Publications by authors named "Amandine Everard"

48 Publications

Beneficial Effects of Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists.

Cells 2021 Jan 19;10(1). Epub 2021 Jan 19.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium.

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 . Results from multivariate analyses suggested that the beneficial effects of 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 (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by in human metabolic syndrome.
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http://dx.doi.org/10.3390/cells10010185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832901PMC
January 2021

Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models.

Cells 2021 Jan 5;10(1). Epub 2021 Jan 5.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium.

The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity.
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http://dx.doi.org/10.3390/cells10010071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824762PMC
January 2021

Laryngopharyngeal reflux: The microbiota theory.

Med Hypotheses 2021 Jan 16;146:110460. Epub 2020 Dec 16.

Laryngopharyngeal Reflux Study Group of Young-Otolaryngologists of the International Federations of Oto-rhino-laryngological Societies (YO-IFOS), Belgium; Department of Otorhinolaryngology and Head and Neck Surgery, CHU de Bruxelles, CHU Saint-Pierre, School of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Department of Otorhinolaryngology and Head and Neck Surgery, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Paris, France.

Laryngopharyngeal reflux (LPR) is a prevalent disease associated with non-specific symptoms and findings. Many gray areas persist in the pathogenesis of LPR, the diagnosis and the treatment. Symptoms are poorly correlated with fiberoptic signs or hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring findings. The therapeutic response remains uncertain with some resistant patients to medical or surgical treatment. The development of LPR-symptoms and findings may be related to the refluxate of a myriad of gastroduodenal enzymes, which may modify the laryngopharyngeal and oral microbiome leading to mucosa maintenance and recovery impairments. The diet of patient is important because it may impact the microbiome composition and some foods are known to increase the number of hypopharyngeal reflux events. The number of hypopharyngeal reflux events may be increased by autonomic nerve dysfunction that may have an important role in the persistence of LPR-symptoms.
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http://dx.doi.org/10.1016/j.mehy.2020.110460DOI Listing
January 2021

Inflammation-induced cholestasis in cancer cachexia.

J Cachexia Sarcopenia Muscle 2021 Feb 22;12(1):70-90. Epub 2020 Dec 22.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.

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 < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017).

Conclusions: We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.
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http://dx.doi.org/10.1002/jcsm.12652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890151PMC
February 2021

Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice.

Gut 2020 Oct 5. Epub 2020 Oct 5.

IRSD, INSERM, Toulouse, Occitanie, France

Objective: The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes.

Design: We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human.

Results: We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic.

Conclusions: Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.
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http://dx.doi.org/10.1136/gutjnl-2019-320230DOI Listing
October 2020

Comparison of the effects of soluble corn fiber and fructooligosaccharides on metabolism, inflammation, and gut microbiome of high-fat diet-fed mice.

Am J Physiol Endocrinol Metab 2020 10 24;319(4):E779-E791. Epub 2020 Aug 24.

Université Catholique de Louvain, Université Catholique de Louvain, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and Biotechnology, Metabolism and Nutrition Research Group, Brussels, Belgium.

Dietary fibers are essential components of a balanced diet and have beneficial effects on metabolic functions. To gain insight into their impact on host physiology and gut microbiota, we performed a direct comparison of two specific prebiotic fibers in mice. During an 8-wk follow up, mice fed a high-fat diet (HFD) were compared with mice on a normal diet (basal condition, controls) and to mice fed the HFD but treated with one of the following prebiotics: fructooligosaccharides (FOS) or soluble corn fiber (SCF). Both prebiotic fibers led to a similar reduction of body weight and fat mass, lower inflammation and improved metabolic parameters. However, these health benefits were the result of different actions of the fibers, as SCF impacted energy excretion, whereas FOS did not. Interestingly, both fibers had very distinct gut microbial signatures with different short-chain fatty acid profiles, indicating that they do not favor the growth of the same bacterial communities. Although the prebiotic potential of different fibers may seem physiologically equivalent, our data show that the underlying mechanisms of action are different, and this by targeting different gut microbes. Altogether, our data provide evidence that beneficial health effects of specific dietary fibers must be documented to be considered a prebiotic and that studies devoted to understanding how structures relate to specific microbiota modulation and metabolic effects are warranted.
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http://dx.doi.org/10.1152/ajpendo.00108.2020DOI Listing
October 2020

Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis.

Am J Physiol Endocrinol Metab 2020 09 10;319(3):E647-E657. Epub 2020 Aug 10.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Bruxelles, Belgium.

Our objective was to explore the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD) and understand the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking in the intestinal epithelial cells (IECs). We generated a murine model harboring an inducible NAPE-PLD deletion in IECs (). After an overnight fast, we exposed wild-type (WT) and mice to different forms of lipid challenge (HFD or gavage), and we compared the modification occurring in the hypothalamus, in the vagus nerve, and at endocrine level 30 and 60 min after the stimulation. mice displayed lower hypothalamic levels of -oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic occurred in the hypothalamus of mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in mice. Following lipid administration, WT and mice had similar portal levels of glucagon-like peptide-1 (GLP-1) and similar rates of GLP-1 inactivation. Administration of exendin-4, a full agonist of GLP-1 receptor (GLP-1R), prevented the hyperphagia of mice upon HFD. We conclude that in response to lipid, mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased levels of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, we elucidated novel physiological mechanisms regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.
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http://dx.doi.org/10.1152/ajpendo.00146.2020DOI Listing
September 2020

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

Gut Microbes 2020 09 13;11(5):1231-1245. Epub 2020 Mar 13.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique De Louvain , Brussels, Belgium.

Accumulating evidence points to as a novel candidate to prevent or treat obesity-related metabolic disorders. We recently observed, in mice and in humans, that pasteurization of 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 on whole-body energy metabolism during high-fat diet feeding by using metabolic chambers. We confirmed that daily oral administration of pasteurized 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 . Finally, we observed that treatment with pasteurized 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 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.
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http://dx.doi.org/10.1080/19490976.2020.1737307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524283PMC
September 2020

Acute environmental hypoxia potentiates satellite cell-dependent myogenesis in response to resistance exercise through the inflammation pathway in human.

FASEB J 2020 01 10;34(1):1885-1900. Epub 2019 Dec 10.

Institute of Neuroscience, UCLouvain, Université catholique de Louvain, Louvain la Neuve, Belgium.

Acute environmental hypoxia may potentiate muscle hypertrophy in response to resistance training but the mechanisms are still unknown. To this end, twenty subjects performed a 1-leg knee extension session (8 sets of 8 repetitions at 80% 1 repetition maximum, 2-min rest between sets) in normoxic or normobaric hypoxic conditions (FiO2 14%). Muscle biopsies were taken 15 min and 4 hours after exercise in the vastus lateralis of the exercised and the non-exercised legs. Blood samples were taken immediately, 2h and 4h after exercise. In vivo, hypoxic exercise fostered acute inflammation mediated by the TNFα/NF-κB/IL-6/STAT3 (+333%, +194%, + 163% and +50% respectively) pathway, which has been shown to contribute to satellite cells myogenesis. Inflammation activation was followed by skeletal muscle invasion by CD68 (+63%) and CD197 (+152%) positive immune cells, both known to regulate muscle regeneration. The role of hypoxia-induced activation of inflammation in myogenesis was confirmed in vitro. Acute hypoxia promoted myogenesis through increased Myf5 (+300%), MyoD (+88%), myogenin (+1816%) and MRF4 (+489%) mRNA levels in primary myotubes and this response was blunted by siRNA targeting STAT3. In conclusion, our results suggest that hypoxia could improve muscle hypertrophic response following resistance exercise through IL-6/STAT3-dependent myogenesis and immune cells-dependent muscle regeneration.
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http://dx.doi.org/10.1096/fj.201902244RDOI Listing
January 2020

abundance is lower in severe obesity, but its increased level after bariatric surgery is not associated with metabolic health improvement.

Am J Physiol Endocrinol Metab 2019 09 2;317(3):E446-E459. Epub 2019 Jul 2.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Nutrition & Obesity-Systemic Approaches Research Group (NutriOmics), Institute of Cardiometabolism and Nutrition, Paris, France.

The gut bacterial species is associated with a healthier clinical profile. The purpose of this study was to determine the association between 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 data were available at follow-up [1, 3, and 12 mo; GB ( = 10) or RYGB ( = 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 relative abundance was assessed with 16S rRNA quantitative PCR. relative abundance was significantly lower in severe obesity [mean body mass index, 45.7 kg/m (SD 5.4)] than in moderate obesity [33.2 kg/m (SD 3.8)] but not associated with glucose homeostasis markers. A significant increase in relative abundance after RYGB was not correlated with metabolic improvement. Baseline abundance was correlated with bacterial gene richness and was highest in the high-richness Ruminococcaceae enterotype. increased in relative abundance after BS in patients with low baseline . abundance, especially those with a type 2 enterotype classification. Although decreased in severe obesity, relative abundance of was not associated with glucose homeostasis before or after BS. A certain level of 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.
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http://dx.doi.org/10.1152/ajpendo.00140.2019DOI Listing
September 2019

Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

Nat Med 2019 07 1;25(7):1096-1103. Epub 2019 Jul 1.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, WELBIO, Walloon Excellence in Life Sciences and BIOtechnology, UCLouvain, Université catholique de Louvain, Brussels, Belgium.

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 mellitus. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension. 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 10 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.
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http://dx.doi.org/10.1038/s41591-019-0495-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699990PMC
July 2019

Hepatic MyD88 regulates liver inflammation by altering synthesis of oxysterols.

Am J Physiol Endocrinol Metab 2019 07 30;317(1):E99-E108. Epub 2019 Apr 30.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain and Walloon Excellence in Life Sciences and Biotechnology , Brussels , Belgium.

This study aimed to investigate the function of hepatic myeloid differentiation primary response gene 88 (MyD88), a central adaptor of innate immunity, in metabolism. Although its role in inflammation is well known, we have recently discovered that MyD88 can also mediate energy, lipid, and glucose metabolism. More precisely, we have reported that mice harboring hepatocyte-specific deletion of (Myd88) were predisposed to glucose intolerance, liver fat accumulation, and inflammation. However, the molecular events explaining the onset of hepatic disorders and inflammation remain to be elucidated. To investigate the molecular mechanism, Myd88 and wild-type (WT) mice were challenged by two complementary approaches affecting liver lipid metabolism and immunity. The first approach consisted of a short-term exposure to high-fat diet (HFD), whereas the second was an acute LPS injection. We discovered that upon 3 days of HFD Myd88 mice displayed an increase in liver weight and liver lipids compared with WT mice. Moreover, we found that bile acid and oxysterol metabolism were deeply affected by the absence of hepatic MyD88. Our data suggest that the negative feedback loop suppressing bile acid synthesis was impaired (i.e., ERK activity was decreased) in Myd88 mice. Finally, the predisposition to inflammation sensitivity displayed by Myd88 mice may be caused by the accumulation of 25-hydroxycholesterol, an oxysterol linked to inflammatory response and metabolic disorders. This study highlights the importance of MyD88 on both liver fat accumulation and cholesterol-derived bioactive lipid synthesis. These are two key features associated with metabolic syndrome. Therefore, investigating the regulation of hepatic MyD88 could lead to discovery of new therapeutic targets.
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http://dx.doi.org/10.1152/ajpendo.00082.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689736PMC
July 2019

Intestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis.

Nat Commun 2019 01 28;10(1):457. Epub 2019 Jan 28.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200, Bruxelles, Belgium.

Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities. Their role in the gut remains unclear. Therefore, we generated a mouse model of inducible intestinal epithelial cell (IEC)-specific deletion of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), a key enzyme involved in NAE biosynthesis (Napepld). We discovered that Napepld mice are hyperphagic upon first high-fat diet (HFD) exposure, and develop exacerbated obesity and steatosis. These mice display hypothalamic Pomc neurons dysfunctions and alterations in intestinal and plasma NAE and 2-acylglycerols. After long-term HFD, Napepld mice present reduced energy expenditure. The increased steatosis is associated with higher gut and liver lipid absorption. Napepld mice display altered gut microbiota. Akkermansia muciniphila administration partly counteracts the IEC NAPE-PLD deletion effects. In conclusion, intestinal NAPE-PLD is a key sensor in nutritional adaptation to fat intake, gut-to-brain axis and energy homeostasis and thereby constitutes a novel target to tackle obesity and related disorders.
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http://dx.doi.org/10.1038/s41467-018-08051-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349942PMC
January 2019

Microbial regulation of organismal energy homeostasis.

Nat Metab 2019 01 7;1(1):34-46. Epub 2019 Jan 7.

Metabolism and Nutrition Research Group, WELBIO-Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.

The gut microbiome has emerged as a key regulator of host metabolism. Here we review the various mechanisms through which the gut microbiome influences the energy metabolism of its host, highlighting the complex interactions between gut microbes, their metabolites and host cells. Among the most important bacterial metabolites are short-chain fatty acids, which serve as a direct energy source for host cells, stimulate the production of gut hormones and act in the brain to regulate food intake. Other microbial metabolites affect systemic energy expenditure by influencing thermogenesis and adipose tissue browning. Both direct and indirect mechanisms of action are known for specific metabolites, such as bile acids, branched chain amino acids, indole propionic acid and endocannabinoids. We also discuss the roles of specific bacteria in the production of specific metabolites and explore how external factors, such as antibiotics and exercise, affect the microbiome and thereby energy homeostasis. Collectively, we present a large body of evidence supporting the concept that gut microbiota-based therapies can be used to modulate host metabolism, and we expect to see such approaches moving from bench to bedside in the near future.
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http://dx.doi.org/10.1038/s42255-018-0017-4DOI Listing
January 2019

Prebiotics Supplementation Impact on the Reinforcing and Motivational Aspect of Feeding.

Front Endocrinol (Lausanne) 2018 29;9:273. Epub 2018 May 29.

Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.

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 microbiota-gut-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.
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http://dx.doi.org/10.3389/fendo.2018.00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987188PMC
May 2018

Reduced obesity, diabetes, and steatosis upon cinnamon and grape pomace are associated with changes in gut microbiota and markers of gut barrier.

Am J Physiol Endocrinol Metab 2018 04 5;314(4):E334-E352. Epub 2017 Sep 5.

Université Catholique de Louvain, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Metabolism and Nutrition Research Group , Brussels , Belgium.

Increasing evidence suggests that polyphenols have a significant potential in the prevention and treatment of risk factors associated with metabolic syndrome. The objective of this study was to assess the metabolic outcomes of two polyphenol-containing extracts from cinnamon bark (CBE) and grape pomace (GPE) on C57BL/6J mice fed a high-fat diet (HFD) for 8 wk. Both CBE and GPE were able to decrease fat mass gain and adipose tissue inflammation in mice fed a HFD without reducing food intake. This was associated with reduced liver steatosis and lower plasma nonesterified fatty acid levels. We also observed a beneficial effect on glucose homeostasis, as evidenced by an improved glucose tolerance and a lower insulin resistance index. These ameliorations of the overall metabolic profile were associated with a significant impact on the microbial composition, which was more profound for the GPE than for the CBE. At the genus level, Peptococcus were decreased in the CBE group. In the GPE-treated group, several key genera that have been previously found to be linked with HFD, metabolic effects, and gut barrier integrity were affected: we observed a decrease of Desulfovibrio, Lactococcus, whereas Allobaculum and Roseburia were increased. In addition, the expression of several antimicrobial peptides and tight junction proteins was increased in response to both CBE and GPE supplementation, indicating an improvement of the gut barrier function. Collectively, these data suggest that CBE and GPE can ameliorate the overall metabolic profile of mice on a high-fat diet, partly by acting on the gut microbiota.
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http://dx.doi.org/10.1152/ajpendo.00107.2017DOI Listing
April 2018

Odor-Induced Neuronal Rhythms in the Olfactory Bulb Are Profoundly Modified in ob/ob Obese Mice.

Front Physiol 2017 19;8. Epub 2017 Jan 19.

UMR 8165 Centre National de la Recherche Scientifique, IMNC, Paris Sud University, Paris Diderot UniversityOrsay, France; UMR 8251 Centre National de la Recherche Scientifique, BFA, Paris Diderot University, Sorbonne Paris Cité UniversityParis, France.

Leptin, the product of the Ob(Lep) gene, is a peptide hormone that plays a major role in maintaining the balance between food intake and energy expenditure. In the brain, leptin receptors are expressed by hypothalamic cells but also in the olfactory bulb, the first central structure coding for odors, suggesting a precise function of this hormone in odor-evoked activities. Although olfaction plays a key role in feeding behavior, the ability of the olfactory bulb to integrate the energy-related signal leptin is still missing. Therefore, we studied the fate of odor-induced activity in the olfactory bulb in the genetic context of leptin deficiency using the obese ob/ob mice. By means of an odor discrimination task with concomitant local field potential recordings, we showed that ob/ob mice perform better than wild-type (WT) mice in the early stage of the task. This behavioral gain of function was associated in parallel with profound changes in neuronal oscillations in the olfactory bulb. The distribution of the peaks in the gamma frequency range was shifted toward higher frequencies in ob/ob mice compared to WT mice before learning. More notably, beta oscillatory activity, which has been shown previously to be correlated with olfactory discrimination learning, was longer and stronger in expert ob/ob mice after learning. Since oscillations in the olfactory bulb emerge from mitral to granule cell interactions, our results suggest that cellular dynamics in the olfactory bulb are deeply modified in ob/ob mice in the context of olfactory learning.
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http://dx.doi.org/10.3389/fphys.2017.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244437PMC
January 2017

Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety.

Mol Metab 2017 01 4;6(1):48-60. Epub 2016 Nov 4.

Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK; Division of Diabetes and Nutritional Sciences, King's College London, London, SE1 9RT, UK. Electronic address:

Objective: Dietary supplementation with fermentable carbohydrate protects against body weight gain. Fermentation by the resident gut microbiota produces short-chain fatty acids, which act at free fatty acid receptor 2 (FFAR2). Our aim was to test the hypothesis that FFAR2 is important in regulating the beneficial effects of fermentable carbohydrate on body weight and to understand the role of gut hormones PYY and GLP-1.

Methods: Wild-type or mice were fed an inulin supplemented or control diet. Mice were metabolically characterized and gut hormone concentrations, enteroendocrine cell density measurements were carried out. Intestinal organoids and colonic cultures were utilized to substantiate the findings.

Results: We provide new mechanistic insight into how fermentable carbohydrate regulates metabolism. Using mice that lack FFAR2, we demonstrate that the fermentable carbohydrate inulin acts via this receptor to drive an 87% increase in the density of cells that produce the appetite-suppressing hormone peptide YY (PYY), reduce food intake, and prevent diet-induced obesity.

Conclusion: Our results demonstrate that FFAR2 is predominantly involved in regulating the effects of fermentable carbohydrate on metabolism and does so, in part, by enhancing PYY cell density and release. This highlights the potential for targeting enteroendocrine cell differentiation to treat obesity.
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http://dx.doi.org/10.1016/j.molmet.2016.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220466PMC
January 2017

Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome.

Brain Behav Immun 2017 Aug 24;64:33-49. Epub 2016 Dec 24.

INRA, Nutrition and Integrative Neurobiology, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286, 33076 Bordeaux, France. Electronic address:

Mounting evidence shows that the gut microbiota, an important player within the gut-brain communication axis, can affect metabolism, inflammation, brain function and behavior. Interestingly, gut microbiota composition is known to be altered in patients with metabolic syndrome (MetS), who also often display neuropsychiatric symptoms. The use of prebiotics, which beneficially alters the microbiota, may therefore be a promising way to potentially improve physical and mental health in MetS patients. This hypothesis was tested in a mouse model of MetS, namely the obese and type-2 diabetic db/db mice, which display emotional and cognitive alterations associated with changes in gut microbiota composition and hippocampal inflammation compared to their lean db/+ littermates. We assessed the impact of chronic administration (8weeks) of prebiotics (oligofructose) on both metabolic (body weight, food intake, glucose homeostasis) and behavioral (increased anxiety-like behavior and impaired spatial memory) alterations characterizing db/db mice, as well as related neurobiological correlates, with particular attention to neuroinflammatory processes. Prebiotic administration improved excessive food intake and glycemic dysregulations (glucose tolerance and insulin resistance) in db/db mice. This was accompanied by an increase of plasma anti-inflammatory cytokine IL-10 levels and hypothalamic mRNA expression of the anorexigenic cytokine IL-1β, whereas unbalanced mRNA expression of hypothalamic orexigenic (NPY) and anorexigenic (CART, POMC) peptides was unchanged. We also detected signs of improved blood-brain-barrier integrity in the hypothalamus of oligofructose-treated db/db mice (normalized expression of tight junction proteins ZO-1 and occludin). On the contrary, prebiotic administration did not improve behavioral alterations and associated reduction of hippocampal neurogenesis displayed by db/db mice, despite normalization of increased hippocampal IL-6 mRNA expression. Of note, we found a relationship between the effect of treatment on dentate gyrus neurons and spatial memory. These findings may prove valuable for introducing novel approaches to treat some of the comorbidities associated with MetS.
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http://dx.doi.org/10.1016/j.bbi.2016.12.022DOI Listing
August 2017

A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.

Nat Med 2017 01 28;23(1):107-113. Epub 2016 Nov 28.

Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.

Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.
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http://dx.doi.org/10.1038/nm.4236DOI Listing
January 2017

High-fat diet feeding differentially affects the development of inflammation in the central nervous system.

J Neuroinflammation 2016 08 26;13(1):206. Epub 2016 Aug 26.

Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCL), Av. E.Mounier, 72 (B1.72.01), 1200, Brussels, Belgium.

Background: Obesity and its associated disorders are becoming a major health issue in many countries. The resulting low-grade inflammation not only affects the periphery but also the central nervous system. We set out to study, in a time-dependent manner, the effects of a high-fat diet on different regions of the central nervous system with regard to the inflammatory tone.

Methods: We used a diet-induced obesity model and compared at several time-points (1, 2, 4, 6, 8, and 16 weeks) a group of mice fed a high-fat diet with its respective control group fed a standard diet. We also performed a large-scale analysis of lipids in the central nervous system using HPLC-MS, and we then tested the lipids of interest on a primary co-culture of astrocytes and microglial cells.

Results: We measured an increase in the inflammatory tone in the cerebellum at the different time-points. However, at week 16, we evidenced that the inflammatory tone displayed significant differences in two different regions of the central nervous system, specifically an increase in the cerebellum and no modification in the cortex for high-fat diet mice when compared with chow-fed mice. Our results clearly suggest region-dependent as well as time-dependent adaptations of the central nervous system to the high-fat diet. The differences in inflammatory tone between the two regions considered seem to involve astrocytes but not microglial cells. Furthermore, a large-scale lipid screening coupled to ex vivo testing enabled us to identify three classes of lipids-phosphatidylinositols, phosphatidylethanolamines, and lysophosphatidylcholines-as well as palmitoylethanolamide, as potentially responsible for the difference in inflammatory tone.

Conclusions: This study demonstrates that the inflammatory tone induced by a high-fat diet does not similarly affect distinct regions of the central nervous system. Moreover, the lipids identified and tested ex vivo showed interesting anti-inflammatory properties and could be further studied to better characterize their activity and their role in controlling inflammation in the central nervous system.
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http://dx.doi.org/10.1186/s12974-016-0666-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002131PMC
August 2016

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism.

Gut 2017 04 5;66(4):620-632. Epub 2016 May 5.

WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.

Objective: To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.

Design: To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of . We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).

Results: Hepatocyte-specific deletion of predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.

Conclusions: Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.
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http://dx.doi.org/10.1136/gutjnl-2015-310904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529962PMC
April 2017

Losing weight for a better health: Role for the gut microbiota.

Clin Nutr Exp 2016 Apr;6:39-58

Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Av. E. Mounier, 73 Box B1.73.11, B-1200 Brussels, Belgium.

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) 2) 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.
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http://dx.doi.org/10.1016/j.yclnex.2015.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567023PMC
April 2016

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

Mol Nutr Food Res 2017 01 1;61(1). Epub 2016 Jun 1.

Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Université catholique de Louvain, Brussels, Belgium.

Scope: Binge consumption of alcohol is an alarming global health problem. Acute ethanol intoxication is characterized by hepatic inflammation and oxidative stress, which could be promoted by gut barrier function alterations. In this study, we have tested the hypothesis of the hepatoprotective effect of rhubarb extract in a mouse model of binge drinking and we explored the contribution of the gut microbiota in the related metabolic effects.

Methods And Results: Mice were fed a control diet supplemented with or without 0.3% rhubarb extract for 17 days and were necropsied 6 h after an alcohol challenge. Supplementation with rhubarb extract changed the microbial ecosystem (assessed by 16S rDNA pyrosequencing) in favor of Akkermansia muciniphila and Parabacteroides goldsteinii. Furthermore, it improved alcohol-induced hepatic injury, downregulated key markers of both inflammatory and oxidative stresses in the liver tissue, without affecting significantly steatosis. In the gut, rhubarb supplementation increased crypt depth, tissue weight, and the expression of antimicrobial peptides.

Conclusions: These findings suggest that some bacterial genders involved in gut barrier function, are promoted by phytochemicals present in rhubarb extract, and could therefore be involved in the modulation of the susceptibility to hepatic diseases linked to acute alcohol consumption.
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http://dx.doi.org/10.1002/mnfr.201500899DOI Listing
January 2017

Endocannabinoids--at the crossroads between the gut microbiota and host metabolism.

Nat Rev Endocrinol 2016 Mar 18;12(3):133-43. Epub 2015 Dec 18.

Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 73, Box B1.73.11, Brussels B-1200, Belgium.

Various metabolic disorders are associated with changes in inflammatory tone. Among the latest advances in the metabolism field, the discovery that gut microorganisms have a major role in host metabolism has revealed the possibility of a plethora of associations between gut bacteria and numerous diseases. However, to date, few mechanisms have been clearly established. Accumulating evidence indicates that the endocannabinoid system and related bioactive lipids strongly contribute to several physiological processes and are a characteristic of obesity, type 2 diabetes mellitus and inflammation. In this Review, we briefly define the gut microbiota as well as the endocannabinoid system and associated bioactive lipids. We discuss existing literature regarding interactions between gut microorganisms and the endocannabinoid system, focusing specifically on the triad of adipose tissue, gut bacteria and the endocannabinoid system in the context of obesity and the development of fat mass. We highlight gut-barrier function by discussing the role of specific factors considered to be putative 'gate keepers' or 'gate openers', and their role in the gut microbiota-endocannabinoid system axis. Finally, we briefly discuss data related to the different pharmacological strategies currently used to target the endocannabinoid system, in the context of cardiometabolic disorders and intestinal inflammation.
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http://dx.doi.org/10.1038/nrendo.2015.211DOI Listing
March 2016

Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice.

Sci Rep 2015 Nov 13;5:16643. Epub 2015 Nov 13.

Université catholique de Louvain, Louvain Drug Research Institute, WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Metabolism and Nutrition Research Group, Brussels, Belgium.

Recent evidence indicates that the gut microbiota plays a key role in the pathophysiology of obesity. Indeed, diet-induced obesity (DIO) has been associated to substantial changes in gut microbiota composition in rodent models. In the context of obesity, enhanced adiposity is accompanied by low-grade inflammation of this tissue but the exact link with gut microbial community remains unknown. In this report, we studied the consequences of high-fat diet (HFD) administration on metabolic parameters and gut microbiota composition over different periods of time. We found that Akkermansia muciniphila abundance was strongly and negatively affected by age and HFD feeding and to a lower extend Bilophila wadsworthia was the only taxa following an opposite trend. Different approaches, including multifactorial analysis, showed that these changes in Akkermansia muciniphila were robustly correlated with the expression of lipid metabolism and inflammation markers in adipose tissue, as well as several circulating parameters (i.e., glucose, insulin, triglycerides, leptin) from DIO mice. Thus, our data shows the existence of a link between gut Akkermansia muciniphila abundance and adipose tissue homeostasis on the onset of obesity, thus reinforcing the beneficial role of this bacterium on metabolism.
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http://dx.doi.org/10.1038/srep16643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643218PMC
November 2015

Harnessing Genes and Diet to Fine-Tune the Gut Microbial Fitness.

Cell Metab 2015 Nov;22(5):754-6

Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Metabolism and Nutrition research group, Avenue E. Mounier, 73 Box B1.73.11, 1200 Brussels, Belgium.

Microbe communication with host mammalian cells and external factors such as diet influences this multifaceted ecosystem. A recent study shows that interactions between microbial genes and dietary elements are dynamic processes that may help to characterize an organism's niche and eventually its impact on the overall community and host metabolism.
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http://dx.doi.org/10.1016/j.cmet.2015.10.006DOI Listing
November 2015

Gut microorganisms as promising targets for the management of type 2 diabetes.

Diabetologia 2015 Oct 31;58(10):2206-17. Epub 2015 Jul 31.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, B1.73.11, 1200, Brussels, Belgium.

Each human intestine harbours not only hundreds of trillions of bacteria but also bacteriophage particles, viruses, fungi and archaea, which constitute a complex and dynamic ecosystem referred to as the gut microbiota. An increasing number of data obtained during the last 10 years have indicated changes in gut bacterial composition or function in type 2 diabetic patients. Analysis of this 'dysbiosis' enables the detection of alterations in specific bacteria, clusters of bacteria or bacterial functions associated with the occurrence or evolution of type 2 diabetes; these bacteria are predominantly involved in the control of inflammation and energy homeostasis. Our review focuses on two key questions: does gut dysbiosis truly play a role in the occurrence of type 2 diabetes, and will recent discoveries linking the gut microbiota to host health be helpful for the development of novel therapeutic approaches for type 2 diabetes? Here we review how pharmacological, surgical and nutritional interventions for type 2 diabetic patients may impact the gut microbiota. Experimental studies in animals are identifying which bacterial metabolites and components act on host immune homeostasis and glucose metabolism, primarily by targeting intestinal cells involved in endocrine and gut barrier functions. We discuss novel approaches (e.g. probiotics, prebiotics and faecal transfer) and the need for research and adequate intervention studies to evaluate the feasibility and relevance of these new therapies for the management of type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-015-3712-7DOI Listing
October 2015

Talking microbes: When gut bacteria interact with diet and host organs.

Mol Nutr Food Res 2016 Jan 26;60(1):58-66. Epub 2015 Aug 26.

Metabolism and Nutrition Research Group, WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.

Obesity and diabetes have reached epidemic proportions. Evidence suggests that besides dietary habits and physical activity, other environmental factors, such as gut microbes, are recognized as additional partners implicated in the control of energy homeostasis. Studies on the human gut microbiota have shown that the general population can be stratified on the sole basis of three dominant bacteria (i.e., the concept of enterotypes), while some others have suggested categorizing the population according to their microbiome gene richness. Both aspects have been strengthened by recent studies investigating the impact of nutrients (e.g., dietary fibers, fat feeding) and dietary habits (i.e., vegans versus omnivores) of different populations. Using preclinical models, quite a few novel mechanisms have been proposed in these gut microbiota-host interactions, including the role of novel bacteria, the regulation of antimicrobial peptide production, the maintenance of the gut barrier function and intestinal innate immunity. In this review, we discuss several of the aforementioned aspects. Nonetheless, determining the overall mechanisms by which microbes dialogue with host cells will require further investigations before anticipating the development of next-generation nutritional interventions using prebiotics, probiotics, synbiotics, or even specific nutrients for promoting health benefits.
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http://dx.doi.org/10.1002/mnfr.201500406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014210PMC
January 2016

Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology.

Gut 2016 Mar 22;65(3):426-36. Epub 2015 Jun 22.

Institute of Cardiometabolism and Nutrition, ICAN, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière hospital, Paris, France INSERM, UMR S U1166, Nutriomics Team, Paris, France Sorbonne Universités, UPMC University Paris 06, UMR_S 1166 I, Nutriomics Team, Paris, France.

Objective: Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with body fat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between faecal A. muciniphila abundance, faecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR).

Design: The intervention consisted of a 6-week CR period followed by a 6-week weight stabilisation diet in overweight and obese adults (N=49, including 41 women). Faecal A. muciniphila abundance, faecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and weight stabilisation.

Results: At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. These participants also experienced a reduction in A. muciniphila abundance, but it remained significantly higher than in individuals with lower baseline abundance. A. muciniphila was associated with microbial species known to be related to health.

Conclusions: A. muciniphila is associated with a healthier metabolic status and better clinical outcomes after CR in overweight/obese adults. The interaction between gut microbiota ecology and A. muciniphila warrants further investigation.

Trial Registration Number: NCT01314690.
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http://dx.doi.org/10.1136/gutjnl-2014-308778DOI Listing
March 2016