Crosstalk between organs is crucial for controlling numerous homeostatic systems (e.g. energy balance, glucose metabolism and immunity). Several pathological conditions, such as obesity and type 2 diabetes, are characterised by a loss of or excessive inter-organ communication that contributes to the development of disease. Recently, we and others have identified several mechanisms linking the gut microbiota with the development of obesity and associated disorders (e.g. insulin resistance, type 2 diabetes, hepatic steatosis). Among these, we described the concept of metabolic endotoxaemia (increase in plasma lipopolysaccharide levels) as one of the triggering factors leading to the development of metabolic inflammation and insulin resistance. Growing evidence suggests that gut microbes contribute to the onset of low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. We have demonstrated that enteroendocrine cells (producing glucagon-like peptide-1, peptide YY and glucagon-like peptide-2) and the endocannabinoid system control gut permeability and metabolic endotoxaemia. Recently, we hypothesised that specific metabolic dysregulations occurring at the level of numerous organs (e.g. gut, adipose tissue, muscles, liver and brain) rely from gut microbiota modifications. In this review, we discuss the mechanisms linking gut permeability, adipose tissue metabolism, and glucose homeostasis, and recent findings that show interactions between the gut microbiota, the endocannabinoid system and the apelinergic system. These specific systems are discussed in the context of the gut-to-peripheral organ axis (intestine, adipose tissue and brain) and impacts on metabolic regulation. In the present review, we also briefly describe the impact of a variety of non-digestible nutrients (i.e. inulin-type fructans, arabinoxylans, chitin glucans and polyphenols). Their effects on the composition of the gut microbiota and activity are discussed in the context of obesity and type 2 diabetes.