Research
The Gut Microbiota
The complex microbial community that resides within the human gut, known as the gut microbiota or microbiome, is a control center for multiple aspects of our biology including our immune status, metabolism, and neurobiology. Many of the metabolic activities and developmental signals that the microbiota deploys are complementary to our own, a reflection of humans as composite organisms with hundreds to thousands of species (one of which is Homo sapiens) working in concert.
Microbiota composition varies considerably between individuals, and factors like variation in host genotype and diet impact the community. Changes in our microbial communities, in turn, influence aspects of host biology (e.g., immune function) and likely explain aspects of biological 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 for a diverse spectrum of diseases. Furthermore, the profound shifts and deterioration in the microbiome over recent generations in industrialized societies may underlie many modern diseases, and presents the possibility that microbiome therapies will be a key part of reversing current disease trends. The importance of the gut community to human health necessitates the pursuit of a fundamental and mechanistic understanding of how extrinsic and intrinsic factors alter its composition, function, and interaction with the host.
Our Lab's Approach
Our research program aims to elucidate the basic principles that govern interactions within the intestinal microbiota and between the microbiota and the host. Specifically, we are exploring the effects of perturbations in the intestinal environment, such as changes in diet, lifestyle, microbial community composition, pathogen exposure, host genotype, and microbiota-targeted small molecules. Our lab uses a wide range of approaches including human dietary intervention trials, characterization of non-industrialized microbiomes, deep metagenomic sequencing, gnotobiotic models, high resolution imaging, metabolomics, and genetic manipulation of bacterial strains to gain mechanistic insight into emergent properties of the host-microbial superorganism.
Research Topics in the Lab
Understanding the Global Microbiota in Maternal and Infant Health, and the Impact of Industrialization
Microbiome data to date has been severely biased to industrialized populations. We employ ultra-deep metagenomic sequencing of microbiome samples from non-industrialized populations to extend our fundamental understanding of what defines the human gut microbiome across diverse lifestyles around the planet. We are collaborating with diverse groups, many centered in low/middle income countries to gain insight into improving maternal and infant health. These projects also provide important context for interpreting microbiome changes brought on by industrialization and understanding the role of an industrialized microbiome in the altered inflammatory status driving the global expansion of non-communicable, chronic diseases.
Reintroducing Key Lost Functions into the Industrialized Gut Microbiome
The gut microbiome of industrialized populations appear to be lacking in species that are essential for conferring the full benefit of plant-based diets rich in complex carbohydrates, resulting in reduced production of short-chain fatty acids like butyrate, key metabolite-mediators of host biology. This project aims to identify, isolate, and introduce species of bacteria that are capable of converting plant-based microbiota-accessible carbohydrates (MACs) into the short-chain fatty acids critical to barrier function, immune tolerance, and metabolic health. In addition, we are interested in mechanistic understanding of how MACs shape the genetic and functional traits of Bacteroides, a dominant taxa within the human microbiota.
The Role of Redox State in Shaping the Microbiota and Host Response
One of the distinguishing features of a healthy gut microbiome is its anoxic, or anaerobic, nature. Our detailed study of non-industrialized populations around the world (e.g., hunter-gatherers, rural farmers) has revealed that industrialized microbiomes are enriched in genes involved in managing oxidative stress. With the knowledge that oxidative stress is associated with inflammatory processes and shapes microbiome composition and metabolism, we are defining the mechanisms and interplay between host and microbiome that establishes and alters this redox state and investigating how gut redox state connects to human health and disease. These projects represent an intersection of our ongoing work understanding the global and ancestral human microbiome, and our previous work investigating interactions between commensals and pathogens within the gut.
Impact of Fermented Foods on the Microbiota and Host Immune Status
We have shown in a human clinical trial that fermented food consumption increases gut microbiota diversity and decreases markers of inflammation. We are now focused on investigating the mechanism by which fermented food consumption facilitates the engraftment of new strains within the microbiota, alters microbial metabolism within the gut, and modulates immune status. We are also defining the microbial metabolites produced during food fermentation and the effect of these metabolites on host physiology.
Human Dietary Intervention Studies
Given the power of diet to influence the microbiota, our laboratory has embarked upon several human dietary intervention studies in tight collaboration with Christopher Gardner’s group (Stanford) and Stanford’s Human Immune Monitoring Center with the goal of understanding how specific dietary components or patterns impact the microbiota and human biology. Collecting longitudinal microbiome profiles along with multi-omic data in the context of human dietary interventions provides critical data for understanding the diet-microbiome-immune axis in humans and identifies associations that can be reverse translated into the lab to investigate causation and mechanism. The aggregated data is being assembled into a diet-microbiome-immune map to enable rational, precision manipulation of human biology via microbiota-targeted food. Ultimately we plan to combine diet with microbial therapies to treat and prevent diseases by addressing current deficiencies in the industrialized gut microbiota.
Microbiome-dependent Metabolites and Chronic Kidney Disease
A vast, dynamic, and structurally diverse array of microbiome-dependent metabolites (MDMs) produced by gut microbiota can reach high concentrations (mM) in systemic circulation. In most cases, the kidneys efficiently clear many of these MDMs; however, in chronic kidney disease MDMs can be difficult to clear via dialysis alone. We are interested in identifying MDMs that accumulate in kidney failure using metabolomics approaches pioneered in our lab.
Additional Projects
Microbiota Influence on Cancer Immunotherapy Efficacy
Cancer immunotherapy and specifically immune checkpoint blockade (ICB), has proven to be one of the greatest breakthroughs in oncology in the last decade. Microbiome composition is associated with checkpoint blockade response in numerous human studies. Our research is aimed at understanding the relationship between gut microbiome function and ICB response; investigating how intestinal immunity intersects with anti-tumor immune responses.
Exercise and the Gut Microbiota
Understanding the mechanisms underlying exercise-induced microbial remodeling could shed light on how athletic microbiomes evolve and offer tangible interventions to improve athletic performance. We aim to define how exercise shapes the microbiome leveraging our significant expertise in the gut microbiome, gnotobiotic mouse models, multi-omic inquiry of microbiome-host interaction, and host metabolic and physiological assessment.
Engineering Gut Microbes for Therapeutics
The relationship between gut microbes and humans offers opportunities to develop therapeutic strategies that harness or modify microbial functions. Current efforts to deliver engineered bacterial therapies have encountered significant challenges, particularly in achieving stable colonization and the high microbial densities required for therapeutic efficacy. We have overcome these limitations with key technologies engineered into Bacteroides, the dominant genus in the US gut microbiome. This project aims to further advance synthetic biology approaches for the therapeutic application of gut-resident bacteria.
Developing New Genetic Systems for Diverse Gut Microbes
The many associations of diverse bacterial species with human health and disease require thorough experimental validation, emphasizing the need for tools that enable mechanistic study. Advancing genetic manipulation techniques in gut microbiome species is crucial for investigating community function and host interactions. Historically, the introduction of genetic tools for previously intractable organisms has led to foundational discoveries, preclinical breakthroughs, and propelled further innovations. In collaboration with KC Huang (Stanford), Adam Deutschbauer (Berkeley), Cullen Buie (MIT), and Carlotta Ronda (Berkeley), we have developed versatile protocols and models, focusing on transposon libraries, to advance gut microbiome research from observational studies to targeted manipulation in numerous new bacterial species, creating a community resource and laying the groundwork for therapeutics across intestinal diseases.