Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome\u27s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Immune cells in cardiometabolic diseases : phenotypic and functional alterations

L’inflammation de bas grade est un trait commun aux maladies cardiométaboliques (CMDs). Dans l’obésité et le diabète de type-2 (DT2) en particulier, l’insulino-résistance a été associée à une inflammation dans plusieurs tissus. L’objectif de ce travail est d’évaluer les interactions entre les altérations des cellules immunitaires et les perturbations du métabolisme dans les CMDs. Dans une première étude, nous avons étudié l’immunité intestinale et la production cytokinique des lymphocytes T (LT) jéjunaux de sujets minces et obèses et évalué la relation fonctionnelle entre LT et entérocytes. Nous montrons que la densité des LT est augmentée dans la muqueuse dans l’obésité et que l’augmentation de la production de cytokines par les LT de sujets obèses induit une résistance à l’insuline sur les entérocytes in vitro. Dans une deuxième étude, nous avons caractérisé les cellules MAIT (mucosal-associated invariant T cells), une sous-population de LT qui reconnait des métabolites bactériens dérivés de la vitamine B, dans le sang de 5 groupes de patients présentant différentes CMDs par rapport à des sujets contrôles. Dans tous les groupes de patients, nous observons une diminution des cellules MAIT circulantes qui est corrélée avec l’HbA1c. Nous montrons ex vivo que cette diminution pourrait être liée à une plus forte apoptose provoquée par une glucotoxicité. Nos résultats indiquent que l’environnement immunitaire intestinal pourrait participer aux perturbations métaboliques locales et systémiques dans l’obésité humaine. De plus, l’abondance de certaines cellules immunitaires, comme les MAIT, pourrait servir de marqueur précoce de la dysfonction cardiométabolique.A common feature between cardiometabolic diseases (CMDs) is a state of chronic low-grade inflammation. In obesity and type-2-diabetes (T2D) notably, insulin resistance has been linked to inflammation in several tissues. The objective of this project is to evaluate the interactions between immune cell alterations and metabolic perturbations in CMDs. In a first study, we investigated intestinal immunity and cytokine production of intestinal T cells in a cohort of lean and obese subjects and evaluated the functional relationship between T cells and enterocytes. We demonstrated that T cell density and cytokine production was increased in the jejunal mucosa of obese subjects and promoted insulin resistance in enterocytes in vitro. In a second study, we characterized mucosal-associated invariant T (MAIT) cells, a subset of T cells recognizing bacterial vitamin B derivatives, in 5 groups of patients with different forms CMDs (metabolic syndrome, obesity, T2D, coronary artery disease with or without heart failure) compared to healthy subjects. We demonstrated that MAIT cell decrease is correlated with HbA1c and is a common feature in all CMD groups. In an ex vivo study, we show that their depletion in the blood could be explained by a higher propensity to apoptosis under high glucose concentrations. Altogether, our findings suggest that the jejunal immune microenvironment could participate in local and systemic metabolic perturbations in human obesity. We also demonstrate that the abundance immune cells, such as circulating MAIT cells could serve as an early marker of cardiometabolic dysfunction

Cellules immunitaires dans les maladies cardiométaboliques : altérations phénotypiques et fonctionnelles

A common feature between cardiometabolic diseases (CMDs) is a state of chronic low-grade inflammation. In obesity and type-2-diabetes (T2D) notably, insulin resistance has been linked to inflammation in several tissues. The objective of this project is to evaluate the interactions between immune cell alterations and metabolic perturbations in CMDs. In a first study, we investigated intestinal immunity and cytokine production of intestinal T cells in a cohort of lean and obese subjects and evaluated the functional relationship between T cells and enterocytes. We demonstrated that T cell density and cytokine production was increased in the jejunal mucosa of obese subjects and promoted insulin resistance in enterocytes in vitro. In a second study, we characterized mucosal-associated invariant T (MAIT) cells, a subset of T cells recognizing bacterial vitamin B derivatives, in 5 groups of patients with different forms CMDs (metabolic syndrome, obesity, T2D, coronary artery disease with or without heart failure) compared to healthy subjects. We demonstrated that MAIT cell decrease is correlated with HbA1c and is a common feature in all CMD groups. In an ex vivo study, we show that their depletion in the blood could be explained by a higher propensity to apoptosis under high glucose concentrations. Altogether, our findings suggest that the jejunal immune microenvironment could participate in local and systemic metabolic perturbations in human obesity. We also demonstrate that the abundance immune cells, such as circulating MAIT cells could serve as an early marker of cardiometabolic dysfunction.L’inflammation de bas grade est un trait commun aux maladies cardiométaboliques (CMDs). Dans l’obésité et le diabète de type-2 (DT2) en particulier, l’insulino-résistance a été associée à une inflammation dans plusieurs tissus. L’objectif de ce travail est d’évaluer les interactions entre les altérations des cellules immunitaires et les perturbations du métabolisme dans les CMDs. Dans une première étude, nous avons étudié l’immunité intestinale et la production cytokinique des lymphocytes T (LT) jéjunaux de sujets minces et obèses et évalué la relation fonctionnelle entre LT et entérocytes. Nous montrons que la densité des LT est augmentée dans la muqueuse dans l’obésité et que l’augmentation de la production de cytokines par les LT de sujets obèses induit une résistance à l’insuline sur les entérocytes in vitro. Dans une deuxième étude, nous avons caractérisé les cellules MAIT (mucosal-associated invariant T cells), une sous-population de LT qui reconnait des métabolites bactériens dérivés de la vitamine B, dans le sang de 5 groupes de patients présentant différentes CMDs par rapport à des sujets contrôles. Dans tous les groupes de patients, nous observons une diminution des cellules MAIT circulantes qui est corrélée avec l’HbA1c. Nous montrons ex vivo que cette diminution pourrait être liée à une plus forte apoptose provoquée par une glucotoxicité. Nos résultats indiquent que l’environnement immunitaire intestinal pourrait participer aux perturbations métaboliques locales et systémiques dans l’obésité humaine. De plus, l’abondance de certaines cellules immunitaires, comme les MAIT, pourrait servir de marqueur précoce de la dysfonction cardiométabolique

T Cell Populations and Functions Are Altered in Human Obesity and Type 2 Diabetes

International audiencePurpose of the Review: Obesity and type 2 diabetes (T2D) are considered chronic inflammatory diseases. While early publications have reported the implication of innate immune cells such as macrophages to promote systemic inflammation and metabolic dysfunctions, recent publications underline the alterations of the T cell compartment in human obesity and type 2 diabetes. These recent findings are the focus of this review.Recent Findings: In humans, obesity and T2D induce the expansion of proinflammatory T cells such as CD4 Th1, Th17 and CD8 populations whereas innate T cells such as MAIT and iNKT cells are decreased. These alterations reflect a loss of total T cell homeostasis that may contribute to tissue and systemic inflammation.Summary: Whether these changes are adaptive to nutritional variations and/or contribute to the progression of metabolic diseases remains to be clarified. T cell phenotyping may improve obese and/or T2D patient stratification with therapeutic and prognostic implications

Adipose tissue adaptive response to trans-10,cis-12-conjugated linoleic acid engages alternatively activated M2 macrophages

In mice, nutritional supplementation with the trans-10,cis-12 isomer of linoleic acid (t10,c12-CLA) promotes lipoatrophy, hyperinsulinemia, and macrophage infiltration in white adipose tissue (WAT). We explored the dynamics of these interrelated responses over 2 consecutive 7 d periods of t10,c12-CLA administration and withdrawal. t10,c12-CLA down-regulated lipogenic and lipolytic gene expression and increased collagen deposition, but with no evidence of cross-linking. An abundant CD45(+) cell infiltrate, comprising prominently CD206(+)CD11c(-) macrophages, was found in WAT in association with an anti-inflammatory gene signature. Infiltration of natural killer (NK) and dendritic cells contributed to WAT's innate immune response to t10,c12-CLA. Less abundant adaptive immune cells colonized WAT, including B, NK T, γδ T, and αβ T cells. By contrast, T-regulatory cell abundance was not affected. Interruption of treatment allowed recovery of WAT mass and normalization of insulinemia, coincident with regain of WAT homeostasis owing to a coordinated reversion of genic, structural, and immune deregulations. These data revealed a striking resilience of WAT after a short-term metabolic injury induced by t10,c12-CLA, which relies on alternatively activated M2 macrophage engagement. In addition, the temporal links between variations in WAT alterations and insulinemia upon t10,c12-CLA manipulation strengthen the view that WAT dysfunctional status is critically involved in altered glucose homeostasis.-Pini, M., Touch, S., Poirier, H., Dalmas, E., Niot, I., Rouault, C., Druart, C., Delzenne, N., Clément, K., André, S., Guerre-Millo, M. Adipose tissue adaptive response to trans-10,cis-12-conjugated linoleic acid engages alternatively activated M2 macrophages

Mucosal-associated invariant T (MAIT) cells are depleted and prone to apoptosis in cardiometabolic disorders

International audienceThe disruption of systemic immune homeostasis is a key mediator in the progression of cardiometabolic diseases (CMDs). We aimed to extend knowledge regarding the clinical relevance of CMD-associated variation of circulating mucosal-associated invariant T (MAIT) cell abundance and to explore underlying cellular mechanisms. We analyzed cross-sectional data from 439 participants of the Metagenomics in Cardiometabolic Diseases (MetaCardis) study, stratified into 6 groups: healthy control subjects and patients with metabolic syndrome (MS), obesity, type 2 diabetes mellitus (T2DM), and coronary artery disease (CAD) without, or with congestive heart failure (CAD-CHF). Blood MAIT cell frequency was significantly decreased in all CMD groups, including early (MS) and later (CAD and CAD-CHF) stages of disease progression. Reduced MAIT cell abundance was associated with increased glycosylated hemoglobin, inflammation markers, and deterioration of cardiac function. Glucose dose dependently promoted MAIT cell apoptosis in vitro, independently of anti-CD3 and cytokine-mediated activation. This outcome suggests the prominence of metabolic over an antigenic or cytokine-rich environment to promote MAIT cell reduction in patients with CMD. In summary, all stages of CMDs are characterized by reduced circulating MAIT cells. Chronically elevated blood glucose levels could contribute to this decline. These data extend the pathologic relevance of MAIT cell loss and suggest that MAIT cell abundance may serve as an indicator of cardiometabolic health.-Touch, S

Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model

International audienceBackground:Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented.Objectives:We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice.Methods:Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet.Results:Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD.Conclusions:Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice

Human CD4+/CD8α+ regulatory T cells induced by Faecalibacterium prausnitzii protect against intestinal inflammation

International audienceFaecalibacterium prausnitzii (F. prausnitzii), a dominant bacterium of the human microbiota, is decreased in patients with inflammatory bowel diseases (IBD) and exhibits anti-inflammatory effects. In human, colonic lamina propria contains IL-10-secreting, Foxp3-negative regulatory T cells (Treg) characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet. Here, using a humanized model of NOD.Prkcscid IL2rγ-/- (NSG) immunodeficient mouse strain that expresses the human leucocyte antigen D-related allele HLA-DR*0401 but not murine class II (NSG-Ab° DR4) molecules, we demonstrated a protective effect of a HLA-DR*0401-restricted DP8α Treg clone combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn's disease