PURPOSE OF REVIEW: To analyze the respective roles of macronutrient-derived moieties, of a gut mucosal function [intestinal gluconeogenesis (IGN)] and its capacity of influencing the brain control of energy homeostasis, and of the microbiota 'function' versus 'genomic composition' in the control of host metabolism. RECENT FINDINGS: Small products deriving from protein digestion (peptides) or from fermentation by the gut microbiota (short-chain fatty acids and succinate) activate IGN, a mucosal function sensed by the peripheral gut nervous system, which intitiates metabolic benefits deriving from brain control of energy homeostasis. The microbiota function (fermentation) rather than its genomic composition is a key in these processes. SUMMARY: Short-chain fatty acids and succinate produced from the fermentation of macronutrients by the gut microbiota positively influence the brain's control of energy homeostasis via the activation of IGN. The microbiota function rather than genomic composition is a key in these processes.