Chitin-glucan supplementation improved postprandial metabolism and altered gut microbiota in subjects at cardiometabolic risk in a randomized trial.

Chitin-glucan (CG), an insoluble dietary fiber, has been shown to improve cardiometabolic disorders associated with obesity in mice. Its effects in healthy subjects has recently been studied, revealing its interaction with the gut microbiota. In this double-blind, randomized, cross-over, twice 3-week exploratory study, we investigated the impacts of CG on the cardiometabolic profile and gut microbiota composition and functions in 15 subjects at cardiometabolic risk. They consumed as a supplement 4.5 g of CG daily or maltodextrin as control. Before and after interventions, fasting and postprandial metabolic parameters and exhaled gases (hydrogen [H2] and methane [CH4]) were evaluated. Gut microbiota composition (16S rRNA gene sequencing analysis), fecal concentrations of bile acids, long- and short-chain fatty acids (LCFA, SCFA), zonulin, calprotectin and lipopolysaccharide binding protein (LBP) were analyzed. Compared to control, CG supplementation increased exhaled H2 following an enriched-fiber breakfast ingestion and decreased postprandial glycemia and triglyceridemia response to a standardized test meal challenge served at lunch. Of note, the decrease in postprandial glycemia was only observed in subjects with higher exhaled H2, assessed upon lactulose breath test performed at inclusion. CG decreased a family belonging to Actinobacteria phylum and increased 3 bacterial taxa: Erysipelotrichaceae UCG.003, Ruminococcaceae UCG.005 and Eubacterium ventriosum group. Fecal metabolites, inflammatory and intestinal permeability markers did not differ between groups. In conclusion, we showed that CG supplementation modified the gut microbiota composition and improved postprandial glycemic response, an early determinant of cardiometabolic risk. Our results also suggest breath H2 production as a non-invasive parameter of interest for predicting the effectiveness of dietary fiber intervention.

Metabolite profiling reveals the interaction of chitin-glucan with the gut microbiota.

Dietary fibers are considered beneficial nutrients for health. Current data suggest that their interaction with the gut microbiota largely contributes to their physiological effects. In this context, chitin-glucan (CG) improves metabolic disorders associated with obesity in mice, but its effect on gut microbiota has never been evaluated in humans. This study explores the effect of a 3-week intervention with CG supplementation in healthy individuals on gut microbiota composition and bacterial metabolites. CG was given to healthy volunteers (n = 15) for three weeks as a supplement (4.5 g/day). Food diary, visual analog and Bristol stool form scales and a "quality of life" survey were analyzed. Among gut microbiota-derived metabolites, bile acids (BA), long- and short-chain fatty acids (LCFA, SCFA) profiling were assessed in stool samples. The gut microbiota (primary outcome) was analyzed by Illumina sequencing. A 3-week supplementation with CG is well tolerated in healthy humans. CG induces specific changes in the gut microbiota composition, with Eubacterium, Dorea and Roseburia genera showing the strongest regulation. In addition, CG increased bacterial metabolites in feces including butyric, iso-valeric, caproic and vaccenic acids. No major changes were observed for the fecal BA profile following CG intervention. In summary, our work reveals new potential bacterial genera and gut microbiota-derived metabolites characterizing the interaction between an insoluble dietary fiber -CG- and the gut microbiota.

Discovery of the gut microbial signature driving the efficacy of prebiotic intervention in obese patients.

OBJECTIVE: The gut microbiota has been proposed as an interesting therapeutic target for metabolic disorders. Inulin as a prebiotic has been shown to lessen obesity and related diseases. The aim of the current study was to investigate whether preintervention gut microbiota characteristics determine the physiological response to inulin. DESIGN: The stools from four obese donors differing by microbial diversity and composition were sampled before the dietary intervention and inoculated to antibiotic-pretreated mice (hum-ob mice; humanised obese mice). Hum-ob mice were fed with a high-fat diet and treated with inulin. Metabolic and microbiota changes on inulin treatment in hum-ob mice were compared with those obtained in a cohort of obese individuals supplemented with inulin for 3 months. RESULTS: We show that hum-ob mice colonised with the faecal microbiota from different obese individuals differentially respond to inulin supplementation on a high-fat diet. Among several bacterial genera, Barnesiella, Bilophila, Butyricimonas, Victivallis, Clostridium XIVa, Akkermansia, Raoultella and Blautia correlated with the observed metabolic outcomes (decrease in adiposity and hepatic steatosis) in hum-ob mice. In addition, in obese individuals, the preintervention levels of Anaerostipes, Akkermansia and Butyricicoccus drive the decrease of body mass index in response to inulin. CONCLUSION: These findings support that characterising the gut microbiota prior to nutritional intervention with prebiotics is important to increase the positive outcome in the context of obesity and metabolic disorders.

Nutritional interest of dietary fiber and prebiotics in obesity: Lessons from the MyNewGut consortium.

The aim of EU project MyNewGut is to contribute to future public health-related recommendations supported by new insight in gut microbiome and nutrition-host relationship. In this Opinion Paper, we first revisit the concept of dietary fiber, taking into account their interaction with the gut microbiota. This paper also summarizes the main effects of dietary fibers with prebiotic properties in intervention studies in humans, with a particular emphasis on the effects of arabinoxylans and arabinoxylo-oligosaccharides on metabolic alterations associated with obesity. Based on the existing state of the art and future development, we elaborate the steps required to propose dietary guidelines related to dietary fibers, taking into account their interaction with the gut microbiota.

Chitin-glucan and pomegranate polyphenols improve endothelial dysfunction.

The vascular dysfunction is the primary event in the occurrence of cardio-vascular risk, and no treatment exists until now. We tested for the first time the hypothesis that chitin-glucan (CG) - an insoluble fibre with prebiotic properties- and polyphenol-rich pomegranate peel extract (PPE) can improve endothelial and inflammatory disorders in a mouse model of cardiovascular disease (CVD), namely by modulating the gut microbiota. Male Apolipoprotein E knock-out (ApoE-/-) mice fed a high fat (HF) diet developed a significant endothelial dysfunction attested by atherosclerotic plaques and increasing abundance of caveolin-1 in aorta. The supplementation with CG + PPE in the HF diet reduced inflammatory markers both in the liver and in the visceral adipose tissue together with a reduction of hepatic triglycerides. In addition, it increased the activating form of endothelial NO-synthase in mesenteric arteries and the heme-nitrosylated haemoglobin (Hb-NO) blood levels as compared with HF fed ApoE-/- mice, suggesting a higher capacity of mesenteric arteries to produce nitric oxide (NO). This study allows to pinpoint gut bacteria, namely Lactobacillus and Alistipes, that could be implicated in the management of endothelial and inflammatory dysfunctions associated with CVD, and to unravel the role of nutrition in the modulation of those bacteria.

A Preventive Prebiotic Supplementation Improves the Sweet Taste Perception in Diet-Induced Obese Mice.

Orosensory perception of sweet stimulus is blunted in diet-induced obese (DIO) rodents. Although this alteration might contribute to unhealthy food choices, its origin remains to be understood. Cumulative evidence indicates that prebiotic manipulations of the gut microbiota are associated with changes in food intake by modulating hedonic and motivational drive for food reward. In the present study, we explore whether a prebiotic supplementation can also restore the taste sensation in DIO mice. The preference and licking behavior in response to various sucrose concentrations were determined using respectively two-bottle choice tests and gustometer analysis in lean and obese mice supplemented or not with 10% inulin-type fructans prebiotic (P) in a preventive manner. In DIO mice, P addition reduced the fat mass gain and energy intake, limited the gut dysbiosis and partially improved the sweet taste perception (rise both of sucrose preference and number of licks/10 s vs. non-supplemented DIO mice). No clear effect on orosensory perception of sucrose was found in the supplemented control mice. Therefore, a preventive P supplementation can partially correct the loss of sweet taste sensitivity found in DIO mice, with the efficiency of treatment being dependent from the nutritional status of mice (high fat diet vs. regular chow).

Milk Polar Lipids in a High-Fat Diet Can Prevent Body Weight Gain: Modulated Abundance of Gut Bacteria in Relation with Fecal Loss of Specific Fatty Acids.

SCOPE: Enhanced adiposity and metabolic inflammation are major features of obesity associated with altered gut microbiota and intestinal barrier. How these metabolic outcomes can be impacted by milk polar lipids (MPL), naturally containing 25% of sphingomyelin, is investigated in mice fed a mixed high-fat (HF) diet . METHODS AND RESULTS: Male C57Bl/6 mice receive a HF-diet devoid of MPL (21% fat, mainly palm oil, in chow), or supplemented with 1.1% or 1.6% of MPL (HF-MPL1; HF-MPL2) via a total-lipid extract from butterserum concentrate for 8 weeks. HF-MPL2 mice gain less weight versus HF (p < 0.01). Diets do not impact plasma markers of inflammation but in the liver, HF-MPL2 tends to decrease hepatic gene expression of macrophage marker F4/80 versus HF-MPL1 (p = 0.06). Colonic crypt depth is the maximum in HF-MPL2 (p < 0.05). In cecal microbiota, HF-MPL1 increases Bifidobacterium animalis versus HF (p < 0.05). HF-MPL2 decreases Lactobacillus reuteri (p < 0.05), which correlates negatively with the fecal loss of milk sphingomyelin-specific fatty acids (p < 0.05). CONCLUSION: In mice fed a mixed HF diet, MPL can limit HF-induced body weight gain and modulate gut physiology and the abundance in microbiota of bacteria of metabolic interest. This supports further exploration of how residual unabsorbed lipids reaching the colon can impact HF-induced metabolic disorders.

Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction.

OBJECTIVE: To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction. DESIGN: We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe-/-) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed. RESULTS: ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe-/- mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation. CONCLUSIONS: We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.

A polyphenolic extract from green tea leaves activates fat browning in high-fat-diet-induced obese mice.

Fat browning has emerged as an attractive target for the treatment of obesity and related metabolic disorders. Its activation leads to increased energy expenditure and reduced adiposity, thus contributing to a better energy homeostasis. Green tea extracts (GTEs) were shown to attenuate obesity and low-grade inflammation and to induce the lipolytic pathway in the white adipose tissue (WAT) of mice fed a high-fat diet. The aim of the present study was to determine whether the antiobesity effect of an extract from green tea leaves was associated with the activation of browning in the WAT and/or the inhibition of whitening in the brown adipose tissue (BAT) in HF-diet induced obese mice. Mice were fed a control diet or an HF diet supplemented with or without 0.5% polyphenolic GTE for 8 weeks. GTE supplementation significantly reduced HF-induced adiposity (WAT and BAT) and HF-induced inflammation in WAT. Histological analysis revealed that GTE reduced the adipocyte size in the WAT and the lipid droplet size in the BAT. Markers of browning were induced in the WAT upon GTE treatment, whereas markers of HF-induced whitening were reduced in the BAT. These results suggest that browning activation in the WAT and whitening reduction in the BAT by the GTE could participate to the improvement of metabolic and inflammatory disorders mediated by GTE upon HF diet. Our study emphasizes the importance of using GTE as a nutritional tool to activate browning and to decrease fat storage in all adipose tissues, which attenuate obesity.

Spirulina Protects against Hepatic Inflammation in Aging: An Effect Related to the Modulation of the Gut Microbiota?

Aging predisposes to hepatic dysfunction and inflammation that can contribute to the development of non-alcoholic fatty liver disease. Spirulina, a cyanobacterium used as a food additive or food supplement, has been shown to impact immune function. We have tested the potential hepatoprotective effect of a Spirulina in aged mice and to determine whether these effects can be related to a modulation of the gut microbiota. Old mice have been fed a standard diet supplemented with or without 5% Spirulina for six weeks. Among several changes of gut microbiota composition, an increase in Roseburia and Lactobacillus proportions occurs upon Spirulina treatment. Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice. Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice. We conclude that the oral administration of a Spirulina is able to modulate the gut microbiota and to activate the immune system in the gut, a mechanism that may be involved in the improvement of the hepatic inflammation in aged mice. Those data open the way to new therapeutic tools in the management of immune alterations in aging, based on gut microbe-host interactions.

Rhubarb extract prevents hepatic inflammation induced by acute alcohol intake, an effect related to the modulation of the gut microbiota.

SCOPE: Binge consumption of alcohol is an alarming global health problem. Acute ethanol intoxication is characterized by hepatic inflammation and oxidative stress, which could be promoted by gut barrier function alterations. In this study, we have tested the hypothesis of the hepatoprotective effect of rhubarb extract in a mouse model of binge drinking and we explored the contribution of the gut microbiota in the related metabolic effects. METHODS AND RESULTS: Mice were fed a control diet supplemented with or without 0.3% rhubarb extract for 17 days and were necropsied 6 h after an alcohol challenge. Supplementation with rhubarb extract changed the microbial ecosystem (assessed by 16S rDNA pyrosequencing) in favor of Akkermansia muciniphila and Parabacteroides goldsteinii. Furthermore, it improved alcohol-induced hepatic injury, downregulated key markers of both inflammatory and oxidative stresses in the liver tissue, without affecting significantly steatosis. In the gut, rhubarb supplementation increased crypt depth, tissue weight, and the expression of antimicrobial peptides. CONCLUSIONS: These findings suggest that some bacterial genders involved in gut barrier function, are promoted by phytochemicals present in rhubarb extract, and could therefore be involved in the modulation of the susceptibility to hepatic diseases linked to acute alcohol consumption.

Nutritional depletion in n-3 PUFA in apoE knock-out mice: A new model of endothelial dysfunction associated with fatty liver disease.

SCOPE: Western diets are characterized by low intake of n-3 PUFA compensated by constant amounts of n-6 PUFA. Reduced intake of n-3 PUFA is associated with increased cardiovascular risk, as observed in nonalcoholic fatty liver disease patients. The study aimed to evaluating the impact of dietary n-3 PUFA depletion on endothelial function, an early key event of cardiovascular diseases. METHODS AND RESULTS: C57Bl/6J or apolipoprotein E knock-out (apoE-/- ) were fed control (CT) or n-3 PUFA-depleted diets (DEF) for 12 wks. Mice fed n-3 DEF diet developed a hepatic steatosis, linked to changes in hepatic expression of genes controlled by Sterol Regulatory Element Binding Protein-1 and -2. Vascular function was assessed on second- and third-order mesenteric arteries and n-3 PUFA-depleted apoE-/- mice presented endothelial dysfunction characterized by decreased vasorelaxation in response of acetylcholine. The presence of a nitric oxide synthase (NOS) inhibitor blunted the relaxation in each groups and heme-nitrosylated hemoglobin blood (Hb-NO) level was significantly lower in n-3 PUFA-depleted apoE-/- mice. CONCLUSION: Twelve weeks of n-3 DEF diet promote steatosis and accelerate the process of endothelial dysfunction in apoE-/- mice by a mechanism involving the NOS/NO pathway. We propose n-3 PUFA-depleted apoE-/- mice as a new model to study endothelial dysfunction related to hepatic steatosis independently of obesity.

Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice.

We tested the hypothesis that changing the gut microbiota using pectic oligosaccharides (POS) or inulin (INU) differently modulates the progression of leukemia and related metabolic disorders. Mice were transplanted with Bcr-Abl-transfected proB lymphocytes mimicking leukemia and received either POS or INU in their diet (5%) for 2 weeks. Combination of pyrosequencing, PCR-DGGE and qPCR analyses of the 16S rRNA gene revealed that POS decreased microbial diversity and richness of caecal microbiota whereas it increased Bifidobacterium spp., Roseburia spp. and Bacteroides spp. (affecting specifically B. dorei) to a higher extent than INU. INU supplementation increased the portal SCFA propionate and butyrate, and decreased cancer cell invasion in the liver. POS treatment did not affect hepatic cancer cell invasion, but was more efficient than INU to decrease the metabolic alterations. Indeed, POS better than INU delayed anorexia linked to cancer progression. In addition, POS treatment increased acetate in the caecal content, changed the fatty acid profile inside adipose tissue and counteracted the induction of markers controlling ß-oxidation, thereby hampering fat mass loss. Non digestible carbohydrates with prebiotic properties may constitute a new nutritional strategy to modulate gut microbiota with positive consequences on cancer progression and associated cachexia.

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.

Ability of the gut microbiota to produce PUFA-derived bacterial metabolites: Proof of concept in germ-free versus conventionalized mice.

SCOPE: The gut microbiota is able to modulate host physiology through the production of bioactive metabolites. Our recent studies suggest that changes in gut microbiota composition upon prebiotics supplementation alter tissue levels of PUFA-derived metabolites in mice. However, in vivo evidence that gut microbes produces PUFA-derived metabolites is lacking. This study aimed to decipher the contribution of gut microbes versus that of the host in PUFA-derived metabolite production. METHODS AND RESULTS: To achieve this goal, we compared the proportion of PUFA-derived metabolites and the expression of fatty acid desaturases in germ-free (GF) and conventionalized (CONV) mice fed either a low fat or Western diet. Higher concentrations of PUFA-derived metabolites were found in the colonic contents of conventionalized mice (CONV) mice compared to GF mice. The abundance of these metabolites in host tissues was modulated by dietary treatments but not by microbial status. Although microbial status did significantly influence desaturase expression, no correlations between host enzymes and tissue PUFA-derived metabolite levels were observed. CONCLUSION: Together, these results highlight the ability of the gut microbiota to produce PUFA-derived metabolites from dietary PUFA. However, microbial production of these metabolites in colonic contents is not necessarily associated with modifications of their concentration in host tissues.

Role of the lower and upper intestine in the production and absorption of gut microbiota-derived PUFA metabolites.

In vitro studies have suggested that isolated gut bacteria are able to metabolize PUFA into CLA (conjugated linoleic acids) and CLnA (conjugated linolenic acids). However, the bioavailability of fatty acid metabolites produced in vivo by the gut microbes remains to be studied. Therefore, we measured intestinal concentration and plasma accumulation of bacterial metabolites produced from dietary PUFA in mice, first injected with a lipoprotein lipase inhibitor, then force-fed with either sunflower oil (200 µl) rich in n-6 PUFA or linseed oil (200 µl) rich in n-3 PUFA. The greatest production of bacterial metabolites was observed in the caecum and colon, and at a much lesser extent in the jejunum and ileum. In the caecal content, CLA proportions were higher in sunflower oil force-fed mice whereas CLnA proportions were higher in linseed oil force-fed mice. The accumulation of the main metabolites (CLA cis-9,trans-11-18:2 and CLnA cis-9,trans-11,cis-15-18:3) in the caecal tissue was not associated with their increase in the plasma, therefore suggesting that, if endogenously produced CLA and CLnA have any biological role in host metabolism regulation, their effect would be confined at the intestinal level, where the microbiota is abundant.

Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue.

BACKGROUND: Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. METHODOLOGY/PRINCIPAL FINDINGS: Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. CONCLUSIONS/SIGNIFICANCE: These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

Implication of fermentable carbohydrates targeting the gut microbiota on conjugated linoleic acid production in high-fat-fed mice.

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.

Polyphenol-rich extract of pomegranate peel alleviates tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice: potential implication of the gut microbiota.

Pomegranate extracts have been used for centuries in traditional medicine to confer health benefits in a number of inflammatory diseases, microbial infections and cancer. Peel fruit are rich in polyphenols that exhibit antioxidant and anti-inflammatory capacities in vitro. Recent studies strongly suggest that the gut microbiota is an environmental factor to be taken into account when assessing the risk factors related to obesity. The aim of the present study was to test the prebiotic potency of a pomegranate peel extract (PPE) rich in polyphenols in a nutritional model of obesity associated with hypercholesterolaemia and inflammatory disorders. Balb/c mice were fed either a control diet or a high-fat (HF) diet with or without PPE (6 mg/d per mouse) over a period of 4 weeks. Interestingly, PPE supplementation increased caecal content weight and caecal pool of bifidobacteria. It did not significantly modify body weight gain, glycaemia, glucose tolerance and inflammatory markers measured in the serum. However, it reduced the serum level of cholesterol (total and LDL) induced by HF feeding. Furthermore, it counteracted the HF-induced expression of inflammatory markers both in the colon and the visceral adipose tissue. Together, these findings support that pomegranate constitutes a promising food in the control of atherogenic and inflammatory disorders associated with diet-induced obesity. Knowing the poor bioavailability of pomegranate polyphenols, its bifidogenic effect observed after PPE consumption suggests the involvement of the gut microbiota in the management of host metabolism by polyphenolic compounds present in pomegranate.

Prebiotic approach alleviates hepatic steatosis: implication of fatty acid oxidative and cholesterol synthesis pathways.

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.