Microbial Control of Intestinal Homeostasis via Enteroendocrine Cell Innate Immune Signaling

The intestinal microbiota of flies and mammals resides in the most proximal and most distal portions of the gastrointestinal tract, respectively. Enteroendocrine cells express innate immune signaling pathways that respond to microbial metabolites and patterns by upregulating transcription of antimicrobial and the enteroendocrine peptides DH31 and tachykinin (Tk). The IMD pathway of enteroendocrine cells controls intestinal levels of antimicrobial peptides (AMPs) as well as DH31-regulated intestinal contractions and Tk-regulated lipid synthesis. The AMP DH31, and Tk control the antimicrobial, mechanical, and metabolic branches of the intestinal innate immune system. Small molecules that target the enteroendocrine innate immune system may represent therapies for chronic metabolic diseases such as obesity and diabetes. 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. 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.