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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

(1) Background: Obesity and type 2 diabetes have been suspected to impact both intrinsic metabolism and function of circulating immune cells. (2) Methods: To further investigate this immunometabolic modulation, we profiled the phospholipidome of the peripheral blood mononuclear cells (PBMCs) in lean, normoglycemic obese (OBNG) and obese with dysglycemia (OBDysG) individuals. (3) Results: The global PBMCs phospholipidome is significantly downmodulated in OBDysG unlike OBNG patients when compared to lean ones. Multiple linear regression analyses show a strong negative relationship between the global PBMCs phospholipidome and parameters assessing insulin resistance. Even though all classes of phospholipid are affected, the relative abundance of each class is maintained with the exception of Lyso-PC/PC and Lyso-PE/PE ratios that are downmodulated in PBMCs of OBDysG compared to OBNG individuals. Interestingly, the percentage of saturated PC is positively associated with glycated hemoglobin (HbA1c). Moreover, a few lipid species are significantly downmodulated in PBMCs of OBDysG compared to OBNG individuals, making possible to distinguish the two phenotypes. (4) Conclusions: This lipidomic study highlights for the first-time modulations of the PBMCs phospholipidome in obese patients with prediabetes and type 2 diabetes. Such phospholipidome remodeling could disrupt the cell membranes and the lipid mediator's levels, driving an immune cell dysfunction. ispartof: NUTRIENTS vol:13 issue:10 ispartof: location:Switzerland status: published

Background: The gut microbiota is altered in obesity and is strongly influenced by nutrients and xenobiotics. We have tested the impact of native inulin as prebiotic present in vegetables and added as a supplement on gut microbiota-related outcomes in obese patients. Metformin treatment was analyzed as a potential modulator of the response. Methods: A randomized, single-blinded, multicentric, placebo-controlled trial was conducted in 150 obese patients who received 16 g/d native inulin versus maltodextrin, coupled to dietary advice to consume inulin-rich versus -poor vegetables for 3 months, respectively, in addition to dietary caloric restriction. Anthropometry, diagnostic imaging (abdominal CT-scan, fibroscan), food-behavior questionnaires, serum biology and fecal microbiome (primary outcome; 16S rDNA sequencing) were analyzed before and after the intervention. Results: Both placebo and prebiotic interventions lowered energy intake, BMI, systolic blood pressure, and serum γ-GT. The prebiotic induced greater weight loss and additionally decreased diastolic blood pressure, AST and insulinemia. Metformin treatment compromised most of the gut microbiota changes and metabolic improvements linked to prebiotic intervention. The prebiotic modulated specific bacteria, associated with the improvement of anthropometry (i.e. a decrease in Desulfovibrio and Clostridium sensu stricto). A large increase in Bifidobacterium appears as a signature of inulin intake rather than a driver of prebiotic-linked biological outcomes. Conclusions: Inulin-enriched diet is able to promote weight loss in obese patients, the treatment efficiency being related to gut microbiota characteristics. This treatment is more efficacious in patients who did not receive metformin as anti-diabetic drugs prior the intervention, supporting that both drug treatment and microbiota might be taken into account in personalized nutrition interventions. Registered under ClinicalTrials.gov Identifier no NCT03852069., info:eu-repo/semantics/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 .

The maintenance of the characteristic lipid compositions and physicochemical properties of biological membranes is essential for their proper function. Mechanisms allowing to sense and restore membrane homeostasis have been identified in prokaryotes for a long time and more recently in eukaryotes. A membrane remodeling can result from aberrant metabolism as seen in obesity. In this review, we describe how such lipid bilayer stress can account for the modulation of membrane proteins involved in the pathogenesis of obesity-linked inflammatory and metabolic disorders. We address the case of the Toll-like receptor 4 that is implicated in the obesity-related low grade inflammation and insulin resistance. The lipid raft-mediated TLR4 activation is promoted by an enrichment of the plasma membrane with saturated lipids or cholesterol increasing the lipid phase order. We discuss of the plasma membrane Na, K-ATPase that illustrates a new concept according to which direct interactions between specific residues and particular lipids determine both stability and activity of the pump in parallel with indirect effects of the lipid bilayer. The closely related sarco(endo)-plasmic Ca-ATPase embedded in the more fluid ER membrane seems to be more sensitive to a lipid bilayer stress as demonstrated by its inactivation in cholesterol-loaded macrophages or its inhibition mediated by an increased PtdCho/PtdEtn ratio in obese mice hepatocytes. Finally, we describe the model recently proposed for the activation of the conserved IRE-1 protein through alterations in the ER membrane lipid packing and thickness. Such IRE-1 activation could occur in response to abnormal lipid synthesis and membrane remodeling as observed in hepatocytes exposed to excess nutrients. Since the IRE-1/XBP1 branch also stimulates the lipid synthesis, this pathway could create a vicious cycle "lipogenesis-ER lipid bilayer stress-lipogenesis" amplifying hepatic ER pathology and the obesity-linked systemic metabolic defects.

NLRP3 inflammasome plays a key role in Western diet-induced systemic inflammation and was recently shown to mediate long-lasting trained immunity in myeloid cells. Saturated fatty acids (SFAs) are sterile triggers able to induce the assembly of the NLRP3 inflammasome in macrophages, leading to IL-1β secretion while unsaturated ones (UFAs) prevent SFAs-mediated NLRP3 activation. Unlike previous studies using LPS-primed bone marrow derived macrophages, we do not see any ROS or IRE-1α involvement in SFAs-mediated NLRP3 activation in human monocytes-derived macrophages. Rather we show that SFAs need to enter the cells and to be activated into acyl-CoA to lead to NLRP3 activation in human macrophages. However, their β-oxidation is dispensable. Instead, they are channeled towards phospholipids but redirected towards lipid droplets containing triacylglycerol in the presence of UFAs. Lipidomic analyses and Laurdan fluorescence experiments demonstrate that SFAs induce a dramatic saturation of phosphatidylcholine (PC) correlated with a loss of membrane fluidity, both events inhibited by UFAs. The silencing of CCTα, the key enzyme in PC synthesis, prevents SFA-mediated NLRP3 activation, demonstrating the essential role of the de novo PC synthesis. This SFA-induced membrane remodeling promotes a disruption of the plasma membrane Na, K-ATPase, instigating a K+ efflux essential and sufficient for NLRP3 activation. This work opens novel therapeutic avenues to interfere with Western diet-associated diseases such as those targeting the glycerolipid pathway. ispartof: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS vol:1864 issue:7 pages:1017-1030 ispartof: location:Netherlands status: published

Introduction et but de l’etude L’inflammation chronique et l’activation du systeme immunitaire sont impliquees dans le developpement du diabete de type 2 chez les patients obeses. La production d’IL-1β conduite par l’inflammasome NLRP3 au sein des macrophages du tissus adipeux et des monocytes circulants joue un role crucial dans le developpement de la resistance a l’insuline. Nous avons montre que contrairement a l’oleate (C18:1), le stearate (C18:0), second acide gras sature le plus abondant, conduit a l’activation de l’inflammasome NLRP3 dans des macrophages/monocytes humains avec une augmentation concomitante du pourcentage de phospholipides membranaires satures. L’addition de C18:1 au C18:0 empeche ces evenements en redirigeant les acides gras satures vers la synthese des triglycerides. Cependant, le lien entre la saturation des phospholipides et l’activation de l’inflammasome NLRP3 n’a pas encore ete elucidee. Materiel et methodes Des cellules THP-1 differenciees au PMA ont ete traitees 8 h avec la BSA (controle), avec le C18:0 seul ou associe avec le C18:1. La [K+] cellulaire et la secretion d’IL-1β ont ete quantifiees par spectroscopie d’emission atomique et par Elisa. Du 86Rb+ a ete utilise pour monitorer l’activite de la Na, K-ATPase cellulaire. Resultats et analyse statistique L’efflux de K+ est une etape commune dans de nombreux modeles etudiant l’activation de l’inflammasome NLRP3. Nous avons teste son implication dans l’activation de l’inflammasome NLRP3 par le C18:0 et avons demontre que l’augmentation de la [K+] extracellulaire est suffisante pour inhiber l’inflammasome NLRP3 dans ces conditions, suggerant l’implication de l’efflux de K+. En effet, des diminutions significatives de la [K+] cellulaire et de l’activite Na, K-ATPase sont mesurees en reponse au C18:0 vs BSA (85,72 % vs 102,80 % de la [K+] cellulaire ; p Conclusion En induisant une augmentation des niveaux de phospholipides satures, le stearate conduit a un efflux de K+ et une activation de l’inflammasome NLRP3 via l’inhibition de la Na, K-ATPase. L’oleate, en maintenant des niveaux bas de phospholipides satures, previens la diminution d’activite de la Na, K-ATPase, l’efflux de K+ et l’activation de l’inflammasome NLRP3.

Introduction et but de l’etude L’inflammation chronique et l’activation du systeme immunitaire sont impliquees dans le developpement du diabete de type 2 chez les patients obeses. Des macrophages sont recrutes dans le tissu adipeux de ces patients et secretent des cytokines pro-inflammatoires dont l’IL-1β impliquee dans la resistance a l’insuline. Il a ete montre que l’inflammasome NLRP3, requis pour la maturation de l’IL-1β, conduit au developpement de l’inflammation induite par l’obesite et de la resistance a l’insuline. Contrairement a l’oleate (C18 :1), le stearate (C18 :0), second acide gras sature le plus abondant, conduit a l’activation de l’inflammasome NLRP3 dans des macrophages humains. L’addition de C18 :1 au C18 :0 empeche cette activation. Cependant, les mecanismes moleculaires sont inconnus. Materiel et methodes Des analyses lipidomiques ont ete realisees sur des cellules THP-1 differenciees au PMA apres 8 h de traitement avec la BSA (temoin), le C18 :0 seul ou associe avec le C18 :1 pour etudier la composition en phospholipides cellulaires. La fluidite membranaire et la formation de gouttelettes lipidiques ont ete observees par microscopie confocale avec les sondes fluorescentes Laurdan et HCS LipidTOX. Du C18 :0 radiomarque a ete utilise pour suivre son incorporation dans les differentes classes lipidiques separees par chromatographie sur couche mince. Resultats Le C18 :0 conduit a une rigidification de la membrane plasmique sans formation de gouttelettes lipidiques et induit un changement spectaculaire dans le profil des phospholipides, avec une augmentation des especes saturees de phosphatidylcholine (PC) (10,54 % contre 46,35 % des PCs totales ; p p p p p = 0,0002) et PE (33,24 % contre 39,97 % des PEs totales ; p = 0,0127). Conclusion L’augmentation de la saturation des phospholipides en presence de C18 :0 induit la rigidification de la membrane plasmique et pourrait mener a l’activation de l’inflammasome NLRP3. L’effet protecteur du C18 :1 est conduit par une reorientation de l’incorporation du C18 :0 des phospholipides vers les gouttelettes lipidiques, combine a une fluidification membranaire due a l’augmentation des phospholipides insatures.