Introduction: Humans co-exist with trillions of microorganisms (microbiome). When the delicate balance between the microbiome and people is disturbed, illness ensues. Our lab aims to bring innovative and cutting-edge molecular biological, microbiological, clinical informatics and bioinformatics skills to understand the impact (positive and negative) of the microbiome on patient outcomes, especially as it pertains to individuals with cancer. As a group that sees the role for novel approaches to improving patient care, we are committed to leveraging advances in genomics and translational biology to manipulate the microbiome safely and effectively in this vulnerable patient population.

Patient-centered genetic research: Patient participation is a critical part of our research success and our efforts to make impact in this realm of research. In addition to collecting comprehensive clinical information about hundreds of cancer patients treated at Stanford, the lab also has a rich resource of biospecimens from these individuals. Beginning with efforts in 2015 in the blood and marrow transplantation (BMT) Unit at Stanford Hospital, the lab has collected >1000 samples for >400 patients. The stool collection combined with curiosity and clever ideas of our lab members has already potentiated the development of many testable hypotheses regarding microbial biomarkers of disease and drug response, which are actively being investigated.

Genome plasticity: Projects in the laboratory range from those that focus solely on the bacterial side of the host-microbe interface, to those that enumerate and characterize host responses at the cellular, genomic and genetic level. Evaluating “real patient samples” also allows us to investigate the strengths and pitfalls of existing sequencing methodologies. For example, a current project in the lab studies the plasticity of bacterial genomes within human microbiomes over clinical time courses. The bacteria that live in our gut have genomes that behave differently than those in animals; they swap genes, duplicate genes, and generally “shuffle the deck” in ways that challenge our existing sequencing technologies.  By applying new sequencing approaches, the lab hopes to solve these challenges through single molecule barcoding and extra-long read sequencing. 

Clinical Interventions: While detailed hypothesis testing in vitro and characterization of genome plasticity over clinical time courses is of great interest, the ultimate translational intention of our group is to identify safe and effective methods for microbiome manipulation and subsequent improvement of health. This has led the lab to pursue projects focusing on fecal microbiota transplantation. When we lose the complex bacterial communities that are found in healthy guts, we become susceptible to infection. Ironically, this can be caused by the antibiotics used to treat bacterial infections in the first place.  The lab explores the use of other treatments, including bacterial transplants and prebiotics, for preventing and treating bacterial infections in the gut. Our first phase 1 clinical trial in patients at Stanford has just finished enrolling. In this study, we have investigated the tolerability of a prebiotic in BMT and we plan to study the effects of prebiotics on the community of commensal bacteria in this vulnerable patient population.

The microbiome-host interface: Fundamentally, alterations in the microbiome are likely to impact host health by directly or indirectly impacting host cell biology. Through interdisciplinary collaborations with other laboratories at Stanford (including the Pritchard, Snyder, Montgomery and Kundaje labs in Genetics as well as the Negrin lab in Medicine), we hopes to define specific microbe-host interactions critical for host adaptation, immunity and beyond. For example, using Big Data and sophisticated computational approaches, genes that are potentially critical for host adaptation of microbes have been identified and are being characterized. The hope is to define genes that are required for host-adaptation and thus may be responsible for health-altering effects. Additionally, we study how the intestinal immune cell composition and microbial signatures can be used as a potential diagnostic tools for post-BMT care in the setting of inflammation, and they seek to investigate how microbial metabolites affect human hosts at the level of gene regulation. The production of microbial metabolites greatly depends on diet, gut microbial composition, and microbial gene expression. By studying a panel of abundant microbial metabolites, the lab hopes to mechanistically understand how these compounds impact the structure and folding of the genome (chromatin landscape) and how this may lead to the turning on and off of specific genes.  

 

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