Barbara D Pachikian

Catholic University of Louvain, Walloon Region, Belgium

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Publications (14)40.77 Total impact

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    ABSTRACT: SCOPE: Recent data suggest that gut microbiota contributes to the regulation of host lipid metabolism. We report how fermentable dietary fructo-oligosaccharides (FOS) control hepatic steatosis induced by n-3 PUFA depletion, which leads to hepatic alterations similar to those observed in non-alcoholic fatty liver disease patients. METHODS AND RESULTS: C57Bl/6J mice fed an n-3 PUFA-depleted diet for 3 months were supplemented with FOS during the last 10 days of treatment. FOS-treated mice exhibited higher caecal Bifidobacterium spp. and lower Roseburia spp. content. Microarray analysis of hepatic mRNA revealed that FOS supplementation reduced hepatic triglyceride accumulation through a proliferator-activated receptor α-stimulation of fatty acid oxidation and lessened cholesterol accumulation by inhibiting sterol regulatory element binding protein 2-dependent cholesterol synthesis. Cultured precision-cut liver slices confirmed the inhibition of fatty acid oxidation. FOS effects were related to a decreased hepatic micro-RNA33 expression and to an increased colonic glucagon-like peptide 1 production. CONCLUSIONS: The changes in gut microbiota composition by n-3 PUFA-depletion and prebiotics modulate hepatic steatosis by changing gene expression in the liver, a phenomenon that could implicate micro-RNA and gut-derived hormones. Our data underline the advantage of targeting the gut microbiota by colonic nutrients in the management of liver disease.
    Molecular Nutrition & Food Research 12/2012; · 4.31 Impact Factor
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    ABSTRACT: The gut microbiota has recently been proposed as a novel component in the regulation of host homeostasis and immunity. We have assessed for the first time the role of the gut microbiota in a mouse model of leukemia (transplantation of BaF3 cells containing ectopic expression of Bcr-Abl), characterized at the final stage by a loss of fat mass, muscle atrophy, anorexia and inflammation. The gut microbial 16S rDNA analysis, using PCR-Denaturating Gradient Gel Electrophoresis and quantitative PCR, reveals a dysbiosis and a selective modulation of Lactobacillus spp. (decrease of L. reuteri and L. johnsonii/gasseri in favor of L. murinus/animalis) in the BaF3 mice compared to the controls. The restoration of Lactobacillus species by oral supplementation with L. reuteri 100-23 and L. gasseri 311476 reduced the expression of atrophy markers (Atrogin-1, MuRF1, LC3, Cathepsin L) in the gastrocnemius and in the tibialis, a phenomenon correlated with a decrease of inflammatory cytokines (interleukin-6, monocyte chemoattractant protein-1, interleukin-4, granulocyte colony-stimulating factor, quantified by multiplex immuno-assay). These positive effects are strain- and/or species-specific since L. acidophilus NCFM supplementation does not impact on muscle atrophy markers and systemic inflammation. Altogether, these results suggest that the gut microbiota could constitute a novel therapeutic target in the management of leukemia-associated inflammation and related disorders in the muscle.
    PLoS ONE 01/2012; 7(6):e37971. · 3.53 Impact Factor
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    ABSTRACT: BACKROUND: Western diet is characterized by an insufficient n-3 polyunsaturated fatty acid (PUFA) consumption which is known to promote the pathogenesis of several diseases. We have previously observed that mice fed with a diet poor in n-3 PUFA for two generations exhibit hepatic steatosis together with a decrease in body weight. The gut microbiota contributes to the regulation of host energy metabolism, due to symbiotic relationship with fermentable nutrients provided in the diet. In this study, we have tested the hypothesis that perturbations of the gut microbiota contribute to the metabolic alterations occurring in mice fed a diet poor in n-3 PUFA for two generations (n-3/- mice). C57Bl/6J mice fed with a control or an n-3 PUFA depleted diet for two generations were supplemented with prebiotic (inulin-type Fructooligosaccharides, FOS, 0.20 g/day/mice) during 24 days. n-3/-mice exhibited a marked drop in caecum weight, a decrease in lactobacilli and an increase in bifidobacteria in the caecal content as compared to control mice (n-3/+ mice). Dietary supplementation with FOS for 24 days was sufficient to increase caecal weight and bifidobacteria count in both n-3/+ and n-3/-mice. Moreover, FOS increased lactobacilli content in n-3/-mice, whereas it decreased their level in n-3/+ mice. Interestingly, FOS treatment promoted body weight gain in n-3/-mice by increasing energy efficiency. In addition, FOS treatment decreased fasting glycemia and lowered the higher expression of key factors involved in the fatty acid catabolism observed in the liver of n-3/-mice, without lessening steatosis. the changes in the gut microbiota composition induced by FOS are different depending on the type of diet. We show that FOS may promote lactobacilli and counteract the catabolic status induced by n-3 PUFA depletion in mice, thereby contributing to restore efficient fat storage.
    Nutrition & Metabolism 06/2011; 8(1):44. · 3.16 Impact Factor
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    ABSTRACT: Patients with non-alcoholic fatty liver disease are characterised by a decreased n-3/n-6 polyunsaturated fatty acid (PUFA) ratio in hepatic phospholipids. The metabolic consequences of n-3 PUFA depletion in the liver are poorly understood. We have reproduced a drastic drop in n-3 PUFA among hepatic phospholipids by feeding C57Bl/6J mice for 3 months with an n-3 PUFA depleted diet (DEF) versus a control diet (CT), which only differed in the PUFA content. DEF mice exhibited hepatic insulin resistance (assessed by euglycemic-hyperinsulinemic clamp) and steatosis that was associated with a decrease in fatty acid oxidation and occurred despite a higher capacity for triglyceride secretion. Microarray and qPCR analysis of the liver tissue revealed higher expression of all the enzymes involved in lipogenesis in DEF mice compared to CT mice, as well as increased expression and activation of sterol regulatory element binding protein-1c (SREBP-1c). Our data suggest that the activation of the liver X receptor pathway is involved in the overexpression of SREBP-1c, and this phenomenon cannot be attributed to insulin or to endoplasmic reticulum stress responses. In conclusion, n-3 PUFA depletion in liver phospholipids leads to activation of SREBP-1c and lipogenesis, which contributes to hepatic steatosis.
    PLoS ONE 01/2011; 6(8):e23365. · 3.53 Impact Factor
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    ABSTRACT: Inulin-type fructans (ITF) are nondigestible/fermentable carbohydrates which are able - through the modification of the gut microbiota - to counteract high-fat (HF) diet-induced obesity, endotoxemia and related-metabolic alterations. However, their influence on adipose tissue metabolism has been poorly studied until now. The aim of this study was to assess the influence of ITF supplementation on adipose tissue metabolism, by focusing on a G protein-coupled receptor (GPR), GPR43, as a potential link between gut fermentation processes and white adipose tissue development. Male C57bl6/J mice were fed a standard diet or an HF diet without or with ITF (0.2 g/day per mouse) during 4 weeks. The HF diet induced an accumulation of large adipocytes, promoted peroxisome proliferator activated receptor gamma (PPARγ)-activated differentiation factors and led to a huge increase in GPR43 expression in the subcutaneous adipose tissue. All those effects were blunted by ITF treatment, which modulated the gut microbiota in favor of bifidobacteria at the expense of Roseburia spp. and of Clostridium cluster XIVa. The dietary modulation of GPR43 expression seems independent of endotoxemia, in view of data obtained in vivo (acute and chronic lipopolysaccharides treatment). In conclusion, ITF, which promote gut fermentation, paradoxically counteract GPR43 overexpression induced in the adipose tissue by an HF diet, a phenomenon that correlates with a beneficial effect on adiposity and with potential decrease in PPARγ-activated processes.
    The Journal of nutritional biochemistry 11/2010; 22(8):712-22. · 4.29 Impact Factor
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    ABSTRACT: Introduction Les acides gras polyinsaturés (AGPI) n-3 jouent un rôle important sur le métabolisme lipidique de part leur capacité à stimuler la β-oxydation et à diminuer la lipogenèse. Une augmentation du ratio n-6/n-3 est observée dans les phospholipides du foie de patientes atteintes de stéatose hépatique non alcoolique. L’implication d’une diminution en AGPI n-3 dans l’accumulation de lipides au niveau du foie a été peu étudié jusqu’à ce jour. Cette étude a pour but d’explorer le mécanisme impliqué dans l’accumulation des triglycérides dans le foie chez la souris carencée en AGPI n-3. Matériels et Méthodes 24 souris mâles C57Bl6J ont été nourries avec une diète contrôle (n-6/n-3 = 6,9) ou une diète carencée en AGPI n-3 (n-6/n-3 = 120) durant 3 mois. Résultats La carence en n-3 induit une accumulation de lipides dans le foie (triglycéride et cholestérol). L’incubation de tranches de foie en présence de 14C-acetate et de 14C-palmitate a révélé une augmentation de la synthèse et de l’estérification des acides gras dans le foie des souris carencées. La sécrétion hépatique de triglycérides, évaluée par inhibition de la lipoprotéine lipase, est également augmentée chez les souris carencées. Les analyses microarrays démontrent, dans le foie des souris carencées, une augmentation de l’expression de toutes les enzymes impliquées dans la lipogenèse et de SREBP-1c, un facteur de transcription clé dans le contrôle de leur expression. L’augmentation de l’expression de SREBP-1c ne peut pas être expliquée par une augmentation de l’insulinémie, mais pourrait être tributaire de l’activation de LXR (augmentation de l’expression d’ABCA1) et/ou du stress du réticulum (augmentation de la protéine d’IRE1α). Conclusion La carence en AGPI n-3 provoque une accumulation de lipides dans le foie suite à une stimulation de la lipogenèse. SREBP-1c semble être un facteur clé dans cette activation de la voie lipogénique et l’augmentation de son expression pourrait dépendre de la stimulation de l’activité de LXR ou d’un stress du réticulum.
    Diabetes & Metabolism 03/2010; 36. · 2.39 Impact Factor
  • Diabetes & Metabolism 03/2010; 36. · 2.39 Impact Factor
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    ABSTRACT: Magnesium (Mg) deficiency is a common nutritional disorder that is linked to an inflammatory state characterized by increased plasma acute phase protein and proinflammatory cytokine concentrations. Recent studies have shown that changes in the composition of gut microbiota composition participate in systemic inflammation. In this study, therefore, we assessed the potential role of gut microbiota in intestinal and systemic inflammation associated with Mg deficiency in mice. For this purpose, mice were fed a control or Mg-deficient diet (500 mg vs. 70 mg Mg/kg) for 4 or 21 d. Compared with the mice fed the control diet, mice fed the Mg-deficient diet for 4 d had a lower gut bifidobacteria content (-1.5 log), a 36-50% lower mRNA content of factors controlling gut barrier function in the ileum (zonula occludens-1, occludin, proglucagon), and a higher mRNA content (by approximately 2-fold) in the liver and/or intestine of tumor necrosis factor-alpha, interleukin-6, CCAAT/enhancer binding protein homologous protein, and activating transcription factor 4, reflecting inflammatory and cellular stress. In contrast, mice fed the Mg-deficient diet for 21 d had a higher cecal bifidobacteria content compared with the control group, a phenomenon accompanied by restoration of the intestinal barrier and the absence of inflammation. In conclusion, we show that Mg deficiency, independently of any other changes in nutrient intake, modulates the concentration of bifidobacteria in the gut, a phenomenon that may time-dependently affect inflammation and metabolic disorders in mice.
    Journal of Nutrition 03/2010; 140(3):509-14. · 4.20 Impact Factor
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    ABSTRACT: We have previously shown that gut microbial fermentation of prebiotics promotes satiety and lowers hunger and energy intake in humans. In rodents, these effects are associated with an increase in plasma gut peptide concentrations, which are involved in appetite regulation and glucose homeostasis. Our aim was to examine the effects of prebiotic supplementation on satiety and related hormones during a test meal for human volunteers by using a noninvasive micromethod for blood sampling to measure plasma gut peptide concentrations. This study was a randomized, double-blind, parallel, placebo-controlled trial. A total of 10 healthy adults (5 men and 5 women) were randomly assigned to groups that received either 16 g prebiotics/d or 16 g dextrin maltose/d for 2 wk. Meal tolerance tests were performed in the morning to measure the following: hydrogen breath test, satiety, glucose homeostasis, and related hormone response. We show that the prebiotic treatment increased breath-hydrogen excretion (a marker of gut microbiota fermentation) by approximately 3-fold and lowered hunger rates. Prebiotics increased plasma glucagon-like peptide 1 and peptide YY concentrations, whereas postprandial plasma glucose responses decreased after the standardized meal. The areas under the curve for plasma glucagon-like peptide 1 and breath-hydrogen excretion measured after the meal (0-60 min) were significantly correlated (r = 0.85, P = 0.007). The glucose response was inversely correlated with the breath-hydrogen excretion areas under the curve (0-180 min; r = -0.73, P = 0.02). Prebiotic supplementation was associated with an increase in plasma gut peptide concentrations (glucagon-like peptide 1 and peptide YY), which may contribute in part to changes in appetite sensation and glucose excursion responses after a meal in healthy subjects.
    American Journal of Clinical Nutrition 09/2009; 90(5):1236-43. · 6.50 Impact Factor
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    ABSTRACT: Diabetes and obesity are metabolic disorders induced by an excessive dietary intake of fat, usually related to inflammation and oxidative stress. The aim of the study is to investigate the effect of the antioxidant coenzyme Q10 (CoQ10) on hepatic metabolic and inflammatory disorders associated with diet-induced obesity and glucose intolerance. C57bl6/j mice were fed for 8 weeks, either a control diet (CT) or a high-fat diet plus 21% fructose in the drinking water (HFF). CoQ10 supplementation was performed in this later condition (HFFQ). HFF mice exhibit increased energy consumption, fat mass development, fasting glycaemia and insulinemia and impaired glucose tolerance. HFF treatment promoted the expression of genes involved in reactive oxygen species production (NADPH oxidase), inflammation (CRP, STAMP2) and metabolism (CPT1alpha) in the liver. CoQ10 supplementation decreased the global hepatic mRNA expression of inflammatory and metabolic stresses markers without changing obesity and tissue lipid peroxides compared to HFF mice. HFF diets paradoxically decreased TBARS (reflecting lipid peroxides) levels in liver, muscle and adipose tissue versus CT group, an effect related to vitamin E content of the diet. In conclusion, HFF model promotes glucose intolerance and obesity by a mechanism independent on the level of tissue peroxides. CoQ10 tends to decrease hepatic stress gene expression, independently of any modulation of lipid peroxidation, which is classically considered as its most relevant effect.
    Biochemical pharmacology 08/2009; 78(11):1391-400. · 4.25 Impact Factor
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    ABSTRACT: Recent data reported that chitosan reduces high-fat (HF) diet-induced obesity in mice without describing the metabolic consequences of such an effect. The aim of this study was to investigate the capacity of chitosan derived from edible mushrooms to modify adipocytokine levels and to assess the relevance of this effect on the development of fat mass, and on glucose and lipid metabolism in obese mice. Mice were fed a HF diet or a HF diet supplemented with 5% fungal chitosan for ten weeks. HF-induced hypertriglyceridaemia, fasting hyperinsulinaemia and fat accumulation in liver, muscle and white adipose tissue (WAT) were reduced after chitosan treatment. The higher lipid content in the caecum following treatment with chitosan suggested that this dietary fiber reduced lipid absorption. We postulated that the lower triglyceridaemia observed upon chitosan treatment could also be the result of the lower FIAF (fasting-induced adipose factor) expression observed in visceral adipose tissue. IL-6, resistin and leptin levels decreased in the serum after chitosan supplementation. We conclude that fungal chitosan counteracts some inflammatory disorders and metabolic alterations occurring in diet-induced obese mice since it decreases feed efficiency, fat mass, adipocytokine secretion and ectopic fat deposition in the liver and the muscle.
    International immunopharmacology 04/2009; 9(6):767-73. · 2.21 Impact Factor
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    ABSTRACT: There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic metabolism. n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol) as well as an increase in hepatic cholesteryl ester and triglycerides content. Fatty acid pattern is profoundly modified in hepatic phospholipids and triglycerides. The decrease in tissue n-3/n-6 PUFA ratio correlates with steatosis. Hepatic mRNA content of key factors involved in lipid metabolism suggest a decreased lipogenesis (SREBP-1c, FAS, PPAR gamma), and an increased beta-oxidation (CPT1, PPAR alpha and PGC1 alpha) without modification of fatty acid esterification (DGAT2, GPAT1), secretion (MTTP) or intracellular transport (L-FABP). Histological analysis reveals alterations of liver morphology, which can not be explained by inflammatory or oxidative stress. However, several proteins involved in the unfolded protein response are decreased in depleted mice. n-3 PUFA depletion leads to important metabolic alterations in murine liver. Steatosis occurs through a mechanism independent of the shift between beta-oxidation and lipogenesis. Moreover, long term n-3 PUFA depletion decreases the expression of factors involved in the unfolded protein response, suggesting a lower protection against endoplasmic reticulum stress in hepatocytes upon n-3 PUFA deficiency.
    BMC Physiology 01/2009; 8:21.
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    ABSTRACT: Introduction Les acides gras polyinsaturés n-3 et n-6 présentent des effets importants dans la régulation du métabolisme lipidique (modulation de l’expression de gènes clés impliqués dans la synthèse, la dégradation et l’export d’acides gras). Cette étude analyse l’influence d’une carence alimentaire en acides gras n-3 polyinsaturés instaurée sur deux générations sur le métabolisme hépatique de la souris. Résultats La carence en n-3 entraîne une diminution significative du poids corporel, hépatique et splénique, malgré une consommation calorique similaire. Ces souris développent une hyperglycémie à jeun et une hyperinsulinémie 15 min après une charge orale en glucose, sans amélioration de la réponse glycémique, signant une résistance à l’insuline. Outre les altérations du métabolisme glucidique, la carence en acides gras n-3 induit de nombreux désordres du métabolisme lipidique. En effet, les souris carencées en n-3 sont hypercholestérolémiques (cholestérol total, LDL et HDL) et développent une stéatose hépatique macrovésiculaire associée à une déplétion en n-3 dans les triglycérides et les phospholipides tissulaires. De plus, l’analyse histologique du foie révèle de nombreuses cellules apoptotiques disséminées dans tout le parenchyme. Les ARNm de facteurs clés impliqués dans le métabolisme lipidique du foie révèlent que ces souris ont une lipogenèse diminuée (SREBP1c, FAS, PPARGGG), une β-oxydation accrue (PPARα, CPT1, PGC1α), une sécrétion des triglycérides (MTTP) et une activité de la lipoprotéine lipase (FIAF) non altérées. Curieusement, les souris carencées en n-3 présentent une diminution du contenu hépatique en substances réactives à l’acide thiobarbiturique et une expression du gène de la NADPH oxydase normale, suggérant que le stress oxydatif ne serait pas impliqué dans les effets métaboliques observés. Conclusion La carence en n-3 génère des altérations métaboliques importantes dans le foie des souris, qui promeut la stéatose par des mécanismes indépendants du shift entre β-oxydation et lipogenèse. Plusieurs pistes sont encore à explorer pour élucider les mécanismes moléculaires et cellulaires impliqués dans le phénotype hépatique (stress du réticulum, stress mitochondrial…).
    Diabetes & Metabolism - DIABETES METAB. 01/2008; 34.
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    ABSTRACT: Introduction Une diminution du rapport d’acides gras polyinsaturés n-3/n-6 est observée dans les phospholipides du foie de patients atteints de stéatose hépatique non-alcoolique. Une supplémentation avec l’oligofructose (OFS), un modulateur du microbiote intestinal, réduit la stéatose dans de nombreux modèles d’obésité. Le but de cette étude est d’analyser le lien entre une modification du microbiote intestinale et la stéatose hépatique induite par une déplétion en AGPI n-3. Matériels et méthodes Des souris C57Bl6J mâles ont été nourries avec une diète contrôle (n-3/n-6 = 0,145) ou une diète carencée en AGPI n-3 (n-3/n-6 = 0,008) durant 3 mois. Dix jours avant la fin du traitement, un groupe de souris déficientes a été supplémenté avec de l’OFS (0,25 g/jour). Résultats Les souris carencées en AGPI n-3 présentent une accumulation de triglycéride et de cholestérol estérifié dans le foie, contrée par l’OFS. L’analyse microarray du tissu hépatique révèle que l’OFS stimule la voie d’oxydation des acides gras, via une activation de PPARα, et inhibe la synthèse hépatique du cholestérol, un phénomène lié à l’inhibition de SREBP-2 (confirmée par western blot), sans affecter l’activité métabolique SREBP-1c dépendante. La supplémentation avec l’OFS modifie la composition de la flore intestinale caractérisée par une augmentation du niveau de bifidobactéries et une diminution des roseburia. Conclusion Une supplémentation avec de l’OFS durant 10 jours est suffisante pour contrer l’induction de la synthèse de cholestérol et l’inhibition d’oxydation des acides gras, sans modifier le rapport d’acides gras polyinsaturés dans le tissu hépatique. Le profil de métabolites bactériens des acides gras polyinsaturés est modifié dans le foie après traitement à l’OFS, suggérant un lien métabolique entre le microbiote et les cibles de régulations de l’homéostasie énergétique de l’hôte.
    Diabetes & Metabolism. 38:A18.