Next-Generation Beneficial Microbes : The Case of Akkermansia muciniphila

Metabolic disorders associated with obesity and cardiometabolic disorders are worldwide epidemic. Among the different environmental factors, the gut microbiota is now considered as a key player interfering with energy metabolism and host susceptibility to several non-communicable diseases. Among the next-generation beneficial microbes that have been identified, Akkermansia muciniphila is a promising candidate. Indeed, A. muciniphila is inversely associated with obesity, diabetes, cardiometabolic diseases and low-grade inflammation. Besides the numerous correlations observed, a large body of evidence has demonstrated the causal beneficial impact of this bacterium in a variety of preclinical models. Translating these exciting observations to human would be the next logic step and it now appears that several obstacles that would prevent the use of A. muciniphila administration in humans have been overcome. Moreover, several lines of evidence indicate that pasteurization of A. muciniphila not only increases its stability but more importantly increases its efficacy. This strongly positions A. muciniphila in the forefront of next-generation candidates for developing novel food or pharma supplements with beneficial effects. Finally, a specific protein present on the outer membrane of A. muciniphila, termed Amuc_1100, could be strong candidate for future drug development. In conclusion, as plants and its related knowledge, known as pharmacognosy, have been the source for designing drugs over the last century, we propose that microbes and microbiomegnosy, or knowledge of our gut microbiome, can become a novel source of future therapies.Peer reviewe

Impact of Intestinal Peptides on the Enteric Nervous System: Novel Approaches to Control Glucose Metabolism and Food Intake

The gut is one of the most important sources of bioactive peptides in the body. In addition to their direct actions in the brain and/or peripheral tissues, the intestinal peptides can also have an impact on enteric nervous neurons. By modifying the endogenousproduction of these peptides, one may expect modify the “local” physiology such as glucose absorption, but also could have a “global” action via the gut–brain axis. Due to the various origins of gut peptides (i.e., nutrients, intestinal wall, gut microbiota) and the heterogeneity of enteric neurons population, the potential physiological parameters control by the interaction between the two partners are multiple. In this review, we will exclusively focus on the role of enteric nervous system as a potential target of gut peptides to control glucose metabolism and food intake. Potential therapeutic strategies based on per os administration of gut peptides to treat type 2 diabetes will be described

Gut microbiome and health : mechanistic insights

The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota deviations are linked with many diseases including obesity, type 2 diabetes, hepatic steatosis, intestinal bowel diseases (IBDs) and several types of cancer. Thus, suggesting that various pathways involved in immunity, energy, lipid and glucose metabolism are affected. In this review, specific attention is given to provide a critical evaluation of the current understanding in this field. Numerous molecular mechanisms explaining how gut bacteria might be causally linked with the protection or the onset of diseases are discussed. We examine well-established metabolites (ie, short-chain fatty acids, bile acids, trimethylamine N-oxide) and extend this to more recently identified molecular actors (ie, endocannabinoids, bioactive lipids, phenolic-derived compounds, advanced glycation end products and enterosynes) and their specific receptors such as peroxisome proliferator-activated receptor alpha (PPAR alpha) and gamma (PPAR gamma), aryl hydrocarbon receptor (AhR), and G protein-coupled receptors (ie, GPR41, GPR43, GPR119, Takeda G protein-coupled receptor 5). Altogether, understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed.Peer reviewe

Host-microbiota interaction induces bi-phasic inflammation and glucose intolerance in mice

Objective: Gut microbiota modulates adiposity and glucose metabolism in humans and mice. Here we investigated how colonization of germ-free (GF) mice affects kinetics of adiposity and glucose metabolism. Methods: Adiposity and glucose metabolism were evaluated at different time points in ex-GF and antibiotic treated mice after colonization with gut microbiota from a conventionally raised (CONV-R) mouse. Mouse physiology, microbiome configuration, serum cytokine levels, and gene expression for inflammatory markers were performed in different tissues. Results: Colonization resulted in a bi-phasic glucose impairment: the first phase occurring within 3 days of colonization (early phase) and the second 14–28 days after colonization (delayed phase). The early phase co-occurred with an inflammatory response and was independent of adiposity, while the delayed phase was mostly ascribed to adipose tissue expansion and inflammation. Importantly, re-colonization of antibiotic treated mice displays only the delayed phase of glucose impairment and adiposity, suggesting that the early phase may be unique to colonization of the immature GF mice gut. Conclusions: Our results provide new insights on host–microbiota interaction during colonization of GF mice and the resulting effects on adiposity and glucose metabolism in a time resolved fashion

Targeted nanoparticles towards increased L cell stimulation as a strategy to improve oral peptide delivery in incretin-based diabetes treatment

The delivery of therapeutic peptides via the oral route remains one of biggest challenges in the pharmaceutical industry. Recently, we have described an alternative improved drug delivery system for peptide delivery via the oral route, consisting of a lipidic nanocapsule. Despite the striking effects observed, it is still essential to develop strategies to strengthen the nanocarriers' glucagon-like peptide-1 (GLP-1) secretory effect of the nanocarrier and/or prolong its antidiabetic effect in vivo to facilitate its translation into the clinic. For this purpose, we developed and compared different fatty acid-targeted lipid and polymeric nanoparticles and evaluated the L cell stimulation induced by the nanocarriers in murine L cells in vitro and in normal healthy mice in vivo. We further examined the antidiabetic effect in vivo in an obese/diabetic mouse model induced by high-fat diet feeding and examined the effect of the oral administration frequency. Among the tested nanocarriers, only lipid-based nanocarriers that were surface-modified with DSPE-PEG(2000) on the surface were able to significantly strengthen the biological effect of the nanocarriers. They increased endogenous GLP-1 levels up to 8-fold in vivo in normo-glycemic mice. Moreover, they effectively prolonged the in vivo antidiabetic effect by normalizing the plasma glucose levels in obese/diabetic mice following long-term treatment (one month). Ultimately, the targeted nanocarriers were as effective when the administration frequency was reduced from once daily to once every other day

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

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

Fecal Enterobacteriales enrichment is associated with increased in vivo intestinal permeability in humans

Type 2 diabetes (T2D) has been linked with increased intestinal permeability, but the clinical significance of this phenomenon remains unknown. The objective of this study was to investigate the potential link between glucose control, intestinal permeability, diet and intestinal microbiota in patients with T2D. Thirty‐two males with well‐controlled T2D and 30 age‐matched male controls without diabetes were enrolled in a case–control study. Metabolic parameters, inflammatory markers, endotoxemia, and intestinal microbiota in individuals subdivided into high (HP) and normal (LP) colonic permeability groups, were the main outcomes. In T2D, the HP group had significantly higher fasting glucose (P = 0.034) and plasma nonesterified fatty acid levels (P = 0.049) compared with the LP group. Increased colonic permeability was also linked with altered abundances of selected microbial taxa. The microbiota of both T2D and control HP groups was enriched with Enterobacteriales. In conclusion, high intestinal permeability was associated with poorer fasting glucose control in T2D patients and changes in some microbial taxa in both T2D patients and nondiabetic controls. Therefore, enrichment in the gram‐negative order Enterobacteriales may characterize impaired colonic permeability prior to/independently from a disruption in glucose tolerance