There has been an enormous interest to investigate impact of gut microbiota on host physiology over the past decade. To further understand its role at organismal level, it is important to delineate host-microbiota interaction at tissue and cell level. Diet, antibiotics, disease, or surgery produce shifts in composition of the gut microbiota that further alter levels of microbial-derived metabolites. Enteroendocrine cells (EEGs) are specialized hormone-producing cells in the gut epithelium that sense changes in the intestinal milieu through chemosensing G protein-coupled receptors. Accordingly, microbial metabolites interact with the EECs to stimulate or suppress hormone secretion, which act through endocrine and paracrine signaling to regulate local intestinal and diverse physiological functions and impact overall host metabolism. The remarkable success of glucagon-like peptide-1-based drugs for treatment of type 2 diabetes and obesity highlights the relevance to investigate microbial regulation of EEGs to tackle metabolic diseases through novel microbiota-based therapies.