Gut microbes are now considered as key partners involved in human physiology. Data have shown that microbes contribute to regulate energy, lipid, and glucose homeostasis through several mechanisms. Among them, the role of pathogen-associated molecular pattern and bacterial metabolites has been proposed (for example, metabolic endotoxemia and bioactive lipids). This short review, briefly discusses the role of the gut barrier as well as the impact of both the innate immune system and bioactive molecules (for example, endocannabinoids, cytochrome P450 derived arachidonic acids compounds) in the framework of gut microbes and cardiometabolic disorders.