix disfunció intestinal en rates i que l'alteració de permeabilitat al còlon contribueix en gran mesura a la endotoxemia metabòlica. Aquests efectes van ser atribuïts parcialment a altes concentracions luminals de fructosa i van poder ser revertits amb dosis farmacològiques de GSPE in vivo. Finalment, contrastem aquests resultats amb evidència derivada d'un model humà ex vivo de disfunció colònica. En aquest model vam poder replicar la reducció de permeabilitat i la millora de l'estat inflamatori reportats in vivo. En conclusió, l'administració de GSPE pot millorar la disfunció intestinal i la endotoxemia metabòlica associada. Les dosis efectives en humans són probablement farmacològiques i hauran de ser establertes en estudis clínics posteriors.El tracto intestinal es un sitio de interacción con microorganismos y factores ambientales potencialmente dañinos. En este sentido, un alto consumo de componentes mayoritarios de la dieta occidental como la fructosa y las grasas saturadas se ha asociado con la disfunción intestinal (disrupción de la función de barrera e inflamación) y la entrada de endotoxinas bacterianas con efecto proinflamatorio en la circulación. Adicionalmente, una alta concentración de endotoxina en plasma (endotoxemia metabólica) se vincula con el síndrome metabólico. Así, el intestino está emergiendo como un blanco terapéutico para la prevención y tratamiento de enfermedades. Las proantocianidinas (PACs) son compuestos fenólicos naturales con potente efecto antiinflamatorio en la mucosa intestinal, de acuerdo con evidencia preclínica. Por consiguiente, la administración de PACs es prometedora como estrategia terapéutica complementaria, pero su eficacia debe ser confirmada en humanos. El principal objetivo de la presente tesis doctoral fue evaluar el impacto de un extracto de PACs de la pepita de uva (GSPE) en modelos preclínicos de disfunción intestinal y explorar su efectividad en el humano. Encontramos que una dieta estilo occidental (dieta de cafetería) induce disfunción intestinal en ratas y que la alteración de permeabilidad en el colon contribuye en gran medida a la endotoxemia metabólica. Estos efectos fueron atribuidos parcialmente a altas concentraciones luminales de fructosa y pudieron ser revertidos con dosis farmacológicas de GSPE in vivo. Por último, contrastamos estos resultados con evidencia derivada de un modelo humano ex vivo de disfunción colónica. En este modelo pudimos replicar la reducción de permeabilidad y el mejoramiento del estado inflamatorio reportados in vivo. En conclusión, la administración de GSPE puede mejorar la disfunción intestinal y la endotoxemia metabólica asociada. Las dosis efectivas en humanos son probablemente farmacológicas y tendrán que ser establecidas en estudios clínicos posteriores.The intestinal tract is a site of interaction with microorganisms and potentially detrimental environmental factors. The high intake of fructose and saturated fats typical of the Western diet has been associated with intestinal dysfunction (disruption of barrier function and inflammation) and an increased influx of proinflammatory bacterial endotoxins into the systemic circulation. In turn, high concentrations of plasma endotoxins (metabolic endotoxemia) are a precursor to the onset of metabolic syndrome. In view of the above, the intestine is emerging as a target for disease prevention and therapy. Proanthocyanins (PACs) are naturally occurring phenolic compounds with remarkable anti-inflammatory properties in the intestinal mucosa, according to preclinical studies. Thus, PAC administration is a promising adjunctive therapeutic strategy for the treatment of intestinal dysfunction, but its efficacy in humans is yet to be confirmed. The main objective of this doctoral thesis was to evaluate the impact of a grape-seed PAC extract (GSPE) on a rat and cell culture-based model of intestinal dysfunction and to investigate its effectiveness in humans. We found that a long-term Western-style diet (cafeteria diet) induces intestinal dysfunction in rats, and that alterations in the permeability of the colon largely contribute to metabolic endotoxemia. These effects are partially driven by high luminal concentrations of fructose and could be effectively reversed in vivo by pharmacological doses of GSPE. Lastly, we compared these findings with evidence derived from an ex vivo human model of chemically-induced colonic dysfunction in which we were able to replicate the reduction of intestinal permeability and the amelioration of inflammatory status by means of GSPE found in vivo. In conclusion, the administration of GSPE results in the overall improvement of intestinal dysfunction and associated metabolic endotoxemia. Effective doses in humans are probably pharmacological and will have to be determined in clinical trials

Impact of Proanthocyanidins on Intestinal Dysfunction Induced by Nutritional or Chemical Agents

El tracte intestinal és un lloc d'interacció amb microorganismes i factors ambientals potencialment nocius. En aquest sentit, un alt consum de components majoritaris de la dieta occidental com la fructosa i els greixos saturats s'ha associat amb la disfunció intestinal (disrupció de la funció de barrera i inflamació) i l'entrada d'endotoxines bacterianes amb efecte proinflamatori en la circulació. Addicionalment, una alta concentració d'endotoxina en plasma (endotoxemia metabòlica) es vincula amb la síndrome metabòlica. Així, l'intestí està emergint com un blanc terapèutic per a la prevenció i tractament de malalties. Les proantocianidines (PACs) són compostos fenòlics naturals amb potent efecte antiinflamatori en la mucosa intestinal d'acord amb evidència preclínica. Per tant, l'administració de PACs és prometedora com a estratègia terapèutica complementària, però la seva eficàcia s'ha de confirmar en humans. El principal objectiu de la present tesi doctoral va ser avaluar l'impacte d'un extracte de PACs de la pinyol de raïm (GSPE) en models preclínics de disfunció intestinal i explorar la seva efectivitat en l'humà. Trobem que una dieta estil occidental (dieta de cafeteria) indueix disfunció intestinal en rates i que l'alteració de permeabilitat al còlon contribueix en gran mesura a la endotoxemia metabòlica. Aquests efectes van ser atribuïts parcialment a altes concentracions luminals de fructosa i van poder ser revertits amb dosis farmacològiques de GSPE in vivo. Finalment, contrastem aquests resultats amb evidència derivada d'un model humà ex vivo de disfunció colònica. En aquest model vam poder replicar la reducció de permeabilitat i la millora de l'estat inflamatori reportats in vivo. En conclusió, l'administració de GSPE pot millorar la disfunció intestinal i la endotoxemia metabòlica associada. Les dosis efectives en humans són probablement farmacològiques i hauran de ser establertes en estudis clínics posteriors.El tracto intestinal es un sitio de interacción con microorganismos y factores ambientales potencialmente dañinos. En este sentido, un alto consumo de componentes mayoritarios de la dieta occidental como la fructosa y las grasas saturadas se ha asociado con la disfunción intestinal (disrupción de la función de barrera e inflamación) y la entrada de endotoxinas bacterianas con efecto proinflamatorio en la circulación. Adicionalmente, una alta concentración de endotoxina en plasma (endotoxemia metabólica) se vincula con el síndrome metabólico. Así, el intestino está emergiendo como un blanco terapéutico para la prevención y tratamiento de enfermedades. Las proantocianidinas (PACs) son compuestos fenólicos naturales con potente efecto antiinflamatorio en la mucosa intestinal, de acuerdo con evidencia preclínica. Por consiguiente, la administración de PACs es prometedora como estrategia terapéutica complementaria, pero su eficacia debe ser confirmada en humanos. El principal objetivo de la presente tesis doctoral fue evaluar el impacto de un extracto de PACs de la pepita de uva (GSPE) en modelos preclínicos de disfunción intestinal y explorar su efectividad en el humano. Encontramos que una dieta estilo occidental (dieta de cafetería) induce disfunción intestinal en ratas y que la alteración de permeabilidad en el colon contribuye en gran medida a la endotoxemia metabólica. Estos efectos fueron atribuidos parcialmente a altas concentraciones luminales de fructosa y pudieron ser revertidos con dosis farmacológicas de GSPE in vivo. Por último, contrastamos estos resultados con evidencia derivada de un modelo humano ex vivo de disfunción colónica. En este modelo pudimos replicar la reducción de permeabilidad y el mejoramiento del estado inflamatorio reportados in vivo. En conclusión, la administración de GSPE puede mejorar la disfunción intestinal y la endotoxemia metabólica asociada. Las dosis efectivas en humanos son probablemente farmacológicas y tendrán que ser establecidas en estudios clínicos posteriores.The intestinal tract is a site of interaction with microorganisms and potentially detrimental environmental factors. The high intake of fructose and saturated fats typical of the Western diet has been associated with intestinal dysfunction (disruption of barrier function and inflammation) and an increased influx of proinflammatory bacterial endotoxins into the systemic circulation. In turn, high concentrations of plasma endotoxins (metabolic endotoxemia) are a precursor to the onset of metabolic syndrome. In view of the above, the intestine is emerging as a target for disease prevention and therapy. Proanthocyanins (PACs) are naturally occurring phenolic compounds with remarkable anti-inflammatory properties in the intestinal mucosa, according to preclinical studies. Thus, PAC administration is a promising adjunctive therapeutic strategy for the treatment of intestinal dysfunction, but its efficacy in humans is yet to be confirmed. The main objective of this doctoral thesis was to evaluate the impact of a grape-seed PAC extract (GSPE) on a rat and cell culture-based model of intestinal dysfunction and to investigate its effectiveness in humans. We found that a long-term Western-style diet (cafeteria diet) induces intestinal dysfunction in rats, and that alterations in the permeability of the colon largely contribute to metabolic endotoxemia. These effects are partially driven by high luminal concentrations of fructose and could be effectively reversed in vivo by pharmacological doses of GSPE. Lastly, we compared these findings with evidence derived from an ex vivo human model of chemically-induced colonic dysfunction in which we were able to replicate the reduction of intestinal permeability and the amelioration of inflammatory status by means of GSPE found in vivo. In conclusion, the administration of GSPE results in the overall improvement of intestinal dysfunction and associated metabolic endotoxemia. Effective doses in humans are probably pharmacological and will have to be determined in clinical trials

Health-Promoting Properties of Proanthocyanidins for Intestinal Dysfunction

The intestinal barrier is constantly exposed to potentially harmful environmental factors, including food components and bacterial endotoxins. When intestinal barrier function and immune homeostasis are compromised (intestinal dysfunction), inflammatory conditions may develop and impact overall health. Evidence from experimental animal and cell culture studies suggests that exposure of intestinal mucosa to proanthocyanidin (PAC)-rich plant products, such as grape seeds, may contribute to maintaining the barrier function and to ameliorating the pathological inflammation present in diet-induced obesity and inflammatory bowel disease. In this review, we aim to update the current knowledge on the bioactivity of PACs in experimental models of intestinal dysfunction and in humans, and to provide insights into the underlying biochemical and molecular mechanisms

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

GLP1 Exerts Paracrine Activity in the Intestinal Lumen of Human Colon

GLP1 produced in the upper part of the gut is released after food intake and acts by activating insulin secretion, but the role of GLP1 in the colon, where it is predominantly produced, remains unknown. Here we characterized the apical versus basolateral secretion of GLP1 and PYY and the paracrine mechanisms of action of these enterohormones in the human colon. We stimulated human colon tissue in different ex vivo models with meat peptone and we used immunofluorescence to study the presence of canonical and non-canonical receptors of GLP1. We found that PYY and GLP1 are secreted mainly at the gut lumen in unstimulated and stimulated conditions. We detected DPP4 activity and found that GLP1R and GCGR are widely expressed in the human colon epithelium. Unlike GLP1R, GCGR is not expressed in the lamina propria, but it is located in the crypts of Lieberkühn. We detected GLP1R expression in human colon cell culture models. We show that the apical secretion of PYY and GLP1 occurs in humans, and we provide evidence that GLP1 has a potential direct paracrine function through the expression of its receptors in the colon epithelium, opening new therapeutic perspectives in the use of enterohormones analogues in metabolic pathologies

GLP1 Exerts Paracrine Activity in the Intestinal Lumen of Human Colon

GLP1 produced in the upper part of the gut is released after food intake and acts by activating insulin secretion, but the role of GLP1 in the colon, where it is predominantly produced, remains unknown. Here we characterized the apical versus basolateral secretion of GLP1 and PYY and the paracrine mechanisms of action of these enterohormones in the human colon. We stimulated human colon tissue in different ex vivo models with meat peptone and we used immunofluorescence to study the presence of canonical and non-canonical receptors of GLP1. We found that PYY and GLP1 are secreted mainly at the gut lumen in unstimulated and stimulated conditions. We detected DPP4 activity and found that GLP1R and GCGR are widely expressed in the human colon epithelium. Unlike GLP1R, GCGR is not expressed in the lamina propria, but it is located in the crypts of Lieberkühn. We detected GLP1R expression in human colon cell culture models. We show that the apical secretion of PYY and GLP1 occurs in humans, and we provide evidence that GLP1 has a potential direct paracrine function through the expression of its receptors in the colon epithelium, opening new therapeutic perspectives in the use of enterohormones analogues in metabolic pathologies