Microbial cells react with intestinal surfaces and produce enzymes and metabolites that influence human health, host metabolism and immunity. Gut microbiota and probiotics also influence host physiology. Here, we review 1) the role of host–microbiota composition and microbial enzymes in human well-being and in human metabolism for the degradation of indigestible dietary components; 2) the effects of gut microbiota on drug metabolism; 3) the roles of probiotic composition, metabolites, e.g. vitamins, bacteriocins, acids and bioactive peptides, and effector compounds, e.g. polysaccharides, outer membrane proteins, pili, muropeptides and CpG-rich DNA, for clinical outcomes; and 4) a new perspective of microbial global positioning system (mGPS) for segregation of human disease phenotypes on the basis of their microbiota.