Involvement of gut microbial fermentation in the metabolic alterations occurring in n-3 polyunsaturated fatty acids-depleted mice

<p>Abstract</p> <p>Backround</p> <p>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).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

Restoring Specific Lactobacilli Levels Decreases Inflammation and Muscle Atrophy Markers in an Acute Leukemia Mouse Model

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

Metabolic disorders induced by nutritional deficiency in n-3 polyunsaturated fatty acid or magnesium : potential implication of the gut microbiota

The prevalence of obesity is increasing worldwide. Among environmental factors, involved in this phenomenon, the nutritional dys-balance plays a major role. Surprisingly, the excess of calorie intake is often associated with specific nutritional deficiencies. Moreover, recent data suggest that the gut microbiota is a novel partner to take into account when evaluating the regulation of host energy metabolism by the nutrients provided in the diet. In the context of this thesis, we have focused our work on the assessment of two nutritional deficiencies often occurring in western countries and which have been associated with diabetes, inflammation and/or obesity: namely, magnesium (Mg) and n-3 polyunsaturated fatty acid (PUFA) deficiencies. We have characterized the metabolic alterations occurring in animal models mimicking those deficiencies and we have tested the hypothesis that perturbations of the gut microbiota contribute to the metabolic alterations occurring in deficient mice. We have shown for the first time that Mg deficiency, independent of any other changes in nutrient intake, modulates the concentration of bifidobacteria in the gut in a time dependent manner. A short term (4 days) Mg-deficiency leads to a drop of bifidobacteria, which is associated with intestinal and hepatic inflammation and with a loss of gut barrier integrity. A restoration of the gut microbial changes occurs spontaneously after a few days (21 days), which allows to normalize the metabolic alterations. In the second part of the thesis, we have developed mouse models of n-3 PUFA depletion: one long term (depletion installed for two generations) and one short term (depletion installed for three months). Both long-term and short-term n-3 PUFA depletions induce hepatic steatosis, alterations in glucose metabolism and a metabolic stress in the liver tissue. Moreover, mice depleted in n-3 PUFA for two generations exhibit a lower body weight. A microarray analysis performed in the liver of mice depleted in n-3 PUFA for three months revealed a higher expression of several factors involved in fatty acid and cholesterol synthesis and a lower expression of factors involved in fatty acid oxidation. These metabolic alterations occur together with a modification in the gut microbiota composition, characterized by a lower content in lactobacilli and a higher content in bifidobacteria in long-term depleted mice and characterized by a higher Roseburia spp. content in short-term depleted mice. Supplementation with a prebiotic called fructooligosaccharides (FOS) leads to differential effects depending on the model of n-3 PUFA depletion. In mice depleted for two generations, after FOS feeding, we observed an increased body weight and an improvement of the catabolic state, whereas there was no effect on hepatic steatosis. In mice depleted for three months, FOS supplementation restored the hepatic lipid deposition, mainly by activating fatty acid oxidative pathways and by lessening cholesterol synthesis. In conclusion, a nutritional deficiency in n-3 PUFA or in Mg modulates the gut microbiota composition. In Mg deficiency, a spontaneous adaptation of the gut microbiota composition is observed progressively and is associated with a restoration of the inflammatory state. In n-3 PUFA-depleted mice, changing the gut microbiota composition by FOS supplementation leads to an improvement of several metabolic alterations induced by the depletion. These results support the idea that gut microbiota affects the health of the host and should be taken into account in the treatment of inflammatory conditions and hepatic steatosis.(FARM 3) -- UCL, 201

Effects of Saffron Extract on Sleep Quality: A Randomized Double-Blind Controlled Clinical Trial.

A saffron extract has been found to be effective in the context of depression and anxiety, but its effect on sleep quality has not been investigating yet using objective approaches. For this purpose, a randomized double-blind controlled study was conducted in subjects presenting mild to moderate sleep disorder associated with anxiety. Sixty-six subjects were randomized and supplemented with a placebo (maltodextrin) or a saffron extract (15.5 mg per day) for 6 weeks. Actigraphy was used to collect objective data related to sleep quality at baseline, at the middle and at the end of the intervention. Sleep quality was also assessed by completion of the LSEQ and PSQI questionnaires and quality of life by completion of the SF-36 questionnaire. Six weeks of saffron supplementation led to an increased time in bed assessed by actigraphy, to an improved ease of getting to sleep evaluated by the LSEQ questionnaire and to an improved sleep quality, sleep latency, sleep duration, and global scores evaluated by the PSQI questionnaire, whereas those parameters were not modified by the placebo. In conclusion, those results suggest that a saffron extract could be a natural and safe nutritional strategy to improve sleep duration and quality

Recent advances on bioactivities of black rice.

Black rice has been consumed for centuries in Asian countries such as China, Korea or Japan. Nowadays, extracts and derivatives are considered as beneficial functional foods because of their high content in several bioactive molecules such as anthocyanins, other phenolics and terpenoids. The purpose of this review is to summarize and discuss recent developments on black rice bioactivities. Some sterols and triterpenoids with potential anticancer properties already tested in vitro and in vivo have been isolated and identified from bran extracts of black rice. Protection against osteoporosis has been suggested for the first time for black rice extracts. Because of its antioxidant and anti-inflammatory properties, black rice also protects liver and kidney from injuries. One clinical study reported the interest of black rice in case of alcohol withdrawal. Several advances have been recently achieved on the understanding of the potential biological effects of black rice and its derivatives. They further confirm that black rice should be considered as a promising source of health-promoting functional foods targeting a large set of noninfectious diseases. However, more clinical studies are needed to support the findings highlighted in this review

Intestinal Sucrase as a Novel Target Contributing to the Regulation of Glycemia by Prebiotics.

Inulin-type fructans (ITF) are known for their capacity to modulate gut microbiota, energy metabolism and to improve glycemia in several animal models of obesity, and in humans. The potential contribution of ITF as modulators of sugar digestion by host enzymes has not been evaluated yet. A sucrose challenge has been performed on naive mice fed a standard diet supplemented with or without native chicory inulin (Fibruline 5%) for 3 weeks. The area under the curve of glycemia as well as sucrase activity in the small intestine were lowered after inulin treatment. Pyrosequencing of the 16S rRNA gene confirmed important changes in gut microbiota (mostly in favor of Blautia genus) due to inulin extract supplementation. Interestingly, the suppressive effect of inulin extract on postprandial glycemia also occurred when inulin was directly added to the sucrose solution, suggesting that the effect on sucrose digestion did not require chronic inulin administration. In vitro tests confirmed a direct inhibition of sucrase enzyme by the inulin extract, thereby suggesting that native chicory inulin, in addition to its well-known prebiotic effect, is also able to decrease the digestibility of carbohydrates, a phenomenon that can contribute in the control of post prandial glycemia. We may not exclude that the sucrose escaping the digestion could also contribute to the changes in the gut microbiota after a chronic treatment with inulin

Effects of prebiotics on affect and cognition in human intervention studies.

Studies conducted in rodents have highlighted that neurobiological processes underlying cognition and affect are modulated by the gut microbiota. Certain dietary fibers are able to modulate the composition of gut microbiota and are thus considered prebiotics. A review of the impact of the available prebiotic intervention studies in humans on cognition and affect, addressing the potential mediating role of the microbiota, was conducted. PubMed, Scopus, and PsycINFO were selected as sources. Fourteen articles were eligible for narrative synthesis. Data extraction and quality assessment were performed with characteristics established a priori. Some chronic prebiotic interventions (>28 d) improved affect and verbal episodic memory compared with a placebo. Acute prebiotic interventions (<24 h) were more efficient in improving cognitive variables (eg, verbal episodic memory). Future research should measure microbiota using adequate methodologies and recruit patients with dysbiosis, inflammation, or psychopathology. More research is needed to unravel the conditions required to obtain effects on affect and cognition

Ezetimibe and simvastatin modulate gut microbiota and expression of genes related to cholesterol metabolism

AIMS: Hypolipidemic drugs are prescribed in the most of cases for the treatment of cardiovascular diseases. Several studies have showed that the gut microbiota is able to regulate the host cholesterol metabolism. This study aimed to investigate the potential impact of hypolipidemic drugs on the gut microbiota in mice, and to correlate it to the regulation of cholesterol metabolism. MAIN METHODS: Male C57Bl/6J mice were divided into four groups fed either a control diet alone (CT), or supplemented with simvastatin (0.1% w/w, Zocor®, MSD), or ezetimibe (0.021% w/w, Ezetrol®, MSD) or a combination of simvastatin and ezetimibe (0.1% and 0.021%, respectively) for one week. KEY FINDINGS: The combination of ezetimibe and simvastatin is required to observe a drop in cholesterolemia, linked to a huge activation of hepatic SREBP-2 and the consequent increased expression of genes involved in LDL cholesterol uptake and cholesterol synthesis. The gut microbiota analysis revealed no change in total bacteria, and in major Gram positive and Gram negative bacteria, but a selective significant increase in Lactobacillus spp. in mice treated with the ezetimibe and a decrease by the combination. The changes in lactobacilli level observed in ezetimibe or combination treated-mice are negatively correlated to expression of genes related to cholesterol metabolism. SIGNIFICANCE: The present study showed that ezetimibe taken alone is able to modify the composition of gut microbiota in favor of Lactobacillus spp. These results suggest that members of the genus Lactobacillus play an important role in cholesterol metabolism, even in normocholesterolemic mouse model