Host-microbe interactions in the digestive tract

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 animal models have established that the gut microbiota regulates many aspects of host biology, including metabolism of dietary nutrients and maturation of the immune system. The identification of factors that help establish and sustain host-microbe 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-microbe interactions in the vertebrate gut. The zebrafish is optically transparent from embryogenesis through the onset of adulthood, facilitating in vivo real-time observations of host tissues and their 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. Current research projects in our lab are focused on the following areas:

Innate immune responses to the gut microbiota: The gut microbiota stimulates a range of innate immune responses in the host, including production of antimicrobial and acute phase proteins, improved epithelial barrier function, and activation of leukocytes. We are combining genetic methods in zebrafish with genetic and biochemical analyses in representative bacterial species, to understand the nature of these bacterial signals and the host signaling pathways that transduce them.

Microbial regulation of host nutrient metabolism: Members of the gut microbiota 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 genetic approaches are also being taken to understand how the host interprets and responds to these bacterial signals.

Environmental regulation of adipogenesis: Adipocytes serve as major sites of energy storage and as regulators of energy balance and inflammation. The developmental origins of the adipocyte lineage are not well understood, and the contribution of environmental factors such as microbiota and diet are unresolved. We are addressing these gaps in our knowledge using the zebrafish model in which adipogenesis can be monitored in vivo and in real time.