Diet is known to be capable of achieving clinically relevant weight loss and metabolic health improvements, but the effectiveness is variable and maintenance poor. Recent data indicates that gut microbes profoundly influence our metabolic health and associations between microbial changes and weight loss during dietary intervention have been reported (e.g. change in Firmicutes to Bacteriodetes ratio). However there is limited consistency between studies and currently the therapeutic potential of microbial signatures for obesity intervention remains unclear. An emerging paradigm is that a systems-based view encompassing the nutritional environment, microbiome and host biology is needed. Although diet can drive changes in in microbial influence on host health, this is not a one-way effect. The host system also impacts microbial community structure in multiple ways, including physiological, immunological and behavioural pathways and interactions within the microbial community affect its resistance to change. We are exploring the role of such diet-host-microbiome interactions in shaping the outcomes of diet interventions in obesity and metabolic health. Through systematic exploration of the relationship between nutrient intake and microbiome structure in animal models we have defined major drivers of microbiome composition. These insights are being applied to assess the diagnostic potential of gut microbiota in diet interventions. Our evidence indicates that weight loss is contingent on the susceptibility of the patients microbiome to shift in response to a dietary intervention. Significantly baseline microbiome signatures appear to have high potential as predictive tools in personalizing diet-based obesity management.