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BACKGROUND: Activation of free fatty acid receptor 2 (FFAR2) by microbiota-derived metabolites (e.g., propionate) reduces leukaemic cell proliferation in vitro. This study aims to test whether Ffar2 expression per se also influences leukaemia cell growth in vivo. METHODS: Bcr-Abl-expressing BaF cells were used as a leukaemia model and the role of Ffar2 was evaluated in Balb/c mice after lentiviral shRNA transduction. RESULTS: Our data formally establish that reduced leukaemic cell proliferation is associated with increased Ffar2 expression in vivo and in vitro. Going beyond association, we point out that decreasing Ffar2 expression fosters cancer cell growth in vitro and in vivo. CONCLUSIONS: Our data demonstrate the role of Ffar2 in the control of leukaemic cell proliferation in vivo and indicate that a modulation of Ffar2 expression through nutritional tools or pharmacological agents may constitute an attractive therapeutic approach to tackle leukaemia progression in humans.

OBJECTIVES: To investigate whether inulin-type fructan (ITF) prebiotics could counteract the thiazolidinedione (TZD, PPARγ activator) induced-fat mass gain, without affecting its beneficial effect on glucose homeostasis, in high-fat (HF) diet fed mice. METHODS: Male C57bl6/J mice were fed a HF diet alone or supplemented with ITF prebiotics (0.2 g/day × mouse) or TZD (30 mg pioglitazone (PIO)/kg body weight × day) or both during 4 weeks. An insulin tolerance test was performed after 3 weeks of treatment. RESULTS: As expected, PIO improved glucose homeostasis and increased adiponectinaemia. Furthermore, it induced an over-expression of several PPARγ target genes in white adipose tissues. ITF prebiotics modulated the PIO-induced PPARγ activation in a tissue-dependent manner. The co-treatment with ITF prebiotics and PIO maintained the beneficial impact of TZD on glucose homeostasis and adiponectinaemia. Moreover, the combination of both treatments reduced fat mass accumulation, circulating lipids and hepatic triglyceride content, suggesting an overall improvement of metabolism. Finally, the co-treatment favored induction of white-to-brown fat conversion in subcutaneous adipose tissue, thereby leading to the development of brite adipocytes that could increase the oxidative capacity of the tissue. CONCLUSIONS: ITF prebiotics decrease adiposity and improve the metabolic response in HF fed mice treated with TZD.

In vitro experiments have shown that isolated human gut bacteria are able to metabolise PUFA into conjugated PUFA like conjugated linoleic acids (CLA). The hypothesis of the present paper was that high-fat (HF) diet feeding and supplementation with fermentable carbohydrates that have prebiotic properties modulate the in vivo production of CLA by the mouse gut microbiota. Mice were treated for 4 weeks as follows: control (CT) groups were fed a standard diet; HF groups were fed a HF diet rich in linoleic acid (18 : 2n-6); the third groups were fed with the HF diet supplemented with either inulin-type fructans (HF-ITF) or arabinoxylans (HF-Ax). HF diet feeding increased rumenic acid (cis-9, trans-11-18 : 2 CLA) content both in the caecal and liver tissues compared with the CT groups. ITF supplementation had no major effect compared with the HF diet whereas Ax supplementation increased further rumenic acid (cis-9, trans-11-18 : 2 CLA) in the caecal tissue. These differences between both prebiotics may be linked to the high fat-binding capacity of Ax that provides more substrates for bacterial metabolism and to differential modulation of the gut microbiota (specific increase in Roseburia spp. in HF-Ax v. HF). In conclusion, these experiments supply the proof of concept that the mouse gut microbiota produces CLA in vivo, with consequences on the level of CLA in the caecal and liver tissues. We postulate that the CLA-producing bacteria could be a mediator to consider in the metabolic effects of both HF diet feeding and prebiotic supplementation.

Objective To highlight the contribution of the gut microbiota to the modulation of host metabolism by dietary inulin-type fructans (ITF prebiotics) in obese women.\ud Methods A double blind, placebo controlled, intervention study was performed with 30 obese women treated with ITF prebiotics (inulin/oligofructose 50/50 mix; n=15) or placebo (maltodextrin; n=15) for\ud 3 months (16 g/day). Blood, faeces and urine sampling, oral glucose tolerance test, homeostasis model assessment and impedancemetry were performed before and after treatment. The gut microbial composition in faeces was analysed by phylogenetic microarray and qPCR analysis of 16S rDNA. Plasma and urine metabolic profiles were analysed by 1H-NMR spectroscopy. Results Treatment with ITF prebiotics, but not the placebo, led to an increase in Bifidobacterium and Faecalibacterium prausnitzii; both bacteria negatively correlated with serum lipopolysaccharide levels. ITF prebiotics also decreased Bacteroides intestinalis, Bacteroides vulgatus and Propionibacterium, an effect associated with a slight decrease in fat mass and with plasma lactate and phosphatidylcholine levels. No clear treatment clustering could be detected for gut microbial analysis or plasma and urine metabolomic profile analyses. However, ITF prebiotics led to subtle changes in the gut microbiota that may importantly impact on several key metabolites implicated in obesity and/or diabetes.\ud Conclusions ITF prebiotics selectively changed the gut microbiota composition in obese women, leading to modest changes in host metabolism, as suggested by the correlation between some bacterial species and metabolic endotoxaemia or metabolomic signatures.

BACKGROUND: Metabolites released by the gut microbiota may influence host metabolism and immunity. We have tested the hypothesis that inulin-type fructans (ITF), by promoting microbial production of short-chain fatty acids (SCFA), influence cancer cell proliferation outside the gut. METHODS: Mice transplanted with Bcr-Abl-transfected BaF3 cells, received ITF in their drinking water. Gut microbiota was analysed by 16S rDNA polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and qPCR. Serum Short-chain fatty acids were quantified by UHPLC-MS. Cell proliferation was evaluated in vivo, by molecular biology and histology, and in vitro. RESULTS: Inulin-type fructans treatment reduces hepatic BaF3 cell infiltration, lessens inflammation and increases portal propionate concentration. In vitro, propionate reduces BaF3 cell growth through a cAMP level-dependent pathway. Furthermore, the activation of free fatty acid receptor 2 (FFA2), a Gi/Gq-protein-coupled receptor also known as GPR43 and that binds propionate, lessens the proliferation of BaF3 and other human cancer cell lines. CONCLUSION: We show for the first time that the fermentation of nutrients such as ITF into propionate can counteract malignant cell proliferation in the liver tissue. Our results support the interest of FFA2 activation as a new strategy for cancer therapeutics. This study highlights the importance of research focusing on gut microbes-host interactions for managing systemic and severe diseases such as leukaemia.

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. ispartof: Journal of Nutritional Biochemistry vol:22 issue:8 pages:712-722 ispartof: location:United States status: published

[Background & aims] Inulin-type fructans (ITF) prebiotics promote changes in the composition and activity of the gut microbiota. The aim of this study was to determine variations on fecal short chain fatty acids (SCFA) concentration in obese women treated with ITF and to explore associations between Bifidobacterium species, SCFA and host biological markers of metabolism., [Methods] Samples were obtained in a randomized, double blind, parallel, placebo-controlled trial, with 30 obese women randomly assigned to groups that received either 16 g/day ITF (n = 15) or maltodextrin (n = 15) for 3 months. The qualitative and quantitative analysis of Bifidobacterium spp. was performed in feces by PCR-DGGE and q-PCR, and SCFA profile was analyzed by gas chromatography. Spearman correlation analysis was performed between the different variables analyzed., [Results] The species Bifidobacterium longum, Bifidobacterium pseudocatenulatum and Bifidobacterium adolescentis were significantly increased at the end of the treatment in the prebiotic group (p < 0.01) with being B. longum negatively correlated with serum lipopolysaccharide (LPS) endotoxin (p < 0.01). Total SCFA, acetate and propionate, that positively correlated with BMI, fasting insulinemia and homeostasis model assessment (HOMA) (p < 0.05), were significantly lower in prebiotic than in placebo group after the treatment period., [Conclusions] ITF consumption selectively modulates Bifidobacterium spp. and decreases fecal SCFA concentration in obese women. ITF could lessen metabolic risk factors associated with higher fecal SCFA concentration in obese individuals., This study was supported by Fonds De La Recherche Scientifique - FNRS, Belgium (FNRS grant no. 1.5.095.09F) and by a Spanish grant from Ministry of Economy and Competitiveness (AGL2010-16525). NS is the recipient of a postdoctoral fellowship from the Spanish Ministry of Education, Culture and Sports. LBB is the recipient of a Heritage Fellowship from the Fonds Speciaux de Recherches (FSR, Université Catholique de Louvain). PDC is a Research Associate of the FRS-FNRS and a recipient of ERC Starting Grant 2013 (ENIGMO).

International audience; OBJECTIVES: To investigate whether inulin-type fructan (ITF) prebiotics could counteract the thiazolidinedione (TZD, PPARγ activator) induced-fat mass gain, without affecting its beneficial effect on glucose homeostasis, in high-fat (HF) diet fed mice. METHODS: Male C57bl6/J mice were fed a HF diet alone or supplemented with ITF prebiotics (0.2 g/day × mouse) or TZD (30 mg pioglitazone (PIO)/kg body weight × day) or both during 4 weeks. An insulin tolerance test was performed after 3 weeks of treatment. RESULTS: As expected, PIO improved glucose homeostasis and increased adiponectinaemia. Furthermore, it induced an over-expression of several PPARγ target genes in white adipose tissues. ITF prebiotics modulated the PIO-induced PPARγ activation in a tissue-dependent manner. The co-treatment with ITF prebiotics and PIO maintained the beneficial impact of TZD on glucose homeostasis and adiponectinaemia. Moreover, the combination of both treatments reduced fat mass accumulation, circulating lipids and hepatic triglyceride content, suggesting an overall improvement of metabolism. Finally, the co-treatment favored induction of white-to-brown fat conversion in subcutaneous adipose tissue, thereby leading to the development of brite adipocytes that could increase the oxidative capacity of the tissue. CONCLUSIONS: ITF prebiotics decrease adiposity and improve the metabolic response in HF fed mice treated with TZD.

BackgroundInteractions between the diet and intestinal microbiota play a role in health and disease, including obesity and related metabolic complications. There is great interest to use dietary means to manipulate the microbiota to promote health. Currently, the impact of dietary change on the microbiota and the host metabolism is poorly predictable and highly individual. We propose that the responsiveness of the gut microbiota may depend on its composition, and associate with metabolic changes in the host.MethodologyOur study involved three independent cohorts of obese adults (n = 78) from Belgium, Finland, and Britain, participating in different dietary interventions aiming to improve metabolic health. We used a phylogenetic microarray for comprehensive fecal microbiota analysis at baseline and after the intervention. Blood cholesterol, insulin and inflammation markers were analyzed as indicators of host response. The data were divided into four training set - test set pairs; each intervention acted both as a part of a training set and as an independent test set. We used linear models to predict the responsiveness of the microbiota and the host, and logistic regression to predict responder vs. non-responder status, or increase vs. decrease of the health parameters.Principal findingsOur models, based on the abundance of several, mainly Firmicute species at baseline, predicted the responsiveness of the microbiota (AUC = 0.77-1; predicted vs. observed correlation = 0.67-0.88). Many of the predictive taxa showed a non-linear relationship with the responsiveness. The microbiota response associated with the change in serum cholesterol levels with an AUC of 0.96, highlighting the involvement of the intestinal microbiota in metabolic health.ConclusionThis proof-of-principle study introduces the first potential microbial biomarkers for dietary responsiveness in obese individuals with impaired metabolic health, and reveals the potential of microbiota signatures for personalized nutrition.

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.

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. © 2011 Pachikian et al., SCOPUS: ar.j, info:eu-repo/semantics/published

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. ispartof: The Journal of Nutrition vol:140 issue:3 pages:509-514 ispartof: location:United States status: published

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

The mechanism, by which a high-fat (HF) diet could impair glucose metabolism, is not completely understood but could be related to inflammation, lipotoxicity and oxidative stress. Lipid peroxides have been proposed as key mediators of intracellular metabolic response. The purpose of the present study was to analyse, in mice fed with a HF diet, the possible association between obesity and glucose tolerance on the one hand, and between oxidative stress and lipid peroxidation on the other hand. The present results show that a HF diet (70 % energy as fat),v.a high-carbohydrate chow diet (control), increases body weight and fat mass development, and impairs glycaemia and insulinaemia within 4 weeks. It also promotes the expression of NADPH oxidase in the liver – signing both oxidative and inflammatory stress – but decreases thiobarbituric acid-reactive substances content in the liver as well as in epididymal, subcutaneous and visceral adipose tissues. HF diet, with elevated vitamin E content, induces high concentration of α-tocopherol in liver and adipose tissues, which contributes to the protection against lipid peroxidation. Thus, lipid peroxidation in key organs is not necessarily related to the development of metabolic disorders associated with diabetes and obesity.

Background GPR43 is a G-protein-coupled receptor that participates in adipocyte differentiation in mice and is over-expressed in adipose tissue of obese mice. The aim of this study was to investigate the implication of GPR43 in adipogenesis in humans and to determine the influence of obesity on its expression in human adipose tissue. Findings Preadipocytes were isolated from human omental adipose tissue and cultured during 13 days. One PPARγ agonist (troglitazone) and three GPR43 agonists (two physiological and one synthetic) were tested for their ability to induce differentiation. After 13 days, the three GPR43 agonists had no impact on aP2 expression, a marker of adipocyte differentiation, whereas troglitazone led to a huge over-expression of aP2 in these cells but tended to decrease GPR43 expression (p=0.06). GPR43 and inflammatory markers expression was also quantified in omental adipose tissue from lean and obese individuals. GPR43 expression in total adipose tissue was similar between obese patients and lean subjects and did not correlate with aP2 expression. In contrast, GPR43 expression positively correlated with TNFα mRNA. Conclusions Our results suggest the absence of relationship between GPR43 and adipocyte differentiation in humans, unlike what was observed in mice. Furthermore, GPR43 expression is not increased in adipose tissue from obese subjects but could be related to TNFα-related inflammatory processes.