Our Science
Overview
There are 10-100 trillion microbes that reside in the human gastrointestinal tract, representing thousands of species. The gut microbiota is a control center for multiple aspects of human biology including immunity, metabolism, and neurobiology. Many of the metabolic activities and developmental signals that the microbiota deploys are complementary to our own, affirming that humans are Holobionts – composite organisms consisting of both microbial and human parts.
Microbiota composition varies considerably between individuals, and factors like variation in host genotype and diet impact the community. Changes in our microbial communities differentially influence aspects of host biology (e.g., immune function) and likely explain aspects of variation within and between human populations (e.g., predisposition to disease). The plasticity of the microbiota suggests that it may be a viable therapeutic target. To harness the therapeutic potential of the microbiome it is essential to develop a fundamental understanding of how extrinsic and intrinsic factors alter its composition, function, and interaction with the host.
Spatial Organization Of The Gut Microbiota
We have learned much about the microbiota via survey/sequencing bulk fecal material, however within the gastrointestinal tract there exist a number of distinct microenvironments: the colonic crypts, the loose outer mucus layer, the lumen, and the length of the gut from small intestine to descending colon.
Variations in pH, carbon sources, host immune effectors and small molecules likely shape local community composition and spatial dynamics, which in turn can impact gastrointestinal health. We are using quantitative imaging to define how host diet, genetics and environment affect the localization of commensal microbes in both healthy and perturbed states.
Microbiota-Pathogen Interactions
In a healthy and complex microbiota, space and resources are occupied by commensal species, providing colonization resistance to potential pathogens that may pass through, or reside within, the gut. However, when perturbations like antibiotics or diarrhea disrupt the resident microbes, colonization resistance and efficient nutrient networks are compromised. Our lab seeks to understand the mechanisms by which the gut microbiota protects its host from gastrointestinal infections and how interactions between the microbiota, pathogens, and host steer the course of infection.
Metabolic Functionality Of Complex Communities
The intestinal microbiota continually produces numerous small molecules that may be absorbed into circulation and represent a dynamic and ill- defined contribution to host biology and metabolism. Despite the vast metabolic capabilities encoded by the human microbiome, little is known about the species and genes responsible for producing such molecules or how their production may be manipulated, for instance by diet or by microbiota transplant. We are mapping the relationships between diet, microbial metabolic pathways, and the most abundant and biologically influential drug-like compounds manufactured by the microbiota.
Synthetic Biology And The Microbiota
Gut bacteria possess a repertoire of metabolic strategies, defense mechanisms and environmental sensors highly adapted for thriving in the gut environment, suggesting these microbes can be considered a technology platform for influencing human health. The ability to record the environmental experiences, rewire behavior, or add new functions to these commensal microbes will help us understand how they respond to and influence their environment, and provide a means for engineering bacteria-delivered therapeutics in the future. High-throughput strain modification techniques, tunable protein expression, protein secretion and logic and memory devices are key technologies we are developing to enable a wide range of studies and applications.
Microbiota and Immunity Interactions
The immune system is constantly monitoring and interacting with the microbiota in order to keep it under control and at a properly safe distance from the intestinal mucosa. Various innate immune receptors, such as the flagellin receptor TLR5, play a central role in keeping the intestinal microbiota under control. Animals lacking the TLR5 receptor develop intestinal inflammation that can manifest with the development of chronic colitis or metabolic syndrome. In the liver, TLR5 plays an important protective role during western-style diet consumption. We are studying how TLR5, TLR4, and other innate immune pathways may be manipulated to direct the development of the microbiota in a healthier direction.