Although the microbiome field shows enormous proliferation, it has some major flaws that make its use in the public health domain currently critical. Starting with the quality and representative character of the stool samples, its processing and analysis as well as assembly of metagenome data and the interpretation. Moreover, there is still no consensus of what constitutes a “normal/healthy” microbiome, nor what features characterize a dysbiotic microbiome. And, based on hundreds of individual parameters and environmental factors, the intestinal microbiome shows a huge variability and consequently changing one factor—such as food intake—is likely to have a limited impact in achieving optimized health. The present review intends to summarize the state of consolidated knowledge on human gut microbiome in the context of diet and disease, its key features, and its influencing factors as well as its “add-on” quality for PN offers.