Genomic and Genetic Insight into Gut Microbiota Function and Manipulation

Trillions of microbes live in our digestive tract and influence our biology in profound and diverse ways. Several... » More

Trillions of microbes live in our digestive tract and influence our biology in profound and diverse ways. Several diseases, including obesity and inflammatory bowel diseases, have been associated with large-scale shifts in microbiota composition. The ability to address basic questions concerning community function and plasticity are fundamental to understanding the extent of causal relationships between host biology and microbiota perturbations, and whether the microbiota is a viable therapeutic target. One of our long-term goals is to achieve a level of functional understanding that, if provided the metagenome of an individual’s microbiota, would allow us to accurately predict how the microbial community will functionally adapt to a specific perturbation (e.g., dietary change). To investigate how changes in the intestinal environment alter microbiota function, and how these changes, in turn, influence host biology we have characterized responses of simplified microbiotas living within the gut of gnotobiotic mice to changes in host diet, community membership, and host genotype. These studies have revealed the importance of a finely-tuned system of polysaccharide sensing and utilization in the model symbiont Bacteroides thetaiotaomicron (B. theta). We are currently using a single polysaccharide utilization locus dedicated to dietary fructan utilization of B. theta as a model to understand mechanisms underlying diet-induced changes in microbiota function and composition. Genetic ablation of proteins involved in the multi-step process of sensing, harvesting, degrading, and metabolizing fructans variably cripples B. theta’s utilization of fructose-based polysaccharides depending upon which step of consumption is compromised. These findings are consistent with functional differences in fructan utilization between Bacteroides species. Together these results set the stage for predicting, based on gene content, how microbiotas respond to changes in the nutrient environment and suggest how metagenomics could facilitate personalized therapeutic manipulation of the microbiota. « Hide