La relation hôte-microbiote dans le développement du diabète de type 2 : du mutualisme au parasitisme métabolique

Metabolic diseases such as type 2 diabetes are a major public health issue. A low grade chronic inflammatory reaction is one of the mechanisms appearing early during the development of these diseases. We hypothesized that bacteria could be a direct triggering factor of metabolic inflammation. First, we discovered the existence of a physiological infection. Moreover we found in mice an increased translocation of commensal bacteria towards blood and adipose tissue, before the onset of high-fat diet-induced diabetes, providing a putative direct cellular link between intestinal microbiota and metabolic inflammation. This bacterial translocation was prevented in mice lacking receptors for bacterial patterns NOD1 or CD14, but conversely increased in ob/ob or MyD88-deficient mice. Moreover, a probiotic treatment with Bifidobacterium animalis subsp. lactis, or with Lactococcus lactis delivering active leptine, was able to prevent metabolic infection and inflammation as well as diabetes. We then confirmed in man the existence of a physiological bacteremia. Bacterial DNA was moreover identified as a positive marker of metabolic diseases. Analysis of this microbiota shown a decrease in Gram positive bacteria and an increase in Gram negative ones, as well as an increase in NO reductase-expressing bacteria, in diabetics. These results were confirmed in mice. Moreover, mucus quantity and quality of its glycosylations were modified before diabetes, along with a decrease in defensins’ expression, a loss of physiological inflammation and increased transcellular permeability.Le diabète de type 2 est associé à une inflammation chronique de bas niveau et nous avons pensé que la présence de bactéries pouvait alimenter cette inflammation. Après la découverte d’une infection physiologique, nous avons révélé une augmentation de la translocation de bactéries commensales dans le tissu adipeux et le sang, avant l’apparition d’un diabète induit par un régime gras chez la souris. Cette translocation bactérienne était prévenue chez des souris déficientes pour NOD1 ou CD14, mais au contraire augmentée chez les souris ob/ob ou déficientes pour MyD88. De plus, un traitement probiotique avec Bifidobacterium animalis subsp. lactis, ou Lactococcus lactis délivrant de la leptine active ont prévenu l’infection métabolique, l’inflammation et le diabète. Nous avons ensuite confirmé chez l’homme l’existence d’une bactériémie physiologique. L’ADN bactérien sanguin a été de plus identifié comme marqueur positif du diabète. L’étude du microbiote sanguin humain a montré une diminution des bactéries à Gram positif et une augmentation de celles à Gram négatif, ainsi qu’une présence accrue d’ADN codant pour des réductases du NO, chez les patients diabétiques. Ces résultats ont été confirmés chez la souris. De plus, le mucus était modifié dans l’iléon avant l’apparition du diabète, avec une baisse de l’expression des défensines, une perte de l’inflammation physiologique des entérocytes et une augmentation de la perméabilité transcellulaire. Un comportement parasite de la part de bactéries normalement commensales a été ainsi mis en lumière avant le développement du diabète chez la souris

Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment

A fat-enriched diet modifies intestinal microbiota and initiates a low-grade inflammation, insulin resistance and type-2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high-fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This ‘metabolic bacteremia’ is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue can be reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, which improves the animals' overall inflammatory and metabolic status. Altogether, these data demonstrate that the early onset of HFD-induced hyperglycemia is characterized by an increased bacterial translocation from intestine towards tissues, fuelling a continuous metabolic bacteremia, which could represent new therapeutic targets

Gut microbiota and diabetes: from pathogenesis to therapeutic perspective

More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10–20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain

Intestinal microflora and metabolic diseases.

International audienceRecent advances in molecular sequencing technology have allowed researchers to answer major questions regarding the relationship between a vast genomic diversity-such as found in the intestinal microflora-and host physiology. Over the past few years, it has been established that, in obesity, type 1 diabetes and Crohn's disease-to cite but a few-the intestinal microflora play a pathophysiological role and can induce, transfer or prevent the outcome of such conditions. A few of the molecular vectors responsible for this regulatory role have been determined. Some are related to control of the immune, vascular, endocrine and nervous systems located in the intestines. However, more important is the fact that the intestinal microflora-to-host relationship is bidirectional, with evidence of an impact of the host genome on the intestinal microbiome. This means that the ecology shared by the host and gut microflora should now be considered a new player that can be manipulated, using pharmacological and nutritional approaches, to control physiological functions and pathological outcomes. What now remains is to demonstrate the molecular connection between the intestinal microflora and metabolic diseases. We propose here that the proinflammatory lipopolysaccharides play a causal role in the onset of metabolic disorders

Le microbiote intestinal à l’origine de nouvelles perspectives thérapeutiques pour les maladies métaboliques ?

La dernière décennie a vu la découverte d’un nouvel organe, le microbiote intestinal, caractérisé par d’immenses et pléiotropes fonctions biologiques. Les milliards de cellules qui le constituent sont en très étroite harmonie fonctionnelle avec leur hôte. Ainsi, plus de 4 millions de gènes bactériens répartis dans plus de 1 500 espèces discourent entre eux, avec l’organisme et avec l’environnement pour établir une écologie mutualisée. Tout déséquilibre nutritionnel revient à modifier cette symbiose et, ainsi, à changer les relations qui existent avec les bactéries elles-mêmes pour le contrôle de notre métabolisme énergétique. La pandémie actuelle de diabète de type 2 et d’obésité ne peut être uniquement liée aux variations de notre génome. Ainsi, elle pourrait trouver son origine dans notre métagénome, c’est-à-dire dans des millions de gènes bactériens présents dans notre intestin. Cet organe, dont la génomique plastique se renouvelle au quotidien, nous est transmis par nos parents, mais il est également influencé par nos habitudes de vie et notre environnement à la naissance. Sa diversité, son caractère évolutif rapide, son influence sur le métabolisme, ainsi que la découverte d’un microbiote interne tissulaire à l’intérieur de l’organisme, ouvrent de nouvelles opportunités thérapeutiques pharmacologiques et nutritionnelles, ainsi que la possibilité d’identifier l’état physiopathologique de chaque individu par des biomarqueurs très précis composant la fiche signalétique métagénomique. Ainsi, la médecine individualisée trouve, dans le métagénome, l’origine même de son ambition

Metagenome and metabolism: the tissue microbiota hypothesis.

International audienceOver the last decade, the research community has revealed the role of a new organ: the intestinal microbiota. It is considered as a symbiont that is part of our organism since, at birth, it educates the immune system and contributes to the development of the intestinal vasculature and most probably the nervous system. With the advent of new generation sequencing techniques, a catalogue of genes that belong to this microbiome has been established that lists more than 5 million non-redundant genes called the metagenome. Using germ free mice colonized with the microbiota from different origins, it has been formally demonstrated that the intestinal microbiota causes the onset of metabolic diseases. Further to the role of point mutations in our genome, the microbiota can explain the on-going worldwide pandemic of obesity and diabetes, its dissemination and family inheritance, as well as the diversity of the associated metabolic phenotypes. More recently, the discovery of bacterial DNA within host tissues, such as the liver, the adipose tissue and the blood, which establishes a tissue microbiota, introduces new opportunities to identify targets and predictive biomarkers based on the host to microbiota interaction, as well as to define new strategies for pharmacological, immunomodulatory vaccines and nutritional applications

Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the D.E.S.I.R. study.

AIM: We recently described a human blood microbiome and a connection between this microbiome and the onset of diabetes. The aim of the current study was to assess the association between blood microbiota and incident cardiovascular disease. METHODS AND RESULTS: D.E.S.I.R. is a longitudinal study with the primary aim of describing the natural history of the metabolic syndrome and its complications. Participants were evaluated at inclusion and at 3-, 6-, and 9-yearly follow-up visits. The 16S ribosomal DNA bacterial gene sequence, that is common to the vast majority of bacteria (Eubac) and a sequence that mostly represents Proteobacteria (Pbac), were measured in blood collected at baseline from 3936 participants. 73 incident cases of acute cardiovascular events, including 30 myocardial infarctions were recorded. Eubac was positively correlated with Pbac (r = 0.59; P<0.0001). In those destined to have cardiovascular complications, Eubac was lower (0.14±0.26 vs 0.12±0.29 ng/µl; P = 0.02) whereas a non significant increase in Pbac was observed. In multivariate Cox analysis, Eubac was inversely correlated with the onset of cardiovascular complications, (hazards ratio 0.50 95% CI 0.35-0.70) whereas Pbac (1.56, 95%CI 1.12-2.15) was directly correlated. CONCLUSION: Pbac and Eubac were shown to be independent markers of the risk of cardiovascular disease. This finding is evidence for the new concept of the role played by blood microbiota dysbiosis on atherothrombotic disease. This concept may help to elucidate the relation between bacteria and cardiovascular disease

Standardized hazards ratios for an incident cardiovascular outcome.

<p>Models 1 and 2 were adjusted for gender, smoking status, LDL-cholesterol, fibrinogen, hypertension and diabetes. In addition , in model 2 Pbac was included.</p

Proteobacteria phylum within blood microbiota.

<p>Box and wisker plot, showing medians (dot in middle of box, quartiles at end of box, and as wiskers the extremes), of Eucbacteria: 16S ribosomal DNA gene sequences common to the vast majority of bacteria phyla (Eubac) according to Pbac: 16S ribosomal DNA sequences that belong to the Proteobacteria phylum (both variables are log transformed).</p

Adjusted Hazard ratio of having primary cardiovascular outcome by tertiles of Eubacteria (Eubac) and Proteobacteria (Pbac).

<p>Adjusted Hazard ratio of having primary cardiovascular outcome by tertiles of Eubacteria (Eubac) and Proteobacteria (Pbac).</p