A community of commensal microbes, known as the intestinal microbiota, resides within the gastrointestinal tract of animals and plays a role in maintenance of host metabolic homeostasis and resistance to pathogen invasion. Enteroendocrine cells, which are relatively rare in the intestinal epithelium, have evolved to sense and respond to these commensal microbes. Specifically, they express G-protein-coupled receptors and functional innate immune signaling pathways that recognize products of microbial metabolism and microbe-associated molecular patterns, respectively. Here we review recent evidence from Drosophila melanogaster that microbial cues recruit antimicrobial, mechanical, and metabolic branches of the enteroendocrine innate immune system and argue that this response may play a role not only in maintaining host metabolic homeostasis but also in intestinal resistance to invasion by bacterial, viral, and parasitic pathogens.