"Obesity and type 2 diabetes are characterized by metabolic inflammation and an altered endocannabinoid system (eCB) tone. We have provided evidence that gut microbiota modulate both intestinal and adipose tissue eCB system tone. Insulin resistance and inflammation have been linked to microbiota-host interaction via different Toll-Like Receptors (TLR’s). Our preliminary data show that tamoxifen-induced epithelial intestinal cells deletion of the key signalling adaptor MyD88 (myeloid differentiation primary-response gene 88), that encompass most of the TLR’s, protect mice against diet-induced obesity and inflammation. A phenomenon closely linked with changes in the intestinal eCB system tone and antimicrobial peptides production. Moreover, we discovered that the recently identified bacteria living in the mucus layer, namely Akkermansia muciniphila, plays a central role in the regulation of host energy metabolism by putative mechanisms linking both the intestinal eCB system and the innate immune system. Thus these preliminary data support the existence of unidentified mechanisms linking the innate immune system, the gut microbiota and host metabolism. In this high-risk/high-gain research program, we propose to elucidate what could be one of the most fundamental processes shared by different key hallmarks of obesity and related diseases. A careful and thorough analysis of the molecular and cellular events linking gut microbiota, the innate immune system and eCB system in specific organs has the potential to unravel new therapeutic targets. We anticipate the key role of MyD88 and the enzyme NAPE-PLD (N-acylphosphatidylethanolamine phospholipase-D) involved in the synthesis of N-acylethanolamines family to be key determinant in such pathophysiological aspects. Thus, these approaches could provide different perspectives about disease pathogenesis and knowledge-based evidence of new therapeutic options for obesity and associated metabolic disorders in the future."