The hologenome theory of evolution proposes that natural selection acts not on the individual organism but rather on the “holobiont,” which consists of the organism together with microbiome (its genes and metabolites). When a holobiont is challenged by dramatic changes, such as altered diet or reduced physical activity, it employs adaptive mechanisms in the form of reshuffling its microbiome (resident microbial communities), but the underlying mechanisms of this molecular crosstalk remain to be determined. Effective study of the holobiont requires a systems biology approach: remove one component of the holobiont to study it in reductionist style and other parts also altered will be overlooked. Decades of reductionist research aimed at understanding the mechanisms responsible for the current dramatic epidemic of man-made metabolic diseases have not considered the holobiont perspective and have consequently missed the adaptation strategies of the microbiome but have set the stage to explore the inchoate holobiont perspective. Application of a systems biology approach to decipher molecular mechanisms underlying man-made metabolic diseases presents a unique opportunity to develop novel therapies that sustain health in a personalized manner. This meeting will discuss how the gut microbiome and its metabolites influence major molecular and physiological mechanisms responsible for man-made metabolic diseases. It will therefore incorporate investigators from diverse areas such as medicine, immunology, neurobiology, endocrinology, physiology, psychiatry, systems biology and microbiology. In addition, the nutritional, surgical and pharmacological aspects of innovative therapeutic strategies will be discussed in dialogue with scientists from pharmaceutical/nutritional companies. The gut microbiome is a neuroendocrine and antigenic organ whose rediscovery is necessary for our understanding of man-made metabolic diseases in the context of the holobiont.