Obesity is associated with a cluster of metabolic comorbidities (type 2 diabetes, cardiovascular diseases, and non-alcoholic steatohepatitis). Identify novel targets with therapeutic potential would bring hope to control this epidemic disease and related metabolic disorders. Growing evidence supports the idea that the increased prevalence of obesity and type 2 diabetes cannot be attributed solely to changes in the human genome, nutritional habits, or the reduction of physical activity in our daily lives. Among other candidates, a specific environmental factor evolving with us from birth and our dietary habits has been shown to contribute to energy homeostasis, this is the gut microbiotaWe have contributed to the demonstration that the gut microbiota composition is associated with several hallmarks of metabolic syndrome (e.g., obesity, type 2 diabetes, cardiovascular diseases, and non-alcoholic steatohepatitis). Unequivocal evidence demonstrates that gut microbiota influence whole-body metabolism by affecting the energy balance, gut permeability, serum lipopolysaccharides (i.e., metabolic endotoxemia), and metabolic inflammation that are associated with obesity and associated disorders. Because the gut microbiota is a crucial actor involved in the pathology of obesity and type 2 diabetes, gut microbiota modulations are viewed as an interesting tool to treat these diseases. In the 90’s our lab has discovered and developed the prebiotic concept. Since this discovery, we have shown that, specific gut microbiota modulations using prebiotic (i.e., such as oligofructose a non-digestible carbohydrates) improve gut barrier functions, metabolic endotoxemia, inflammation, glucose and lipid homeostasis in obesity and type 2 diabetes. These targeted nutritional interventions using non-digestible carbohydrates with prebiotic properties have shown promising results in pre-clinical studies in the context of obesity; however the bacteria as well as the mechanisms of interaction between the gut microbiota and the host involved in these beneficial effects of gut microbiota modulations remain poorly understood.Recently, we have revealed that cross-talk between a specific bacterium namely Akkermansia muciniphila and intestinal epithelium is able to reduce diet-induced obesity, type-2 diabetes and gut permeability as well as whole body inflammation associated with obesity. Although these results provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders, this remain to be confirmed in human patients.In conclusion targeting the gut microbiota in the context of obesity have shown promising therapeutically advance in pre-clinical studies, although human intervention studies warrant further investigations.