NON-GENETIC INHERITANCE: MECHANISMS OF MICROBIOME-MEDIATED TRANSGENERATIONAL CHANGE

Project SummaryThe dense microbial communities associated with animals, referred to as the microbiome, can havean important impact on both host development and physiology. Yet, we are only beginning tounderstand the mechanisms by which the microbiome promotes these important functions. There isgreat interest to define and understand how these associations, such as changes in composition, ordysbiosis, are linked to a number of diseases. Moreover, the ability to manipulate or restore themicrobiome is being pursued as a therapeutic target. While the success of fecal transplant therapy foracute and chronic Clostridium difficile infections highlights their potential, the broader applicability ofsuch therapies to other maladies remains unknown. Consequently, there is great need to understandthe relationship between a host and its microbiome with regards to its regulation and molecularsignaling mechanisms. I propose to utilize the fruit fly, Drosophila melanogaster, to investigatemechanisms that contribute to the establishment of normal host physiological conditions, a criticalstep in developing strategies for microbiome therapy. My project will focus on the timing andestablishment of normal parameters of host physiology and development. Specifically, I will study ingerm-free flies and flies that have experienced early-life events that disrupt the microbiome, the latterof which has been linked to chronic diseases in other animal models. The specific goals of thisproposal are to: a) Explore the trans-generational impacts of the microbiota on D.melanogaster. b) Identify host and microbiota factors that promote normal host physiology. c)Develop strategies to restore normal animal physiology through manipulation of themicrobiome. I will use high throughput sequencing technologies in the form of transcriptomes,metabolomes, and epigenomes to investigate gene expression and metabolite production across flydevelopment and through generations, coupled with traditional genetic approaches to characterizeidentified targets. My experiments will focus on comparisons with germ-free, gnotobiotic, andconventionally-reared flies to characterize the effects of host association with the microbiome. I willalso identify microbial signals that induce changes in the host and will experimentally manipulate boththe host and microbial recognition and signaling systems that mediate these associations. Given thehigh conservation of developmental and homeostatic signaling pathways between files and humans,and that 75% of known human disease genes have a match in the D. melanogaster genome, Ianticipate that this work will identify conserved mechanisms that regulate host-microbiomeinteractions in all animals, including humans.