Metabolites produced by the host and microbiota play a crucial role in how human bodies develop and remain healthy. Most of these metabolites are produced by microbiota and hosts in the digestive tract. Metabolites in the gut have important roles in energy metabolism, cellular communication, and host immunity, among other physiological activities. Although numerous host metabolites, such as free fatty acids, amino acids, and vitamins, are found in the intestine, metabolites generated by gut microbiota are equally vital for intestinal homeostasis. Furthermore, microbiota in the gut is the sole source of some metabolites, including short-chain fatty acids (SCFAs). Metabolites produced by microbiota, such as neurotransmitters and hormones, may modulate and significantly affect host metabolism. The gut microbiota is becoming recognized as a second endocrine system. A variety of chronic inflammatory disorders have been linked to aberrant host-microbiota interplays, but the precise mechanisms underpinning these disturbances and how they might lead to diseases remain to be fully elucidated. Microbiome-modulated metabolites are promising targets for new drug discovery due to their endocrine function in various complex disorders. In humans, metabolotherapy for the prevention or treatment of various disorders will be possible if we better understand the metabolic preferences of bacteria and the host in specific tissues and organs. Better disease treatments may be possible with the help of novel complementary therapies that target host or bacterial metabolism. The metabolites, their physiological consequences, and functional mechanisms of the host-microbiota interplays will be highlighted, summarized, and discussed in this overview.