MTM 2: The rules of microbiota colonization of the mammalian gut

Dr. Georg Gerber, Associate Professor at Harvard Medical School and Brigham and Women’s Hospital, and Dr. Harris Wang, Associate Professor at Columbia University, have received a $2.9M grant from the National Science Foundation to develop and apply novel computational and experimental rules to elucidate fundamental rules governing the formation and maintenance of complex microbial ecosystems in the mammalian gut.

Microbiomes, or the collections of trillions of bacteria and other micro-organisms living on, within and around us, have enormous impact on human life. For example, they help people digest food, promote the growth of farm animals and crops, and degrade pollutants in the environment. Despite the importance of microbiomes, the processes governing their formation and maintenance remain poorly understood. The mammalian gut is a particularly intriguing system for microbiome studies, since a diverse collection of microbes has evolved that specifically colonizes and functions in that environment. The goal of the project is to derive fundamental rules that describe and predict the dynamic process of microbial colonization of the mammalian gut. To achieve this goal, the team of investigators will develop new computer-based methods to automatically extract predictive and explanatory rules from large microbiome data sets. The team will also develop new experimental tools and generate data sets in mouse measuring how microbiomes change over time and across space in the mammalian gut. Overall, the project will further the understanding of the formation of microbiomes in mammals and can provide broader insights into the emergence of other microbial ecosystems, such as those in soil and marine environments. These insights could ultimately help scientists to rationally alter or maintain microbiomes in different environments to benefit human activities. The project will also generate practical resources for the scientific community (computer-based tools and datasets) and provide education on the microbiome to college and elementary school students through courses and hands-on labs.

A wealth of genomic data provides information as to which microbes are present in environments, but little insight into underlying factors that explain or predict complex assemblages of microbial consortia. This project aims to elucidate mechanistic factors that drive the dynamic process of microbial colonization of the mammalian gut. These determinants will be investigated at multiple systems scales, from the level of microbial communities down to the level of individual genes. The project will leverage high-throughput experimental methods developed by the investigators, to generate data characterizing functional genetic selection and spatial organization of microbiota in the mammalian gut. From the Computer Science perspective, the project will develop new computational methods to infer human-interpretable rules and other structured outputs from complex and noisy high-throughput microbiome datasets, using Bayesian and neural-style approaches that incorporate prior biological knowledge while scaling to massive datasets. This project has three main thrusts: 1) Learn microbial community-level rules that quantitatively predict population dynamics of mouse gut colonization and assess these rules across differing ranges of microbial diversity and composition, 2) Elucidate microbial gene-level mechanisms that predict mouse gut colonization dynamics, and 3) Profile microbial spatiotemporal organization and dynamics during gut colonization at the species and gene level to predict microbial community dynamics. The project is expected to establish a set of new computational and experimental tools and principles for understanding the rules of microbial colonization of the gut, with potential applications to other ecosystems including gut microbiota of non-mammalian species as well as complex environmental microbiota.