The intestine harbors a large and diverse community of microorganisms, collectively known as the microbiota. The host and its microbiota form a complex relationship, the foundations of which have been forged over the course of animal evolution. Experiments using germ-free vertebrate models have shown that the gut microbiota impacts many aspects of host biology, including modulation of host nutrient metabolism, immune system development, and epithelial cell renewal. These findings indicate that the microbiota serves as a microbial 'organ', playing an integral role in host development and physiology. The characterization of factors that help establish and sustain host-microbial relationships in the digestive tract should lead to new ways of manipulating our biology to promote health, and to treat diseases such as inflammatory bowel disease and obesity. Despite the importance of the microbiota in host biology, many of the host and microbial factors that mediate these interactions are not yet understood.

We are using the zebrafish (Danio rerio) to investigate the mechanisms underlying host-microbial interactions in the vertebrate gut. The zebrafish is optically transparent from organogenesis through the onset of adulthood, facilitating in vivo real-time observations of the digestive tract and its microbial inhabitants. Furthermore, the small size of the zebrafish facilitates high-throughput genetic and chemical screens. We have developed methods for rearing germ-free zebrafish, and used those techniques to identify host responses to the gut microbiota that have been evolutionarily conserved between fish and mammals. To generate simplified experimental platforms, we have also identified individual bacterial members of the gut microbiota that elicit conserved host responses upon colonization of germ-free zebrafish. Our results indicate that different host responses are caused by distinct bacterial signals, and that these host-microbial interactions are regulated by dietary composition. Current research projects in our lab are focused on the following areas:

Microbial regulation of host nutrient metabolism: Members of the gut microbiota are able to process otherwise indigestible nutrients in the diet, leading to increased nutrient absorption and energy storage by the host. We are employing genetic methods in selected members of the gut microbiota to identify and characterize the bacterial factors that mediate this process. Molecular and biochemical approaches are also being taken to understand how the host interprets and responds to these bacterial signals. We are particularly interested in understanding how environmental factors, such as the microbiota and diet, impact upon zebrafish adipocyte development and physiology.

Innate immune responses to the gut microbiota: The gut microbiota stimulates a range of innate immune responses in the host, including production of acute phase proteins, improved epithelial barrier function, and recruitment of granulocytes. We are combining genetic methods in zebrafish with genetic and biochemical analyses in P. aeruginosa, to understand the nature of this bacterial signal and the host signaling pathways that transduce it.