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

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

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

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

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

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 MyD88. 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 MyD88 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 MyD88 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

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

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 bodyfat 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 fecal A. muciniphila abundance, fecal 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 stabilization (WS) diet in overweight and obese adults (N=49, including 41 women). Fecal A. muciniphila abundance, fecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and WS. 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. A. muciniphila was associated with microbial species known to be related to health. Conclusion: A. muciniphila is associated with a healthier metabolic status and better clinicaloutcomes after CR in overweight/obese adults, however the interaction between gut microbiota ecology and A. muciniphila has to be taken into account

Akkermansia muciniphila pasteurisée, un exemple de postbiotique

Des modifications du microbiote intestinal ont été mises en évidence dans différentes pathologies. Même si la plupart des données montrent initialement une association, des liens de causalité sont de plus en plus étudiés, notamment dans les désordres métaboliques associés à l’obésité. Akkermansia muciniphila est l’une des bactéries du microbiote intestinal les plus étudiées actuellement dans différentes pathologies. Dans le cadre de l’obésité et des désordres métaboliques, la bactérie Akkermansia muciniphila MucT permet de limiter la prise de poids et le développement de l’insulinorésistance dans des modèles précliniques. De manière surprenante, la bactérie Akkermansia muciniphila MucT pasteurisée présente des effets bénéfiques plus importants par rapport à la bactérie Akkermansia muciniphila MucT vivante. Cette forme pasteurisée peut donc être considérée comme un potentiel postbiotique. Une étude pilote réalisée chez des volontaires en surpoids ou obèses avec un syndrome métabolique et un prédiabète, a permis de démontrer qu’une supplémentation quotidienne de la bactérie Akkermansia muciniphila MucT pasteurisée par voie orale est sûre et bien tolérée chez ces individus. De plus cette étude pilote a permis de mettre en évidence les effets d’Akkermansia muciniphila MucT pasteurisée sur la sensibilité à l’insuline et les taux plasmatiques de cholestérol. Même si ces données sont encourageantes, il est important de préciser que la supplémentation avec Akkermansia muciniphila MucT pasteurisée ne doit pas être vue comme un traitement, mais plutôt comme une piste supplémentaire qui pourrait participer à limiter le développement de désordres métaboliques, en parallèle d’autres interventions de type hygiéno-diététique

Beïnvloedt het darmmicrobioom ons eetgedrag?

Ons eetgedrag wordt nauwkeurig geregeld door de communicatiekanalen tussen de darmen en de hersenen, met als doel de balans tussen de aangevoerde en verbruikte energie in evenwicht te houden. Het darmmicrobioom speelt een belangrijke rol in de darm-hersenas en kan het honger- en verzadigingsgevoel beïnvloeden. Ons eetgedrag wordt ook beïnvloed door het genot dat we beleven bij het eten van bepaalde voedingsmiddelen, en met van name suiker- en vetrijke voedingsmiddelen die een genotsgevoel opwekken. Die hedonistische component van eten wordt geregeld door het beloningssysteem. Het darmmicrobioom kan ook het eetgenot beïnvloeden. Uit preklinische studies waarin het darmmicrobioom van obese muizen getransplanteerd werd naar slanke muizen, is gebleken dat het darmmicrobioom een causale rol speelt in de ontregeling van het eetgenot en de drang naar smakelijk voedsel bij obesitas. Daarnaast had het darmmicrobioom afkomstig van de obese muizen invloed op de expressie van bepaalde markers die betrokken zijn bij de dopaminerge en opioïde pathways – twee signalisatiepaden van het beloningssysteem. De communicatie tussen het darmmicrobioom en de hersenen verloopt via de zenuwen en via de bloedbaan, en bij die interacties zijn meerdere mediatoren betrokken. Ten eerste maakt het microbioom verbindingen aan waarvan de metabolieten farmacologische effecten hebben, en ten tweede kunnen bepaalde bacteriële bestanddelen van het darmmicrobioom eveneens een interactie aangaan met de gastheer. Er wordt gedacht aan nieuwe behandelingssporen waarbij gericht wordt ingegrepen op het darmmicrobioom om de darm-hersenas te beïnvloeden. Dat zou kunnen leiden tot mogelijke klinische toepassingen die als doel hebben om het eetgedrag te beïnvloeden bij mensen die voortdurend aan calorierijke voeding blootgesteld zijn

Gepasteuriseerde Akkermansia muciniphila, een voorbeeld van een "postbioticum"

Bij diverse ziekten zijn veranderingen in de darmmicrobiota aangetoond. Hoewel de meeste gegevens in eerste instantie een verband aantonen, wordt er steeds meer onderzoek gedaan naar causale verbanden, met name bij stofwisselingsstoornissen die samenhangen met zwaarlijvigheid. Akkermansia muciniphila is een van de meest bestudeerde bacteriën van de darmmicrobiota bij verschillende pathologieën. In de context van obesitas en stofwisselingsstoornissen is de bacterie Akkermansia muciniphila MucT in staat om gewichtstoename en de ontwikkeling van insulineresistentie te beperken in preklinische modellen. Verrassend genoeg leverden gepasteuriseerde ‘Akkermansia muciniphila MucT’-bacteriën grotere gunstige effecten op dan levende ‘Akkermansia muciniphila MucT’-bacteriën. Deze gepasteuriseerde vorm kan daarom worden beschouwd als een mogelijk ‘postbioticum’. Een proefstudie bij vrijwilligers met overgewicht of obesitas met het metabool syndroom en prediabetes heeft aangetoond dat dagelijkse orale suppletie met gepasteuriseerde Akkermansia muciniphila MucT veilig is en goed wordt verdragen bij deze personen. Bovendien toonde deze proefstudie de effecten aan van gepasteuriseerde Akkermansia muciniphila MucT op de insulinegevoeligheid en het cholesterolgehalte in het plasma. Hoewel deze gegevens bemoedigend zijn, is het belangrijk op te merken dat suppletie met gepasteuriseerde Akkermansia muciniphila MucT niet moet worden gezien als een behandeling. Het is eerder een aanvullende weg die de ontwikkeling van metabole stoornissen zou kunnen helpen te beperken, naast andere interventies op het vlak van levensstijl en voeding

Le microbiote intestinal régule-t-il les comportements alimentaires ?

Le comportement alimentaire est finement régulé par l’axe de communication entre l’intestin et le cerveau afin de maintenir la balance énergétique entre les apports et les dépenses à l’équilibre. Le microbiote intestinal est un acteur clé de l’axe intestin-cerveau et peut moduler les sensations de faim et de satiété. Nos comportements alimentaires sont aussi influencés par le plaisir procuré lors de l’ingestion de certains aliments, notamment les aliments riches en sucres et en graisses qui procurent une sensation de plaisir. Cette composante hédonique de la prise alimentaire est régulée par le système de la récompense. Le microbiote intestinal est également capable de moduler le plaisir alimentaire. Des études précliniques de transplantation de microbiote intestinal de souris obèses à des souris minces ont permis de démontrer le rôle causal du microbiote intestinal dans les dérégulations du plaisir alimentaire et de la motivation pour obtenir un aliment palatable au cours de l’obésité. De plus, l’expression de certains marqueurs impliqués dans les signalisations dopaminergique et opioïde – deux voies de signalisation du système de la récompense – est aussi modulée par le microbiote intestinal provenant de souris obèses. Le microbiote intestinal dialogue avec le cerveau par voie nerveuse et via la circulation sanguine. Différents médiateurs sont impliqués dans ces interactions; premièrement, le microbiote produit des molécules dont des métabolites avec des effets pharmacologiques et, deuxièmement, certains constituants bactériens du microbiote intestinal peuvent également interagir avec l’hôte. Une modulation de l’axe intestin-cerveau en utilisant des approches ciblées sur le microbiote intestinal sont suggérées comme de nouvelles pistes thérapeutiques intéressantes. Ceci pourrait mener à de potentielles applications cliniques visant à restaurer les altérations du comportement alimentaire notamment face à l’exposition constante à une alimentation très dense en calories

Interactions between gut microbiota and intestinal epithelium functions in metabolic disorders associated with obesity

Obesity represents a major public health problem in the world and is nowadays recognized as an epidemic disease. Obesity and overweight are associated with a cluster of metabolic disorders such as type-2 diabetes and cardiovascular diseases thereby constituting a leading risk for global deaths. Identifying novel targets with therapeutic potential would bring hope to control obesity whereas actual drugs are particularly ineffective to treat or prevent this epidemic disease. Metabolic alterations related to obesity are associated with a low-grade inflammation that contributes to the onset of these disorders. The gut microbiota has been associated with several hallmarks of metabolic syndrome and growing evidence suggests that gut microbes contribute to the onset of the low-grade inflammation characterizing these metabolic disorders via mechanisms associated with gut barrier dysfunctions. Moreover, gut microbiota modulations using prebiotics such as in inulin-type fructans improve gut barrier functions, metabolic endotoxemia and inflammation in obesity and type-2 diabetes. This work was aimed to identify novel potential mechanisms involved in the cross-talk between gut microbiota and the host to control gut permeability, inflammation and metabolic disorders associated with obesity. We discovered that gut microbiota modulation using prebiotic treatment increases the number of enteroendocrine cells (i.e., L-cells) producing GLP-1 and GLP-2 in the jejunum and colon. These peptides are involved in the beneficial effects of prebiotics on glucose homeostasis and gut barrier functions respectively. Thus, these results suggest that targeting enteroendocrine L-cells could be a novel therapeutic approach to treat the disorders associated with obesity and type-2 diabetes. Moreover we have discovered that gut microbiota is also able to control leptin sensitivity in diet-induced obese and type-2 diabetic mice and this could participate to the beneficial effects of gut microbiota modulation in obesity. By profiling the gut microbiota after prebiotic treatment in obese mice we identified a catalog of putative bacterial targets that may affect host-metabolism in obesity and diabetes. Among these bacteria we concentrated in particular on Akkermansia muciniphila which is a mucin-degrading bacterium that resides in the mucus layer. We found that the abundance of Akkermansia muciniphila is decreased in obese and type-2 diabetic mice and we demonstrated that Akkermansia muciniphila treatment is able to reverse high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. Importantly, these effects could be mediated by mechanisms depending on interactions between gut microbiota, enteroendocrine functions, endocannabinoid system and immune system since Akkermansia muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion and also abolished gut barrier dysfunction by restoring mucus layer thickness and stimulating the production of colon antimicrobial proteins (i.e., regenerating islet-derived 3-gamma, RegIIIγ) during obesity. The last part of the thesis was dedicated to studying the role of the innate immune system in the interaction between gut microbiota, intestinal immune functions and host metabolism. In conclusion, this work revealed novel mechanisms involved in interactions between gut microbiota and the host epithelium to control gut barrier functions and metabolic disorders associated with obesity. We have identified potential targets such as the modulation of host-gut microbiota interactions through the regulation of enteroendocrine functions, the intestine endocannabinoid and the intestine immune system. We propose that some of these targets could constitute interesting novel therapeutic approaches for the development of drugs to treat and, or prevent obesity and type-2 diabetes.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201