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Background Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia. Methods We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51). Results In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of −1.97, −2.16, and −1.34, respectively; all Padj

Epidemiological studies have shown that obese subjects have an increased risk of developing triple‐negative breast cancer (TNBC) and an overall reduced survival. However, the relation between obesity and TNBC remains difficult to understand. We hypothesize that apelin, an adipokine whose levels are increased in obesity, could be a major factor contributing to both tumour growth and metastatization in TNBC obese patients. We observed that development of obesity under high‐fat diet in TNBC tumour‐bearing mice significantly increased tumour growth. By showing no effect of high‐fat diet in obesity‐resistant mice, we demonstrated the necessity to develop obesity‐related disorders to increase tumour growth. Apelin mRNA expression was also increased in the subcutaneous adipose tissue and tumours of obese mice. We further highlighted that the reproduction of obesity‐related levels of apelin in lean mice led to an increased TNBC growth and brain metastases formation. Finally, injections of the apelinergic antagonist F13A to obese mice significantly reduced TNBC growth, suggesting that apelinergic system interference could be an interesting therapeutic strategy in the context of obesity and TNBC.

Gut microorganisms are vital for many aspects of human health, and the commensal bacterium Akkermansia muciniphila has repeatedly been identified as a key component of intestinal microbiota. Reductions in A. muciniphila abundance are associated with increased prevalence of metabolic disorders such as obesity and type 2 diabetes. It was recently discovered that administration of A. muciniphila has beneficial effects and that these are not diminished, but rather enhanced after pasteurization. Pasteurized A. muciniphila is proposed for use as a food ingredient, and was therefore subjected to a nonclinical safety assessment, comprising genotoxicity assays (bacterial reverse mutation and in vitro mammalian cell micronucleus tests) and a 90‐day toxicity study. For the latter, Han Wistar rats were administered with the vehicle or pasteurized A. muciniphila at doses of 75, 375 or 1500 mg/kg body weight/day (equivalent to 4.8 × 109, 2.4 × 1010, or 9.6 × 1010 A. muciniphila cells/kg body weight/day) by oral gavage for 90 consecutive days. The study assessed potential effects on clinical observations (including detailed arena observations and a modified Irwin test), body weight, food and water consumption, clinical pathology, organ weights, and macroscopic and microscopic pathology. The results of both in vitro genotoxicity studies were negative. No test item‐related adverse effects were observed in the 90‐day study; therefore, 1500 mg/kg body weight/day (the highest dose tested, equivalent to 9.6 × 1010 A. muciniphila cells/kg body weight/day) was established as the no‐observed‐adverse‐effect‐level. These results support that pasteurized A. muciniphila is safe for use as a food ingredient., Pasteurized A. muciniphila is proposed for use as a food ingredient and was therefore subjected to in vitro genotoxicity tests and a 90‐day oral (gavage) toxicity study in rats. There was no evidence of genotoxicity, and the highest dose tested in the 90‐day study (1500 mg/kg body weight/day, equivalent to 9.6 × 1010 A. muciniphila cells/kg body weight/day) was established as the no‐observed‐adverse‐effect‐level. These results support the safety of pasteurized A. muciniphila for use as a food ingredient.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

ObjectiveTo investigate the abundance and the prevalence of Dysosmobacter welbionis J115T, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic syndrome. To study the impact of this bacterium on host metabolism using diet-induced obese and diabetic mice.DesignWe analysed the presence and abundance of the bacterium in 11 984 subjects using four human cohorts (ie, Human Microbiome Project, American Gut Project, Flemish Gut Flora Project and Microbes4U). Then, we tested the effects of daily oral gavages with live D. welbionis J115T on metabolism and several hallmarks of obesity, diabetes, inflammation and lipid metabolism in obese/diabetic mice.ResultsThis newly identified bacterium was detected in 62.7%–69.8% of the healthy population. Strikingly, in obese humans with a metabolic syndrome, the abundance of Dysosmobacter genus correlates negatively with body mass index, fasting glucose and glycated haemoglobin. In mice, supplementation with live D. welbionis J115T, but not with the pasteurised bacteria, partially counteracted diet-induced obesity development, fat mass gain, insulin resistance and white adipose tissue hypertrophy and inflammation. In addition, live D. welbionis J115T administration protected the mice from brown adipose tissue inflammation in association with increased mitochondria number and non-shivering thermogenesis. These effects occurred with minor impact on the mouse intestinal microbiota composition.ConclusionsThese results suggest that D. welbionis J115T directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.

Reduction of A. muciniphila relative abundance in the gut microbiota is a widely accepted signature associated with obesity-related metabolic disorders. Using untargeted metabolomics profiling of fasting plasma, our study aimed at identifying metabolic signatures associated with beneficial properties of alive and pasteurized A. muciniphila when administrated to a cohort of insulin-resistant individuals with metabolic syndrome. Our data highlighted either shared or specific alterations in the metabolome according to the form of A. muciniphila administered with respect to a control group. Common responses encompassed modulation of amino acid metabolism, characterized by reduced levels of arginine and alanine, alongside several intermediates of tyrosine, phenylalanine, tryptophan, and glutathione metabolism. The global increase in levels of acylcarnitines together with specific modulation of acetoacetate also suggested induction of ketogenesis through enhanced beta-oxidation. Moreover, our data pinpointed some metabolites of interest considering their emergence as substantial compounds pertaining to health and diseases in the more recent literature.

SIGNIFICANCE: The role of reactive oxygen/nitrogen species as "friend" or "foe" messengers in the whole body is well characterized. Depending on the concentration in the tissue considered, these molecular actors exert beneficial or deleterious impacts leading to a pathological state, as observed in metabolic disorders such as type 2 diabetes and obesity. RECENT ADVANCES: Among the tissues impacted by oxidation and inflammation in this pathological state, the intestine is a site of dysfunction that can establish diabetic symptoms, such as alterations in the intestinal barrier, gut motility, microbiota composition, and gut/brain axis communication. In the intestine, reactive oxygen/nitrogen species (from the host and/or microbiota) are key factors that modulate the transition from physiological to pathological signaling. CRITICAL ISSUES: Controlling the levels of intestinal reactive oxygen/nitrogen species is a complicated balance between positive and negative impacts that is in constant equilibrium. Here, we describe the synthesis and degradation of intestinal reactive oxygen/nitrogen species and their interactions with the host. The development of novel redox-based therapeutics that alter these processes could restore intestinal health in patients with metabolic disorders. FUTURE DIRECTIONS: Deciphering the mode of action of reactive oxygen/nitrogen species in the gut of obese/diabetic patients could result in a future therapeutic strategy that combines nutritional and pharmacological approaches. Consequently, preventive and curative treatments must take into account one of the first sites of oxidative and inflammatory dysfunctions in the body, that is, the intestine.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

International audience; Background : The gut microbiota plays a role in the occurrence of nonalcoholic fatty liver disease (NAFLD), notably through the production of bioactive metabolites. Indole, a bacterial metabolite of tryptophan, has been proposed as a pivotal metabolite modulating inflammation, metabolism, and behavior.Objectives : The aim of our study was to mimic an upregulation of intestinal bacterial indole production and to evaluate its potential effect in vivo in 2 models of NAFLD.Methods : Eight-week-old leptin-deficient male ob/ob compared with control ob/+ mice (experiment 1), and 4–5-wk-old C57BL/6JRj male mice fed a low-fat (LF, 10 kJ%) compared with a high-fat (HF, 60 kJ%) diet (experiment 2), were given plain water or water supplemented with a physiological dose of indole (0.5 mM, n ≥6/group) for 3 wk and 3 d, respectively. The effect of the treatments on the liver, intestine, adipose tissue, brain, and behavior was assessed.Results : Indole reduced hepatic expression of genes involved in inflammation [C-C motif chemokine ligand 2 (Ccl2), C-X-C motif chemokine ligand 2 (Cxcl2); 3.3- compared with 5.0-fold, and 2.4- compared with 3.3-fold of control ob/+ mice, respectively, P < 0.05], and in macrophage activation [Cd68, integrin subunit α X (Itgax); 2.1- compared with 2.5-fold, and 5.0- compared with 6.4-fold of control ob/+ mice, respectively, P < 0.01] as well as markers of hepatic damage (alaninine aminotransferase; −32%, P < 0.001) regardless of genotype in experiment 1. Indole had no effect on hepatic inflammation in mice fed the LF or HF diet in experiment 2. Indole did not change hepatic lipid content, anxiety-like behavior, or inflammation in the ileum, adipose tissue, and brain in experiment 1.Conclusions : Our results support the efficacy of indole to reduce hepatic damage and associated inflammatory response and macrophage activation in ob/ob mice. These modifications appear to be attributable to direct effects of indole on the liver, rather than through effects on the adipose tissue or intestinal barrier.

Among the myriad of molecules produced by the liver, both bile acids and their precursors, the oxysterols are becoming pivotal bioactive lipids which have been underestimated for a long time. Their actions are ranging from regulation of energy homeostasis (i.e., glucose and lipid metabolism) to inflammation and immunity, thereby opening the avenue to new treatments to tackle metabolic disorders associated with obesity (e.g., type 2 diabetes and hepatic steatosis) and inflammatory diseases. Here, we review the biosynthesis of these endocrine factors including their interconnection with the gut microbiota and their impact on host homeostasis as well as their attractive potential for the development of therapeutic strategies for metabolic disorders.

Obesity could lead to metabolic dysfunction-associated fatty liver disease (MAFLD), which severity could be linked to muscle and gut microbiota disturbances. Our prospective study enrolled 52 obese patients whose MAFLD severity was estimated by transient elastography. Patients with severe steatosis (n = 36) had higher ALAT values, fasting blood glucose levels as well as higher visceral adipose tissue area and skeletal muscle index evaluated by computed tomography. Patients with fibrosis (n = 13) had higher ASAT values, increased whole muscle area and lower skeletal muscle density index. In a multivariate logistic regression analysis, myosteatosis was the strongest factor associated with fibrosis. Illumina sequencing of 16S rRNA gene amplicon was performed on fecal samples. The relative abundance of fecal Clostridium sensu stricto was significantly decreased with the presence of liver fibrosis and was negatively associated with liver stiffness measurement and myosteatosis. In addition, 19 amplicon sequence variants were regulated according to the severity of the disease. Linear discriminant analysis effect size (LEfSe) also highlighted discriminant microbes in patients with fibrosis, such as an enrichment of Enterobacteriaceae and Escherichia/Shigella compared to patients with severe steatosis without fibrosis. All those data suggest a gut-liver-muscle axis in the pathogenesis of MAFLD complications.

Obesity is a known factor increasing the risk of developing breast cancer and reducing disease free survival. In addition to these well-documented effects, recent studies have shown that obesity is also affecting response to chemotherapy. Among the multiple dysregulations associated with obesity, increased level of the apelin adipokine has been recently shown to be directly involved in the association between obesity and increased breast cancer progression. In this study, we analyzed in a retrospective cohort of 62 breast cancer patients the impact of obesity and tumoral apelin expression on response to neoadjuvant chemotherapy. In the multivariate logistic regression, obesity and high tumoral apelin expression were associated with a reduced response to NAC in our cohort. However, obesity and high tumoral apelin expression were not correlated, suggesting that those two parameters could be independently associated with reduced NAC response. These findings should be confirmed in independent cohorts.

Hypothalamic regulations of food intake are altered during obesity. The dopaminergic mesocorticolimbic system, responsible for the hedonic response to food intake, is also affected. Gut microbes are other key players involved in obesity. Therefore, we investigated whether the gut microbiota plays a causal role in hedonic food intake alterations contributing to obesity. We transferred fecal material from lean or diet-induced obese mice into recipient mice and evaluated the hedonic food intake using a food preference test comparing the intake of control and palatable diets (HFHS, High-Fat High-Sucrose) in donor and recipient mice. Obese mice ate 58% less HFHS during the food preference test (p

Several studies suggest that microbial alterations (dysbiosis) are intimately linked to chronic inflammation occurring upon aging. The aim of this study was to investigate the potential interest of a synbiotic approach (co-administration of a probiotic bacteria and a prebiotic dietary fibre) to improve gastrointestinal wellness and inflammatory markers in middle-aged people. Middle-aged subjects were randomized to take synbiotic (Bifidobacterium animalis lactis and fructo-oligosaccharides (FOS)) or placebo for 30 days. Stool frequency and consistency were improved in both placebo and synbiotic-treated volunteers while the synbiotic treatment significantly decreased the number of days with abdominal discomfort. Synbiotic treatment had no impact on mood dimensions, quality of life scores or the overall composition of the gut microbiota (16S rRNA gene sequencing of DNA extracted from stool). Importantly, plasma proinflammatory cytokines (interleukin (IL)-6, IL-8, IL-17a and interferon-gamma (IFNγ)) were significantly lower after 30 days of synbiotic supplementation. This effect appears to be independent of the gut barrier function. This study demonstrates that a combination of B. animalis lactis and the well-known prebiotic FOS could be a promising synbiotic strategy to decrease inflammatory status with improvement of gut disorders in middle-aged people.

ObjectiveData from clinical research suggest that certain probiotic bacterial strains have the potential to modulate colonic inflammation. Nonetheless, these data differ between studies due to the probiotic bacterial strains used and the poor knowledge of their mechanisms of action.DesignBy mass-spectrometry, we identified and quantified free long chain fatty acids (LCFAs) in probiotics and assessed the effect of one of them in mouse colitis.ResultsAmong all the LCFAs quantified by mass spectrometry in Escherichia coli Nissle 1917 (EcN), a probiotic used for the treatment of multiple intestinal disorders, the concentration of 3-hydroxyoctadecaenoic acid (C18-3OH) was increased in EcN compared with other E. coli strains tested. Oral administration of C18-3OH decreased colitis induced by dextran sulfate sodium in mice. To determine whether other bacteria composing the microbiota are able to produce C18-3OH, we targeted the gut microbiota of mice with prebiotic fructooligosaccharides (FOS). The anti-inflammatory properties of FOS were associated with an increase in colonic C18-3OH concentration. Microbiota analyses revealed that the concentration of C18-3OH was correlated with an increase in the abundance in Allobaculum, Holdemanella and Parabacteroides. In culture, Holdemanella biformis produced high concentration of C18-3OH. Finally, using TR-FRET binding assay and gene expression analysis, we demonstrated that the C18-3OH is an agonist of peroxisome proliferator activated receptor gamma.ConclusionThe production of C18-3OH by bacteria could be one of the mechanisms implicated in the anti-inflammatory properties of probiotics. The production of LCFA-3OH by bacteria could be implicated in the microbiota/host interactions.

Background Cancer cachexia is a multifactorial syndrome characterized by multiple metabolic dysfunctions. Besides the muscle, other organs such as the liver and the gut microbiota may also contribute to this syndrome. Indeed, the gut microbiota, an important regulator of the host metabolism, is altered in the C26 preclinical model of cancer cachexia. Interventions targeting the gut microbiota have shown benefits, but mechanisms underlying the host–microbiota crosstalk in this context are still poorly understood. Methods To explore this crosstalk, we combined proton nuclear magnetic resonance (1H‐NMR) metabolomics in multiple compartments with 16S rDNA sequencing. These analyses were complemented by molecular and biochemical analyses, as well as hepatic transcriptomics. Results 1H‐NMR revealed major changes between control (CT) and cachectic (C26) mice in the four analysed compartments (i.e. caecal content, portal vein, liver, and vena cava). More specifically, glucose metabolism pathways in the C26 model were altered with a reduction in glycolysis and gluconeogenesis and an activation of the hexosamine pathway, arguing against the existence of a Cori cycle in this model. In parallel, amino acid uptake by the liver, with an up to four‐fold accumulation of nine amino acids (q‐value

Obese subjects present higher risk of developing mammary tumors, worse disease free survival and altered response to neoadjuvant chemotherapy (NAC). The circulating levels of the apelin adipokines are increased in obese subjects and are associated with poorer prognosis in cancer patients. In this study, we showed that obesity and tumoral apelin expression are two factors associated with incomplete response to NAC in breast cancer patients.

Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of β-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations. ispartof: CELL REPORTS vol:33 issue:2 ispartof: location:United States status: published

Background and aims Metabolic and behavioural diseases, which are often related to obesity, have been associated to alterations of the gut microbiota considered as an interesting therapeutic target. We have analyzed in a cohort of obese patients treated with prebiotic inulin versus placebo the potential link between gut microbiota changes occurring upon intervention and their effect on psychological parameters (mood and cognition). Methods A randomized, single-blinded, multicentric, placebo-controlled trial was conducted in 106 obese patients assigned to two groups: prebiotic versus placebo, who received respectively 16 g/d of native inulin or maltodextrin combined with dietary advice to consume inulin-rich or -poor vegetables for 3 months as well as to restrict caloric intake. Anthropometric measurements, food intake, psychological questionnaires, serum measures, and fecal microbiome sequencing were performed before and after the intervention. Results Inulin supplementation in obese subjects had moderate beneficial effect on emotional competence and cognitive flexibility. However, an exploratory analysis revealed that some patients exhibiting specific microbial signature -elevated Coprococcus levels at baseline- were more prone to benefit from prebiotic supplementation in terms of mood. Positive responders toward inulin intervention in term of mood also displayed worse metabolic and inflammatory profiles at baseline (increased levels of IL-8, insulin resistance and adiposity). Conclusion This study shows that inulin intake can be helpful to improve mood in obese subjects exhibiting a specific microbial profile. The present work highlights some microbial, metabolic and inflammatory features (IL-8, insulin resistance) which can predict or mediate the beneficial effects of inulin on behaviour in obesity. Food4gut, clinicaltrial.gov: NCT03852069, https://clinicaltrials.gov/ct2/show/NCT03852069 .

Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (p Akk) could prevent ovx-induced bone loss. Mice were treated with vehicle or p Akk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with p Akk reduced fat mass accumulation confirming earlier findings. However, treatment with p Akk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with p Akk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with p Akk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and p Akk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with p Akk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with p Akk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.

Rationale: Obesity could lead to several metabolic alterations, including non-alcoholic fatty liver disease (NAFLD), muscle dysfunctions and gut dysbiosis. Here, we propose to evaluate the gut microbiota composition depending on the degree of NAFLD severity. Methods: Obese patients recruited prospectively at St-Luc Hospital (FOOD4GUT project, Belgium) were included in this study. Liver stiffness and controlled attenuation parameter (CAP) measurements were performed using liver transient elastography (TE). Physical examination, blood and stool samples and computed tomography (CT) were also assessed. The fecal gut microbiota was analyzed by Illumina sequencing of the 16S rRNA gene. Results: Liver TE allowed us to classify the patients in three groups based on CAP and stiffness measurement: LS (low steatosis, n=10), HS (high steatosis, n=18) and HS+F (high steatosis + fibrosis, n=9). CT data revealed significant muscle alterations in HS+F patients, with an increase of whole muscle area and a lower muscle density index compatible with muscle fat infiltration. Both α- and β- diversity indices of the overall gut microbiota composition were not different between groups. At the taxa level, only Clostridium sensu stricto significantly decreased with the severity of liver steatosis and fibrosis (p=0.018 for HS+F vs LS). However, an analysis based on amplicon sequence variants (ASV) revealed 20 bacterial sequences significantly affected. Spearman’s correlations showed that C. sensu stricto was negatively associated with liver fibrosis, the waist/hip ratio and muscle fat infiltration. Interestingly, many ASV also correlated with clinical outcomes. Conclusions: Liver steatosis and fibrosis severity associates with a set of markers including dysbiosis. Among them, C. sensu stricto decreased with the development of liver fibrosis and related muscle fat infiltration. Other bacterial ASV are pointed out as potential markers to be evaluated in larger cohorts to unravel their link with the degree of NAFLD related complication.

Diverse metabolic disorders have been associated with an alteration of N-acylethanolamine (NAE) levels. These bioactive lipids are synthesized mainly by N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and influence host metabolism. We have previously discovered that NAPE-PLD in the intestine and adipose tissue is connected to the pathophysiology of obesity. However, the physiological function of NAPE-PLD in the liver remains to be deciphered. To study the role of liver NAPE-PLD on metabolism, we generated a new mouse model of inducible Napepld hepatocyte-specific deletion (Napepld∆Hep mice). In this study, we report that Napepld∆Hep mice develop a high-fat diet-like phenotype, characterized by an increased fat mass gain, hepatic steatosis and we show that Napepld∆Hep mice are more sensitive to liver inflammation. We also demonstrate that the role of liver NAPE-PLD goes beyond the mere synthesis of NAEs, since the deletion of NAPE-PLD is associated with a marked modification of various bioactive lipids involved in host homeostasis such as oxysterols and bile acids. Collectively these data suggest that NAPE-PLD in hepatocytes is a key regulator of liver bioactive lipid synthesis and a dysregulation of this enzyme leads to metabolic complications. Therefore, deepening our understanding of the regulation of NAPE-PLD could be crucial to tackle obesity and related comorbidities.

ObjectiveTo fulfil an unmet therapeutic need for treating type 2 diabetes by developing an innovative oral drug delivery nanosystem increasing the production of glucagon-like peptide-1 (GLP-1) and the absorption of peptides into the circulation.DesignWe developed a nanocarrier for the oral delivery of peptides using lipid-based nanocapsules. We encapsulated the GLP-1 analogue exenatide within nanocapsules and investigated in vitro in human L-cells (NCl-H716) and murine L-cells (GLUTag cells) the ability of the nanosystem to trigger GLP-1 secretion. The therapeutic relevance of the nanosystem in vivo was tested in high-fat diet (HFD)-induced diabetic mice following acute (one administration) or chronic treatment (5 weeks) in obese and diabetic mice.ResultsWe demonstrated that this innovative nanosystem triggers GLP-1 secretion in both human and murine cells as well as in vivo in mice. This strategy increases the endogenous secretion of GLP-1 and the oral bioavailability of the GLP-1 analogue exenatide (4% bioavailability with our nanosystem).The nanosystem synergizes its own biological effect with the encapsulated GLP-1 analogue leading to a marked improvement of glucose tolerance and insulin resistance (acute and chronic). The chronic treatment decreased diet-induced obesity, fat mass, hepatic steatosis, together with lower infiltration and recruitment of immune cell populations and inflammation.ConclusionWe developed a novel nanosystem compatible with human use that synergizes its own biological effect with the effects of increasing the bioavailability of a GLP-1 analogue. The effects of the formulation were comparable to the results observed for the marketed subcutaneous formulation. This nanocarrier-based strategy represents a novel promising approach for oral peptide delivery in incretin-based diabetes treatment.

International audience; Gut microbes are considered as major factors contributing to human health. Nowadays, the vast majority of the data available in the literature are mostly exhibiting negative or positive correlations between specific bacteria and metabolic parameters. From these observations, putative detrimental or beneficial effects are then inferred. Akkermansia muciniphila is one of the unique examples for which the correlations with health benefits have been causally validated in vivo in rodents and humans.In this study, based on available metagenomic data in overweight/obese population and clinical variables that we obtained from two cohorts of individuals (n = 108) we identified several metagenomic species (MGS) strongly associated with A. muciniphila with one standing out: Subdoligranulum. By analyzing both qPCR and shotgun metagenomic data, we discovered that the abundance of Subdoligranulum was correlated positively with microbial richness and HDL-cholesterol levels and negatively correlated with fat mass, adipocyte diameter, insulin resistance, levels of leptin, insulin, CRP, and IL6 in humans.Therefore, to further explore whether these strong correlations could be translated into causation, we investigated the effects of the unique cultivated strain of Subdoligranulum (Subdoligranulum variabile DSM 15176 T) in obese and diabetic mice as a proof-of-concept. Strikingly, there were no significant difference in any of the hallmarks of obesity and diabetes measured (e.g., body weight gain, fat mass gain, glucose tolerance, liver weight, plasma lipids) at the end of the 8 weeks of treatment. Therefore, the absence of effect following the supplementation with S. variabile indicates that increasing the intestinal abundance of this bacterium is not translated into beneficial effects in mice.In conclusion, we demonstrated that despite the fact that numerous strong correlations exist between a given bacteria and health, proof-of-concept experiments are required to be further validated or not in vivo. Hence, an urgent need for causality studies is warranted to move from human observations to preclinical validations

INTRODUCTION: Obesity represents a unique challenge for public health in the world and is probably one of the greatest public health threats of this century. The worldwide increase in prevalence is associated with concomitant global burden of cardiometabolic risk factors including insulin resistance, type 2 diabetes, and dyslipidemia but also several forms of cancer. Numerous attempts are made in view of both understanding the reasons of this global problem and finding solutions. [...]

A healthy diet is generally recognised as a diet that supports the physiological and energetic requirements of the body and provides sufficient, though not excessive, amounts of micronutrients and macronutrients. Despite this self-evident definition, the implementation of this basic principle has proven very difficult in modern western society. The benefits of adopting a Mediterranean diet (MedDiet) were already scientifically described more than 50 years ago,1 when a reduction in cardiovascular disease risk was observed among populations whose nutritional habits were consistent with those of people from the Mediterranean basin.2 Today, adherence to a MedDiet has been associated with lower mortality, reductions in obesity, type 2 diabetes, low-grade inflammation, cancer, Alzheimer’s disease and depression, and, more recently, the delayed onset of Crohn’s disease.3–5 Surprisingly, the exact mechanisms of action are not yet fully understood, and various hypotheses have been proposed to explain the potential beneficial effects of the MedDiet. Among them, a presumed link between the MedDiet and the gut microbiota was put forward not more than a few years ago; this idea is therefore considered relatively new. In GUT , two studies conducted in humans have now made progress towards a better understanding of the role of the gut microbiota and the MedDiet in disease risk factors.6 7 In the first paper, Meslier and colleagues studied healthy overweight or obese subjects with sedentary lifestyles who habitually consumed low amounts of fruits and vegetables during an 8-week follow-up.6 In this randomised controlled study, 43 subjects were assigned to the MedDiet group, in which they received a personalised diet adapted to their habitual energy intake. The remaining 39 subjects continued on their regular diet. Among the different food items proposed to the MedDiet group were fewer meat and refined-cereal products and more fish, fruits, vegetables, legumes and …

Purpose: Optimal head and neck squamous cell carcinoma (HNSCC) patient selection for anti–EGFR-based therapy remains an unmet need since only a minority of patients derive long-term benefit from cetuximab treatment. We assessed the ability of state-of-the-art noninvasive in vivo metabolic imaging to probe metabolic shift in cetuximab-sensitive and -resistant HNSCC patient-derived tumor xenografts (PDTXs). Experimental Design: Three models selected based on their known sensitivity to cetuximab in patients (cetuximab-sensitive or acquired-resistant HNC007 PDTXs, cetuximab-naïve UCLHN4 PDTXs, and cetuximab-resistant HNC010 PDTXs) were inoculated in athymic nude mice. Results: Cetuximab induced tumor size stabilization in mice for 4 weeks in cetuximab-sensitive and -naïve models treated with weekly injections (30 mg/kg) of cetuximab. Hyperpolarized 13C-pyruvate–13C-lactate exchange was significantly decreased in vivo in cetuximab-sensitive xenograft models 8 days after treatment initiation, whereas it was not modified in cetuximab-resistant xenografts. Ex vivo analysis of sensitive tumors resected at day 8 after treatment highlighted specific metabolic changes, likely to participate in the decrease in the lactate to pyruvate ratio in vivo. Diffusion MRI showed a decrease in tumor cellularity in the HNC007-sensitive tumors, but failed to show sensitivity to cetuximab in the UCLHN4 model. Conclusions: This study constitutes the first in vivo demonstration of cetuximab-induced metabolic changes in cetuximab-sensitive HNSCC PDTXs that were not present in resistant tumors. Using metabolic imaging, we were able to identify hyperpolarized 13C-pyruvate as a potential marker for response and resistance to the EGFR inhibitor in HNSCC.

Long considered a bystander in the human gastrointestinal tract, the hundred trillion microbes residing in our gut, known as the gut microbiota, are now considered critical for human health (1). These microbial cells outnumber our own cells; hence the gut microbiota harbors at least 100-fold more genes than the human genome (2). This vast catalogue of genes encodes for diverse metabolic activities, allowing the gut microbes to adapt to their environment and to the energy sources available. This complex ecosystem has developed metabolic capacities that we are unable to perform on our own....

International audience; Overweight and obesity are associated with several cardiometabolic risk factors, including insulin resistance, type 2 diabetes, low-grade inflammation and liver diseases. The gut microbiota is a potential contributing factor regulating energy balance. However, although the scientific community acknowledges that the gut microbiota composition and its activity (e.g. production of metabolites and immune-related compounds) are different between healthy subjects and subjects with overweight/obesity, the causality remains insufficiently demonstrated. The development of low-grade inflammation and related metabolic disorders has been connected with metabolic endotoxaemia and increased gut permeability. However, the mechanisms acting on the regulation of the gut barrier and eventually cardiometabolic disorders are not fully elucidated. In this review, we debate several characteristics of the gut microbiota, gut barrier function and metabolic outcomes. We examine the role of specific dietary compounds or nutrients (e.g. prebiotics, probiotics, polyphenols, sweeteners, and a fructose-rich diet) as well as different metabolites produced by the microbiota in host metabolism, and we discuss how they control several endocrine functions and eventually have either beneficial or deleterious effects on host health.

The aim of this study was to determine the impact of different wheat bran fractions on the gut microbiota and fat binding capacity to explain their differential effects on metabolic and inflammatory disorders induced by a western diet (WD) in mice. Wheat bran derived arabinoxylan oligosaccharides (AXOS), a crude fraction of wheat bran (WB), or the same wheat bran with reduced particle size (WBs) were added to the WD of mice for 8 weeks. AXOS shifted the gut microbiota composition, blunted Clostridium and Turicibacter genera and strongly promoted Bifidobacterium and Butyricicoccus genera, independently of changes in gut antimicrobial peptide expression. AXOS was the most efficient to reduce adiposity. Only WB fraction promoted fat excretion and differed from the other fractions by the capacity to increase the Akkermansia genus and to counteract gut interleukin 1 beta (IL1β) overexpression. Strikingly, WBs promoted steatosis and adipose tissue inflammation, despite its ability -like WB- to increase bacterial diversity. In conclusion, wheat bran fractions differently affect metabolic and inflammatory disorders associated with WD feeding, depending on their particle size, their fat binding capacity and their influence on the gut microbiota. Those results might be useful to take into account in nutritional advices to control obesity.

The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of secretory IgA (sIgA) and antimicrobial peptides and proteins. With the exception of sIgA, expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions through the production of short-chain fatty acids (SCFAs) and interactions with innate pattern recognition receptors in the mucosa, driving the steady-state expression of mucus and antimicrobial factors. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability, and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of a variety of gastrointestinal disorders. Additionally, gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the hypothalamus-pituitary-adrenal axis and both mast cell-dependent and mast cell-independent mechanisms. The modulation of gut barrier function through nutritional interventions, including strategies to manipulate the microbiota, is considered a relevant target for novel therapeutic and preventive treatments against a range of diseases. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in intestinal diseases, but there remains a need to explore their use in assessing the effect of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of available biomarkers and their predictive value for gut health in human cohorts.

Visceral fat accumulation is considered one of the most important risk factors for the development of type 2 diabetes. Although the molecular mechanisms linking visceral fat accretion to impaired glucose metabolism are not yet fully elucidated, one commonly accepted trigger is chronic low-grade inflammation in the visceral fat and metabolic organs, such as the liver and muscles, in people with diabetes and obesity. […]

Intake of a high‐fat meal induces a systemic inflammatory response in the postprandial which is augmented in obese subjects. However, the underlying mechanisms of this response have not been fully elucidated. We aimed to assess the effect of gut microbiota modulation on postprandial inflammatory response in lean and obese subjects. Ten lean and ten obese subjects with metabolic syndrome received oral vancomycin 500 mg four times per day for 7 days. Oral high‐fat meal tests (50 g fat/m2 body surface area) were performed before and after vancomycin intervention. Gut microbiota composition, leukocyte counts, plasma lipopolysaccharides (LPS), LPS‐binding protein (LBP), IL‐6 and MCP‐1 concentrations and monocyte CCR2 and cytokine expression were determined before and after the high‐fat meal. Oral vancomycin treatment resulted in profound changes in gut microbiota composition and significantly decreased bacterial diversity in both groups (phylogenetic diversity pre‐ versus post‐intervention: lean, 56.9 ± 7.8 vs. 21.4 ± 6.6, P

Bariatric surgery (BS) is the most efficacious treatment against severe obesity and T2D. Among bariatric procedures, biliopancreatic diversion with duodenal switch (BPD-DS) can produce superior metabolic benefits compared with other surgical options. The mechanisms by which BPD-DS improve metabolic health are not well-understood, but there is evidence implicating the gut microbiota (GM) as contributor to changes in adiposity and consequently blood glucose control. We aimed to determine how the GM before and after BPD-DS alter host metabolism. Fecal samples from female patients subjected to BPD-DS were collected before (pre-surgery) and 12 months after surgery (post-surgery) and used to colonize female C57BL6NTac mice housed either in germ-free (GF) or SPF conditions. Oral glucose tolerance (OGT) was assessed in mice 3 and 7 weeks post-colonization. Three weeks after fecal microbiota transplantation (FMT), glucose tolerance was similar in GF mice receiving pre- and post-surgery fecal slurries. However, GF mice had lower glucose during OGT test 7 weeks after FMT derived from BPD-DS post-surgery compared to GF mice receiving pre-surgery fecal slurry. No changes in fat mass accretion were seen between pre- and post-surgery mice. SPF mice colonized with the fecal microbiota pre- and post-surgery showed no difference in glucose tolerance after 3 and 7 weeks of FMT. These data suggest that the GM after BPD-DS is an independent and transmissible contributor to improved host glucose control. Furthermore, while our data show that the mouse model (e.g., SPF vs. GF) dictates the glycemic response to FMT, exposure time (e.g., at least 7 weeks) is a key factor in microbe transmissible changes in glycemia. Disclosure F. Forato Anhê: None. K.P. Foley: None. N.G. Barra: None. B.M. Duggan: None. J.F. Cavallari: None. B.D. Henriksbo: None. P.D. Cani: Board Member; Self; A-Mansia Biotech. Consultant; Self; Biocodex, Pilèje, Valbiotis. Research Support; Self; Tate & Lyle. Stock/Shareholder; Self; A-Mansia Biotech, Enterosys. L. Biertho: None. A. Tchernof: Research Support; Self; Johnson & Johnson Medical Devices Companies, Medtronic, Pfizer Inc. A. Marette: Advisory Panel; Self; Plexus, Valbiotis. Consultant; Self; Danone Nutricia Research. J.D. Schertzer: None. Funding Canadian Institutes of Health Research; Diabetes Canada

Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus1. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension3–8. Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters. Supplementation with Akkermansia muciniphila, a gut microbe previously associated with metabolic health in preclinical models, is safe and well tolerated in humans and may improve metabolic parameters in overweight and obese patients.

The gut-brain axis is of crucial importance for controlling glucose homeostasis. Alteration of this axis promotes the type 2 diabetes (T2D) phenotype (hyperglycaemia, insulin resistance). Recently, a new concept has emerged to demonstrate the crucial role of the enteric nervous system in the control of glycaemia via the hypothalamus. In diabetic patients and mice, modification of enteric neurons activity in the proximal part of the intestine generates a duodenal hyper-contractility that generates an aberrant message from the gut to the brain. In turn, the hypothalamus sends an aberrant efferent message that provokes a state of insulin resistance, which is characteristic of a T2D state. Targeting the enteric nervous system of the duodenum is now recognized as an innovative strategy for treatment of diabetes. By acting in the intestine, bioactive gut molecules that we called “enterosynes” can modulate the function of a specific type of neurons of the enteric nervous system to decrease the contraction of intestinal smooth muscle cells. Here, we focus on the origins of enterosynes (hormones, neurotransmitters, nutrients, microbiota, and immune factors), which could be considered therapeutic factors, and we describe their modes of action on enteric neurons. This unsuspected action of enterosynes is proposed for the treatment of T2D, but it could be applied for other therapeutic solutions that implicate communication between the gut and brain.

Patients with alcohol use disorder (AUD) present with important emotional, cognitive and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show for the first time that the gut microbiota drives behavioral features of alcohol addiction including reduced sociability. By transplanting the gut microbiota from AUD patients to mice, we pointed out that the production of ethanol by specific bacterial genera, is associated with a lower hepatic synthesis of beta-hydroxybutyrate (BHB), and thereby prevent the protective effect of BHB on social behavior, neuroinflammation and neurotransmission. We confirmed this hypothesis detoxified AUD patients, in which we observed a persisting ethanol production in the feces as well as correlations between low plasma BHB levels and social impairments. Our data support new pathways involved in behavioral disorders associated with alcohol addiction, that could be considered for future treatments.

In 2018, more than 4,000 publications were dedicated to the study of the gut microbiota, and an important proportion investigated cardiometabolic disorders associated with overweight and obesity. Novel mechanisms and strategies have emerged, some of which were focused not only on specific bacteria or nutrients, but also on new metabolites.

The gut bacterial species Akkermansia muciniphila is associated with a healthier clinical profile. The purpose of this study was to determine the association between A. muciniphila and glucose homeostasis in patients undergoing bariatric surgery (BS): gastric banding (GB) or Roux-en-Y gastric bypass (RYGB). This nonrandomized prospective study included 65 women with severe obesity. Longitudinal analysis included subjects for whom A. muciniphila data were available at follow-up [1, 3, and 12 mo; GB ( n = 10) or RYGB ( n = 11)]. Glucose homeostasis markers were measured under fasting conditions (glucose, insulin, and HbA1c) or during an oral glucose tolerance test. Fecal microbiota was analyzed using shotgun metagenomics, and A. muciniphila relative abundance was assessed with 16S rRNA quantitative PCR. A. muciniphila relative abundance was significantly lower in severe obesity [mean body mass index, 45.7 kg/m2 (SD 5.4)] than in moderate obesity [33.2 kg/m2 (SD 3.8)] but not associated with glucose homeostasis markers. A significant increase in A. muciniphila relative abundance after RYGB was not correlated with metabolic improvement. Baseline A. muciniphila abundance was correlated with bacterial gene richness and was highest in the high-richness Ruminococcaceae enterotype. A. muciniphila increased in relative abundance after BS in patients with low baseline A. muciniphila abundance, especially those with a Bacteroides type 2 enterotype classification. Although decreased in severe obesity, relative abundance of A. muciniphila was not associated with glucose homeostasis before or after BS. A certain level of A. muciniphila abundance might be required to observe a beneficial link to health. The severity of obesity and gut dysbiosis may partly explain the discrepancy with previous findings in less obese populations.

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.

Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPAR&alpha, ). We hypothesize that PPAR&alpha, activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome.

The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types. Whereas few results from clinical metagenomic studies in liver disease are available, evidence is accumulating that in liver cirrhosis an oral microbiome is overrepresented in the lower intestinal tract, potentially contributing to disease process and severity. A major role for the gut microbiota in liver disorders is also supported by the accumulating evidence that several complications of severe liver disease such as hepatic encephalopathy are efficiently treated by various prebiotics, probiotics and antibiotics. A better understanding of the gut microbiota and its components in liver diseases might provide a more complete picture of these complex disorders and also form the basis for novel therapies.

The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases.

International audience; In recent years, there have been several reviews on gut microbiota, obesity and cardiometabolism summarizing interventions that may impact the gut microbiota and have beneficial effects on the host (some examples include [1–3]). In this review we discuss how the gut microbiota changes with weight loss (WL) interventions in relation to clinical and dietary parameters. We also evaluate available evidence on the heterogeneity of response to these interventions. Two important questions were generated in this regard: 1) Can response to an intervention be predicted? 2) Could pre-intervention modifications to the gut microbiota optimize WL and metabolic improvement? Finally, we have delineated some recommendations for future research, such as the importance of assessment of diet and other environmental exposures in WL intervention studies, and the need to shift to more integrative approaches of data analysis.

Obesity and obesity-related disorders, such as type 2 diabetes have been progressively increasing worldwide and treatments have failed to counteract their progression. Growing evidence have demonstrated that gut microbiota is associated with the incidence of these pathologies. Hence, the identification of new nutritional compounds, able to improve health through a modulation of gut microbiota, is gaining interest. In this context, the aim of this study was to investigate the gut-driving effects of rhubarb extract in a context of diet-induced obesity and diabetes. Eight weeks old C57BL6/J male mice were fed a control diet (CTRL), a high fat and high sucrose diet (HFHS) or a HFHS diet supplemented with 0.3% (g/g) of rhubarb extract for eight weeks. Rhubarb supplementation fully prevented HFHS-induced obesity, diabetes, visceral adiposity, adipose tissue inflammation and liver triglyceride accumulation, without any modification in food intake. By combining sequencing and qPCR methods, we found that all these effects were associated with a blooming of Akkermansia muciniphila, which is strongly correlated with increased expression of Reg3&gamma, in the colon. Our data showed that rhubarb supplementation is sufficient to protect against metabolic disorders induced by a diet rich in lipid and carbohydrates in association with a reciprocal interaction between Akkermansia muciniphila and Reg3&gamma

We previously investigated whether inhibition of AMP-metabolizing enzymes could enhance AMP-activated protein kinase (AMPK) activation in skeletal muscle for the treatment of type 2 diabetes. Soluble 5'-nucleotidase II (NT5C2) hydrolyzes IMP and its inhibition could potentially lead to a rise in AMP to activate AMPK. In the present study, we investigated effects of NT5C2 deletion in mice fed a normal-chow diet (NCD) or a high-fat diet (HFD). On a NCD, NT5C2 deletion did not result in any striking metabolic phenotype. On a HFD however, NT5C2 knockout (NT5C2-/-) mice displayed reduced body/fat weight gain, improved glucose tolerance, reduced plasma insulin, triglyceride and uric acid levels compared with wild-type (WT) mice. There was a tendency towards smaller and fewer adipocytes in epididymal fat from NT5C2-/- mice compared to WT mice, consistent with a reduction in triglyceride content. Differences in fat mass under HFD could not be explained by changes in mRNA expression profiles of epididymal fat from WT versus NT5C2-/- mice. However, rates of lipolysis tended to increase in epididymal fat pads from NT5C2-/- versus WT mice, which might explain reduced fat mass. In incubated skeletal muscles, insulin-stimulated glucose uptake and associated signalling were enhanced in NT5C2-/- versus WT mice on HFD, which might contribute towards improved glycemic control. In summary, NT5C2 deletion in mice protects against HFD-induced weight gain, adiposity, insulin resistance and associated hyperglycemia. ispartof: MOLECULAR GENETICS AND METABOLISM vol:126 issue:4 pages:377-387 ispartof: location:United States status: published

In the article listed above, Béatrice Morio was inadvertently identified in the byline as Béatrice Morio-Liondor. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db17-1488) has been updated to correct this omission.

IF 7.273 (2017); International audience; Altering the gut microbiome may be beneficial to the host, and it recently arose as a promising strategy to manage obesity. Here, we investigated the relative contribution of ω3 polyunsaturated fatty acid (PUFA)-mediated alterations in the microbiota to metabolic parameter changes in mice. Four groups were compared: male fat-1 transgenic mice (with constitutive production of ω3 PUFAs) and male WT littermates fed either an obesogenic (high fat/high sucrose, HFHS) or a control diet. Unlike WT mice, HFHS-fed fat-1 mice were protected against obesity, glucose intolerance and hepatic steatosis. Unlike WT mice, fat-1 mice maintained a normal barrier function, resulting in a significantly lower metabolic endotoxemia. Fat-1 mice displayed greater phylogenic diversity in the cecum, and fecal microbiota transplantation from fat-1 to WT mice was able to reverse weight gain and to normalize glucose tolerance and intestinal permeability. We concluded that the ω3 fatty acid-mediated alteration of gut microbiota contributed to the prevention of metabolic syndrome in fat-1 mice. It occurred independently of changes in PUFA content of host tissues, and may represent a promising strategy to prevent metabolic disease and to preserve a lean phenotype.

In 2015, 30.3 million Americans had diabetes, and 84.1 million Americans had prediabetes. Up to 70% of individuals with prediabetes will eventually develop type 2 diabetes (T2D). Additional intervention strategies are needed to manage prediabetes. The pathophysiology of T2D is complex and characterized by alterations in many tissues. We have previously shown that Totum-63 is effective to prevent glucose homeostasis impairments in rodent models of T2D. In an open phase I/II clinical study, Totum-63 also improved glucose and insulin responses to a standardized breakfast in healthy subjects. In order to better understand the mechanisms involved in the beneficial effects of Totum-63, we have conducted early interventions with oral administration of Totum-63 in high fat-fed mice and in db/db mice. Body weight gain and fat mass accumulation, known as early mediators of insulin-sensitivity defectiveness, were markedly lowered. Liver and skeletal muscle insulin signaling pathways were activated in a similar fashion despite lower circulating insulin levels, suggesting an improvement in insulin sensitivity. Hepatic triglyceride content, known as a powerful inductor of liver insulin resistance, was reduced. Totum-63 administration increased liver gene expression of FGF-21, which has been involved in the regulation of many metabolic pathways. In db/db mice, Totum-63 administration delayed the defect of insulin secretion, suggesting a protective role on pancreatic beta-cells. Finally, Totum-63 also showed preventive effects on high fat diet-induced gut microbiota dysbiosis, that has been postulated as a key driver of many metabolic disturbances. In conclusion, Totum-63 displays pleiotropic beneficial effects on tissues known as major contributors to T2D development. Totum-63 is a promising intervention strategy to prevent T2D development, and is currently under investigation in phase II clinical trial. Disclosure V. Chavanelle: Employee; Self; Valbiotis. Y.F. Otero: Employee; Self; Valbiotis. P. Sirvent: Employee; Self; Valbiotis. P.D. Cani: Research Support; Self; Tate&Lyle. Consultant; Self; Biocodex. Stock/Shareholder; Self; A-Mansia Biotech SA. Research Support; Self; Pilèje, Valbiotis. S. Peltier: Board Member; Self; Valbiotis.

International audience; Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiotagut-brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight. However, the consequences of manipulating the implication of the microbiota-gut-brain axis in the control motivational and hedonic/reinforcing aspects of food are still underexplored. In this study, we investigate whether and how dietary prebiotic fructo-oligosaccharides (FOS) could oppose, or revert, the change in hedonic and homeostatic control of feeding occurring after a 2-months exposure to high-fat high-sugar (HFHS) diet. The reinforcing and motivational components of food reward were assessed using a two-food choice paradigm and a food operant behavioral test in mice exposed to FOS either during or after HFHS exposure. We also performed mRNA expression analysis for key genes involved in limbic and hypothalamic control of feeding. We show in a preventive-like approach, FOS addition of HFHS diet had beneficial impact of hypothalamic neuropeptides, and decreased the operant performance for food but only after an overnight fast while it did not prevent the imbalance in mesolimbic markers for DA signaling induced by palatable diet exposure nor the spontaneous tropism for palatable food when given the choice. However, when FOS was added to control diet after chronic HFHS exposure, although it did not significantly alter body weight loss, it greatly decreased palatable food tropism and consumption and was associated with normalization of MCL markers for DA signaling. We conclude that the nature of the diet (regular chow or HFHS) as well as the timing at which prebiotic supplementation is introduced (preventive or curative) greatly influence the efficacy of the gut-microbiota-brain axis. This crosstalk selectively alters the hedonic or motivational drive to eat and triggers molecular changes in neural substrates involved in the homeostatic and non-homeostatic control of body weight.