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 β-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. © 2015 Bindels et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.LBB is a Postdoctoral Researcher from the F.R.S.-FNRS (Fond National de la Recherche Scientifique, Belgium). NS is the recipient of a postdoctoral fellowship from the Spanish Ministry of Education, Culture and Sports. CD benefits from a Danone Institute grant. PDC is a research associate at FRS-FNRS (Fonds de la Recherche Scientifique, Belgium). GGM is a recipient of grants from FRS-FNRS and from FSR (UCL, Belgium). Financial support has been provided by a grant from the Walloon Region (Hydrasanté Project, convention 816875) and by a grant from the Spanish Ministry of Economy and Competitiveness (AGL2010-16525). NMD and PDC are recipients of grants from FNRS, and PDC is a recipient of ERC Starting Grant 2013 (European Research Council, Starting Grant 336452-ENIGMO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer Reviewe

Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice

Accumulating evidence points to Akkermansia muciniphila as a novel candidate to prevent or treat obesity-related metabolic disorders. We recently observed, in mice and in humans, that pasteurization of A. muciniphila increases its beneficial effects on metabolism. However, it is currently unknown if the observed beneficial effects on body weight and fat mass gain are due to specific changes in energy expenditure. Therefore, we investigated the effects of pasteurized A. muciniphila on whole-body energy metabolism during high-fat diet feeding by using metabolic chambers. We confirmed that daily oral administration of pasteurized A. muciniphila alleviated diet-induced obesity and decreased food energy efficiency. We found that this effect was associated with an increase in energy expenditure and spontaneous physical activity. Strikingly, we discovered that energy expenditure was enhanced independently from changes in markers of thermogenesis or beiging of the white adipose tissue. However, we found in brown and white adipose tissues that perilipin2, a factor associated with lipid droplet and known to be altered in obesity, was decreased in expression by pasteurized A. muciniphila. Finally, we observed that treatment with pasteurized A. muciniphila increased energy excretion in the feces. Interestingly, we demonstrated that this effect was not due to the modulation of intestinal lipid absorption or chylomicron synthesis but likely involved a reduction of carbohydrates absorption and enhanced intestinal epithelial turnover. In conclusion, this study further dissects the mechanisms by which pasteurized A. muciniphila reduces body weight and fat mass gain. These data also further support the impact of targeting the gut microbiota by using specific bacteria to control whole-body energy metabolism.Peer reviewe

Microbiota-derived metabolites as drivers of gut–brain communication

Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut–brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut–brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut–brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein. Abbreviations:4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood–brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(-N-oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins

The endocannabinoid system links gut microbiota to adipogenesis

We investigated several models of gut microbiota modulation: selective (prebiotics, probiotics, high-fat), drastic (antibiotics, germ-free mice) and mice bearing specific mutations of a key gene involved in the toll-like receptors (TLR) bacteria-host interaction (Myd88−/−). Here we report that gut microbiota modulates the intestinal endocannabinoid (eCB) system-tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels.The activation of the intestinal endocannabinoid system increases gut permeability which in turn enhances plasma LPS levels and inflammation in physiological and pathological conditions such as obesity and type 2 diabetes.The investigation of adipocyte differentiation and lipogenesis (both markers of adipogenesis) indicate that gut microbiota controls adipose tissue physiology through LPS-eCB system regulatory loops and may play a critical role in the adipose tissue plasticity during obesity.In vivo, ex vivo and in vitro studies indicate that LPS acts as a master switch on adipose tissue metabolism, by blocking the cannabinoid-driven adipogenesis

A POSSIBLE ROLE OF GUT MICROBIOTA IN THE BEHAVORIAL CONTROL OF ALCOHOL-DEPENDENT SUBJECTS

These observations suggest that alterations at the level of the gut microbiota influence the gut permeability and activate specific inflammation pathways that are related to psychological symptoms of alcoholdependence. Altogether these observations are consistent with a role of inflammation as one mediator of a gut-brain communication in AD patients

Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women

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. 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 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. 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

Determination of digestible energy values and fermentabilities of dietary fibre supplements: a European interlaboratory study in vivo

The performance of methods to determine energy conversion factors for dietary fibre (DF) supplements and fermentability (D) values of their non-starch polysaccharides (NSP) was investigated. Heats of combustion, digestible energy (DE) and D values were determined on five DF supplements in five European laboratories on five separate occasions. In each instance the DF supplements were fed to juvenile male VVistar rats at two doses, 50 and 100 g/kg basal diet, for 3 weeks with food and faeces collected in the 3rd week. Among-laboratory variations in heats of combustion (DHC<) were <2%. DE values (kJ/g dry weight) at the upper and lower doses respectively were: 10·4 and 9·9 for a high-methoxyl apple pectin, 9·5 and 9·4 for a sugar-beet DF supplement, 12·2 and 12·7 for soyabean DF supplement, 38 and 4·0 for maize bran, and 0·3 and 0·3 for Solka-floc cellulose. Variations among laboratories, among occasions and among animals were <1, <2 and <2·5 kJ/g respectively. The among-occasion: among-laboratory variance ratio for DE was 0·5, suggesting the method performed equally well in all laboratories. There was no evidence of learning or fatigue in the performance of the method. D values were also independent of dose and at the high and lower doses were: pectin 0·92 and 0·95, sugar-beet NSP 0·68 and 0·68, soyabean NSP 0·86 and 0·88, maize bran 0·17 and 0·18, cellulose 0·07 and 0·06. Among-laboratory variance tended to increase with decreasing fermentability and ranged from 0·03 to 0·18. The DE and D data were not significantly different from a previously proposed relationship DE = 0·7 × DHc × D, where DHc is the heat of combustion of the supplement. We conclude that while the among-laboratory variation in the D of difficult-to-ferment NSP is too large for the reliable prediction of energy value the method for the direct determination of DE is both reproducible and repeatable, that DE is independent of dosage of DF supplement up to 100 g/kg diet, and that it is safe to discriminate between energy values with a precision of 3 kJ/g. The conversion of both DE and D to net metabolizable energy for the purpose of food labelling, tables and databases is describe