The mammalian gut, the site of digestion and nutrients absorption, harbors diverse microbes that play an essential role in maintaining physiological homeostasis of the gastrointestinal system. These commensal microbes are important for the normal development of the host immune system and alteration of the microbiota of gastrointestinal system has been found to play an important role in the development of obesity, metabolic syndromes such as type 2 diabetes, and cardiovascular diseases. Several recent studies with mouse models and in humans have demonstrated that intestinal microbiota has important role in host metabolism by regulating energy absorption and modulating the endocrine functions. A variety of nutrients and metabolites derived from commensal bacteria have been proved to be important regulators in improving gut barrier functions and immune homeostasis. Here we review current literature on the interactions between microbes and host in the Gastrointestinal (GI) tract and based on these interactions we proposed a hypothesis in which the microbiota interacts with the host gastrointestine through a gut-brainendocrine- immune system. By understanding this system, we should be in better position to develop treatment for metabolic diseases and inflammation in human and animals.