Molecular dialogues between the gut and its resident microbiota affect the development of the zebrafish intestine

All animals exist in intimate associations with microorganisms that play important roles in the host's normal development and tissue physiology. In vertebrates the most populous and complex community of microbes resides in the digestive tract. We have instituted Danio rerio as a vertebrate model to assess the establishment of the gut microbiota and its role in intestinal maturation. In the absence of the microbiota the gut epithelium is arrested in aspects of its differentiation and physiology. Phenotypes of these germ-free zebrafish can be restored at later stages of development by the addition of the microbiota, and certain phenotypes were even reversible with the addition of microbial factors, indicating that bacteria communicate with the host cells via distinct molecular pathways. Investigations in the germ-free zebrafish model led to the discovery of a molecular dialogue that is crucial to the establishment of gut immune homeostasis mediated by a canonical proinflammatory pathway. Gut immune homeostasis was established by host recognition of lipopolysaccharide, a microbial associated molecular pattern that induces septic shock, through Toll-like receptor and tumor necrosis factor signaling. The brush border enzyme, intestinal alkaline phosphatase, which dephosphorylates lipopolysaccharide, is induced during establishment of the microbiota. Studies using a zebrafish model of septic shock indicate that intestinal alkaline phosphatase functions upstream of the innate immune pathway to limit the proinflammatory potential of resident gut microbes and promote mucosal tolerance to the abundant community of microbes the intestine. Thus intestinal alkaline phosphatase plays an important role to prevent excessive inflammation in response to gut bacteria, which would be detrimental to microbiota and host alike. This dissertation includes both my previously published and my co-authored materials.