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The human intestine is home to trillions of bacteria, which symbiose with our mammalian cells to promote health or disease in the human metaorganism. To maintain this symbiotic relationship, gut microbes and host cells engage in bidirectional cross-talk that relies heavily on common nutrients used by both cell types. It is important to understand this bidirectional metabolic cross-talk because this metaorganismal communication is involved in the pathogenesis of obesity, insulin resistance, cardiovascular disease, and cancer. A key constraint on the types of microbes that can inhabit our intestine is the quality and quantity of our diet. However, the distinct dietary nutrients that impact microbial community structure are poorly understood. Now, Holmes et al . provide evidence that dietary nitrogen content impacts gut microbial diversity and associated host metabolic responses. To identify dietary factors that influence microbiome-host interactions, the researchers designed a series of well-controlled diets with a dynamic range of macronutrients (carbohydrates, protein, and fat) and overall energy density. These defined diets were then fed to mice to examine their effects on gut microbiome community structure, as well as microbe and host nutrient metabolism using stable isotope methodology. This work also leveraged an innovative bioinformatics platform to predict guilds of microbes that have distinct nutrient acquisition preferences. A key observation was that dietary protein intake constrains the host-microbiome metabolic interplay. In particular, the availability of nitrogen can impact both gut microbial community structure and host metabolism. Diets that restricted nitrogen availability to gut microbes promoted healthy aging in the mice, potentially by shaping community structure. These insights offer a potential explanation for the effect of high protein intake on the metabolic health in the host. This work also provides evidence that diet may have a large impact on host-microbiome interactions in health and disease. Forging ahead, it is imperative that we understand that studying microbe-host interactions in chow-fed mice likely has little direct relevance to the human situation. Humans do not consume diets even remotely similar to mouse chow, which is an extremely high-fiber, high-carbohydrate, and low-fat diet. As we move forward to therapeutically intervene on microbe-host interactions to improve human health, consideration of the dietary constraints will be key. A. J. Holmes et al. , Diet-microbiome interactions in health are controlled by intestinal nitrogen source constraints. Cell Metab. 10.1016/j.cmet.2016.10.021 (2016). [[Abstract]][1] [1]: http://www.cell.com/cell-metabolism/abstract/S1550-4131(16)30553-8