La consommation excessive d’acide linoléique altère l’axe intestin - tissu adipeux - foie chez le rat defaçon différente selon la période et le temps d’exposition

National audienceIntroduction et but de l’étude : L’accroissement de la consommation en acide linoléique (LA) est une des caractéristiques des changements alimentaires des dernières décennies dans le monde occidental. L’objectif de notre étude était d’évaluer les effets de la consommation excessive de LA sur les relations entre microbiote, intestin et métabolisme lipidique après différents temps d’exposition aux régimes. Matériel et méthodes : Des rates Wistar ont été nourries avec des régimes isocaloriques et isolipidiques (21% des apports énergétiques totaux (AET)) riche en LA (w6, 12% AET) ou non (ctl, 2% AET) pendant la gestation/lactation. Au sevrage, les ratons mâles ont reçu le même régime que leur mère ou l’autre régime et ont été sacrifiés à 3 et 6 mois. Résultats et Analyse statistique : La consommation du régime w6 après le sevrage, quel que soit le régime maternel, induisait à 3 mois une augmentation de la perméabilité caecale (p=0.01), associée à une augmentation des taux plasmatiques d’IL-1β (p=0.004) et des concentrations hépatiques en CLA T10C12 (p=0.03). Une activation du système endocannabinoïde colique (diminution de l’expression des gènes dagla, p=0.008, et faah, p=0.04, augmentation de l’expression du gène cb1 , p=0.02) était également observée. Ces modifications n’étaient pas retrouvées après 6 mois de régime puisque les animaux w6 présentaient une diminution de l’index d’adiposité (p=0.03) et de la perméabilité caecale (p=0.01), une augmentation de l’activité de la phosphatase alcaline (IAP) colique (p=0.07), une diminution de l’expression des gènes tnfα dans le côlon (p=0.03) et mcp1 dans le tissu adipeux epididymal (TAep, p=0.04) Le système endocannabinoïde n’était plus affecté par le régime w6. Les concentrations hépatiques en T10C12 et en C9T11 étaient augmentées (pConclusion : L’exposition à un régime riche en LA après le sevrage affecte le métabolisme lipidique via des modifications de l’axe intestin-tissu adipeux, dont la production de CLA, qui différent à 3 et 6 mois d’âge. L’exposition au LA via le régime maternel induit des modifications de cet axe principalement à 3 mois et aboutit à long-terme à une stéatose hépatique chez les descendants

Excessive dietary linoleic acid induces proinflammatory markers in rat

Fautrel U991International audienceFollowing the historical dietary recommendations, the substitution of polyunsaturated fatty acids (PUFA) for saturated fatty acids (SFA) resulted in a dramatic increase of linoleic acid (LA) in the western diet. While pro-atherogenic properties of SFA have been described, the involvement of LA on the inflammatory process remains controversial. Herein, we evaluated the effects of an excessive LA intake on the cytokine-induced expression of endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1), through the nuclear factor (NF)-κB pathway, in comparison with a control diet and regarding a “positive” SFA-diet. Wistar rats were fed experimental diets: a control diet or diets enriched with LA or SFA for 11 weeks. Plasma lipid parameters and proinflammatory cytokine production such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α were analysed. Expression of endothelial adhesion molecules and NF-κB was determined by immunohistochemical analysis. No difference was observed in body weight. The enriched diets did not affect triglyceride and total cholesterol levels in plasma. Our results demonstrated that excessive dietary LA intake increased TNF-α levels (p<0.05) in plasma. Rats fed the LA-enriched diet showed a significant higher expression of VCAM-1, ICAM-1 and NF-κB in aortas. In addition, our results demonstrated that an excess of LA is more efficient to activate endothelial molecular process than an excess of SFA. The present study provides further support for the proinflammatory properties of LA and suggests a LA-derivatives pathway involved in the inflammatory proces

Interactive effects of maternal and weaning high linoleic acid intake on hepatic lipid metabolism, oxylipins profile and hepatic steatosis in offspring

International audienceNon-alcoholic fatty liver disease (NAFLD) has been described as a hepatic manifestation of the metabolic syndrome. When several studies correlated maternal linoleic acid (LA) intake with the development of obesity, only few links have been made between n-6 fatty acid (FA) and NAFLD. Herein, we investigated the influence of both maternal and weaning high LA intake on lipid metabolism and susceptibility to develop later metabolic diseases in offspring. Pregnant rats were fed a control-diet (2% LA) or a LA-rich diet (l2% LA) during gestation and lactation. At weaning, offspring was assigned to one of the two diets, i.e. either maintained on the same maternal diet or fed the other diet for six months. Physiological, biochemical parameters and hepatic FA metabolism were analyzed. We demonstrated that the interaction between the maternal and weaning LA intake altered metabolism in offspring and could lead to hepatic steatosis. This phenotype was associated with altered hepatic FA content and lipid metabolism. Interaction between maternal and weaning LA intake led to a specific pattern of n-6 and n-3 oxylipins that could participate to the development of hepatic steatosis in offspring. Our findings highlight the significant interaction between maternal and weaning high LA intake to predispose offspring to later metabolic disease and support the predictive adaptive response hypothesis

Maternal high dietary linoleic acid during gestation and lactation impairs rat offspring gut and metabolic homeostasis

International audienceLinoleic acid (LA) consumption has increased over the last decades. This polyunsaturated fatty acid (PUFA) can be metabolized in various bioactive molecules that might impact gut barrier function, gut microbiota and lipid metabolism. Our objective was to assess if dietary LA excessive consumption during gestation and lactation affect offspring gut ecology and barrier function and lipid metabolism in a rat model

Sciadonic acid derived from pine nuts as a food component to reduce plasma triglycerides by inhibiting the rat hepatic Δ9-desaturase

International audienceSciadonic acid (Scia) is a Δ5-olefinic fatty acid that is particularly abundant in edible pine seeds and that exhibits an unusual polymethylene-interrupted structure. Earlier studies suggested that Scia inhibited the in vitro expression and activity of the Stearoyl-CoA Desaturase 1 (SCD1), the hepatic Δ9-desaturase involved in the formation of mono-unsaturated fatty acids. To confirm this hypothesis, rats were given 10% Scia in diets balanced out with n-6 and n-3 fatty acids. In those animals receiving the Scia supplement, monoene synthesis in the liver was reduced, which was partly attributed to the inhibition of SCD1 expression. As a consequence, the presence of Scia induced a 50% decrease in triglycerides in blood plasma due to a reduced level of VLDL-secreted triglycerides from the liver. In non-fasting conditions, results showed that Scia-induced inhibition of SCD1 led to a decrease in the proportions of 161n-7 and 181n-7 in the liver without impacting on the level of 181n-9, suggesting that only triglycerides with neosynthesized monoenes are marked out for release. In conclusion, this in vivo study confirms that Scia highly inhibits SCD1 expression and activity. The work was performed on normo-triglyceride rats over six weeks, suggesting promising effects on hyper-triglyceridemic models

Programming of the microbiota-gut-adipose tissue axis by maternal dietary n-6 polyunsaturated fatty acid

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Maternal Linoleic Acid Overconsumption Alters Offspring Gut and Adipose Tissue Homeostasis in Young but Not Older Adult Rats.

Maternal -6 polyunsaturated fatty acids (PUFA) consumption during gestation and lactation can predispose offspring to the development of metabolic diseases such as obesity later in life. However, the mechanisms underlying the potential programming effect of -6 PUFA upon offspring physiology are not yet all established. Herein, we investigated the effects of maternal and weaning linoleic acid (LA)-rich diet interactions on gut intestinal and adipose tissue physiology in young (3-month-old) and older (6-month-old) adult offspring. Pregnant rats were fed a control diet (2% LA) or an LA-rich diet (12% LA) during gestation and lactation. At weaning, offspring were either maintained on the maternal diet or fed the other diet for 3 or 6 months. At 3 months of age, the maternal LA-diet favored low-grade inflammation and greater adiposity, while at 6 months of age, offspring intestinal barrier function, adipose tissue physiology and hepatic conjugated linoleic acids were strongly influenced by the weaning diet. The maternal LA-diet impacted offspring cecal microbiota diversity and composition at 3 months of age, but had only few remnant effects upon cecal microbiota composition at 6 months of age. Our study suggests that perinatal exposure to high LA levels induces a differential metabolic response to weaning diet exposure in adult life. This programming effect of a maternal LA-diet may be related to the alteration of offspring gut microbiota

Gut Microbiota Remodeling and Intestinal Adaptation to Lipid Malabsorption After Enteroendocrine Cell Loss in Adult MiceSummary

Background & Aims: Enteroendocrine cells (EECs) and their hormones are essential regulators of whole-body energy homeostasis. EECs sense luminal nutrients and microbial metabolites and subsequently secrete various hormones acting locally or at a distance. Impaired development of EECs during embryogenesis is life-threatening in newborn mice and humans due to compromised nutrient absorption. However, the physiological importance of the EEC system in adult mice has yet to be directedly studied. Herein, we aimed to determine the long-term consequences of a total loss of EECs in healthy adults on energy metabolism, intestinal transcriptome, and microbiota. Methods: We depleted intestinal EECs by tamoxifen treatment of adult Neurog3fl/fl; Villin-CreERT2 male mice. We studied intestinal cell differentiation, food efficiency, lipid absorption, microbiota composition, fecal metabolites, and transcriptomic responses in the proximal and distal small intestines of mice lacking EECs. We also determined the high-fat diet-induced transcriptomic changes in sorted Neurog3eYFP/+ EECs. Results: Induction of EEC deficiency in adults is not life-threatening unless fed with a high-fat diet. Under a standard chow diet, mice lose 10% of weight due to impaired food efficiency. Blood concentrations of cholesterol, triglycerides, and free fatty acids are reduced, and lipid absorption is impaired and delayed in the distal small intestine. Genes controlling lipogenesis, carbohydrate metabolism, and neoglucogenesis are upregulated. Microbiota composition is rapidly altered after EECs depletion and is characterized by decreased α-diversity. Bacteroides and Lactobacillus were progressively enriched, whereas Lachnospiraceae declined without impacting fecal short-chain fatty acid concentrations. Conclusions: EECs are dispensable for survival in adult male mice under a standard chow diet. The absence of EECs impairs intestinal lipid absorption, leading to transcriptomic and metabolic adaptations and remodeling of the gut microbiota

Region-specific remodeling of the enteric nervous system and enteroendocrine cells in the colon of spinal cord injury patients

International audiencePatients with spinal cord injury (SCI) suffer from major bowel dysfunction, whose exact pathophysiology, particularly the involvement of the enteric nervous system or epithelial dysfunction is poorly understood. Herein, we aimed to characterize the mucosal biopsies of the right and left colon in SCI patients vs controls (CT): (1) remodeling of key enteric neurotransmitters, (2) remodeling of enteroendocrine cells, and (3) mucosal inflammation compared to those in controls. In SCI, mucosal ACh concentration was lower in the right colon as compared to CT, but no change was observed in the left colon, and AChE expression was lower in both the right and left colons than in CT. While the VIP concentration was similar in the right and left colons, VIP mRNA expression was increased in the right colon and decreased in the left colon, in SCI patients as compared to CT. Interestingly, 5-HT concentration was reduced in the left colon but not in the right colon in SCI patients. Moreover, in SCI patients, as compared to CT, SERT mRNA expression was selectively increased in the left colon while TPH1 mRNA expression was increased in the right and left colons. Although mucosal TNFα and IL-1β mRNA expression did not significantly differ between SCI and CT groups, we identified a significant positive correlation between TNFα and IL-1β mRNA expression and left colon transit time in the SCI group. In conclusion, region-specific changes occur in the enteric neurotransmitter, serotonergic, and inflammatory pathways in the colon of SCI patients. The significant correlations between these pathways and clinical parameters in the left colon further set a scientific basis for designing therapeutic targets to improve colonic motor dysfunction in patients.Biobank information: Spinal cord injury patients: PHRC ConstiCAPE-clinical trial NCT02566746. Controls: Anosain-clinical trial NCT03054415 and biobank of the "Institut des Maladies de l’Appareil Digestif (IMAD)" registered under number DC-2008-402

Could the Microbiota Be a Predictive Factor for the Clinical Response to Probiotic Supplementation in IBS-D? A Cohort Study

Background: Increasing evidence suggests the beneficial effects of probiotics in irritable bowel syndrome (IBS), but little is known about how they can impact the gut microbiota. Our objective was to evaluate the effects of a multistrain probiotic on IBS symptoms, gut permeability and gut microbiota in patients with diarrhoea-predominant IBS (IBS-D). Methods: Adults with IBS-D were enrolled in an open-label trial to receive a multistrain probiotic for 4 weeks. Abdominal pain, stool frequency, quality of life, gut permeability, and the luminal and adherent microbiota from colonic biopsies were evaluated before and after supplementation. Results: Probiotics significantly improved symptoms and quality of life, despite having no impact on permeability in the global population. In the population stratified by the response, the diarrhoea responders displayed reduced colonic permeability after supplementation. The luminal and adherent microbiota were specifically altered depending on the patients’ clinical responses regarding pain and diarrhoea. Interestingly, we identified a microbial signature in IBS-D patients that could predict a response or lack of response to supplementation. Conclusions: The multistrain probiotic improved the symptoms of IBS-D patients and induced distinct effects on the gut microbiota according to the patient’s clinical response and initial microbiota composition. Our study further supports the need to develop individualised probiotic-based approaches regarding IBS