The mammalian gastrointestinal (GI) tract houses a complex array of microbes critical for promoting essential host functions in local and distant tissues. Dysbiosis of the human gut microbiota has been linked to the development of multi-tissue immunometabolic disorders including inflammatory bowel disease, obesity, and type 2 diabetes. While extensive efforts have been made to understand the complex nature of host-microbiota interactions in regulating host fitness, studies in mice and humans have revealed few specific microbial drivers of distinct disease states. Moreover, how the microbiota controls systemic processes by modulating cellular functions in both local and distant tissues is unclear. In this thesis work we show that the microRNA family miR-181 is regulated by the gut microbiota to 1) regulate whole body glucose homeostasis by modulating cell-intrinsic functions of white adipocytes and 2) protect against severe GI inflammation in response to mucosal injury by regulating the proliferative capacity of intestinal epithelial cells (IECs). Our mechanistic work in white adipocytes shows that tryptophan-derived metabolites produced by the gut microbiota control the expression of the miR-181 family to regulate energy expenditure and insulin sensitivity. Moreover, we show that dysregulation of the gut microbiota-miR-181 axis is required for the development of obesity, insulin resistance, and white adipose tissue inflammation in mice. When we assessed the role of the gut microbiota-miR-181 axis locally in the GI tract, we found that miR-181 expression within IECs is regulated by the gut microbiota and is required for protection against the development of severe colonic inflammation in response to epithelial injury. Moreover, we discovered that miR-181 expression increases the proliferative capacity of IECs, likely through de-repression of Wnt signaling. Altogether, our results indicate that regulation of miR-181 by the gut microbiota is a central mechanism by which host physiology is tuned in response to dietary and environmental stressors. miR-181 thus represents a novel post-transcriptional regulatory factor and potential therapeutic target in IECs and white adipocytes critical for controlling the progression of immuometabolic disorders.