(4bk) Engineering Microbiomes and Diet to Promote Health

The community of microbes that inhabit the human gut, known as the gut microbiome, plays numerous roles in health and disease. This includes local maladies within the gastrointestinal tract as well as systemic effects on the circulatory and nervous systems. Industrialized lifestyles include widespread antibiotic use, consumption of processed foods, and extensive sanitization, that are known or suspected to change the gut microbiome. These changes to the microbiome have been implicated in several diseases such as inflammatory bowel disease (IBD), diabetes and others, although the mechanistic contributions are still emerging.

Dietary and microbiome interventions such as fecal microbiota transplants (FMTs) have shown promise to treat and manage diseases including recurrent Clostridioides difficile infection, celiac disease, functional bowel disorders including irritable bowel syndrome, and IBD. These interventions are strong levers on microbiome ecology and metabolism, yet interindividual variability in response currently limits their utility. The long-term goal of my research program is to understand how interindividual variation in diet-microbiome interactions mediates human health outcomes. Successful implementation of my program will improve fundamental knowledge of how diet and the microbiome influence health and facilitate the design of personalized dietary and microbiome interventions.

Research Experience:

Doctoral Training – Supervisor: Chaitan Khosla, Chemical Engineering, Stanford University

Ph.D. Thesis: Exploring Protein-Protein Interactions and Vectorial Substrate Processing in Modular Polyketide Synthases

For my graduate studies as an NSF GRFP and Stanford Graduate Fellow, I joined the lab of Dr. Chaitan Khosla to work on understanding and engineering the biosynthesis of polyketides, an important class of molecules with numerous therapeutic applications. My first project focused on the ketoreductase domain, which largely controls polyketide stereochemistry that is a significant mediator of biological function. My results quantitatively defined the specificity of ketoreductase domains for the acyl carrier domain that presents substrates for catalysis. My second contribution to the field was a failure analysis of a subset of engineered polyketide synthases, which identified translocation and protein-protein interactions as the primary bottlenecks in developing novel polyketide synthases and products. Finally, I developed an isotope ratio mass spectrometry method to probe the role of released carbon dioxide in the reaction cycle; this assay allowed us to exclude carbon dioxide capture as a causal mechanism for a currently unexplained catalytic state of modular polyketide synthases. Through this work, I advanced our fundamental knowledge of polyketide synthase biochemistry and defined key parameters that will inform effective engineering of these synthases and production of new therapeutics.

Postdoctoral Training – Supervisor: Eric Martens, Microbiology and Immunology, University of Michigan

Project 1: The Food Additive Xanthan Gum Drives Adaptation of the Human Gut Microbiota

Xanthan gum (XG) is a common food additive that was introduced into the human diet ~50 years ago and is consumed in gram quantities in gluten-free baked goods. I led a team that discovered a bacterium from Ruminococcaceae uncultured genus 13 (R. UCG13), present in ~50% of humans, which depolymerizes and consumes XG. We also discovered that XG oligosaccharides are occasionally scavenged by Bacteroides intestinalis (≤11% of people) creating a food chain for this novel polysaccharide. In addition to characterizing most of the enzymes that break down XG oligosaccharides, we discovered a novel enzyme from R. UCG13 that depolymerizes native XG before it is simplified by other enzymes, in direct contrast to XG-degrading pathways from soil microbes. This work provides an initial mechanistic framework to understand how widespread XG consumption differentially effects individuals’ microbiome ecology, metabolism, and gastrointestinal physiology.

Project 2: Abundance and activity of mucin-degrading microbes in inflammatory bowel disease

Previous work in the Martens lab has shown that a low-fiber diet leads to an expansion of mucin-degrading microbes in the microbiome, leading to degradation of the protective intestinal mucus and severe colitis in genetically susceptible mice. I obtained independent funding from the Postdoctoral Translational Scholars Program at the University of Michigan to pursue a translational project on this model’s relevance in pediatric IBD patients. Specifically, I developed and received institutional review board (IRB) approval to collect stool samples from pediatric IBD patients and healthy family members. I am currently using these samples to determine the abundance and activity of mucin-degrading microbes in pediatric IBD patients and whether these microbes group by disease status or familial origin. I am also working on biochemically characterizing a subset of glycoproteases that we hypothesize are involved in mucin degradation. My work has generated publishable data that we used in a recent R01 submission and is part of our larger effort to determine the biochemical sequence by which microbes degrade and consume mucus. Together this work informs our understanding of mucin-degradation by the microbiome as well as its role in IBD pathogenesis; insights from this work could lead to microbiome-targeted therapeutics that modulate or inhibit mucin degradation.

Research Trajectory and Funding:

These combined training experiences have provided me with a unique skillset with advanced biochemical and analytic techniques, anaerobic microbiology methods, germ-free mouse models, bioinformatics, and clinical and public health context. These skills provide the groundwork for me to build a research program exploring how specialized diets and individual microbiomes influence microbiome ecology and metabolism, gastrointestinal physiology, and human health outcomes. My research program will expand our ability to use diet and microbiome interventions to prevent and treat disease. This work will also inform our understanding of the emergence and trajectory of the industrialized microbiome which may have long-term public health implications. I will seek funding to support my research portfolio through grants from various NIH institutes (NCCIH, NIEHS, NIDDK, or NIGMS), disease-oriented foundations such as the Crohn’s and Colitis Foundation or Kenneth Rainin Foundation, the NSF and USDA (e.g NIFA) as appropriate, and industrial partnerships as opportunities arise.

Grants and Fellowships

NIH Pathway to Independence Award: K99/R00 (pending, submitted 6/2021)

Postdoctoral Translational Scholars Program, University of Michigan, 2019-2021 (no-cost extension, 2022)

Stanford Graduate Fellowship in Science and Engineering, Stanford University, 2012-2017

National Science Foundation Graduate Research Fellow, National Science Foundation, 2012-2017.

Teaching Interests:

My aspiration to improve human welfare and society is rooted in my interdisciplinary background and I am convinced that the most complex societal challenges we face will only be solved with interdisciplinary approaches. Chemical engineering is an inherently interdisciplinary field with methods that traverse several disciplines and applications across diverse problems and industries. With both undergraduate and graduate training in chemical engineering, I am well-positioned to teach core courses and excited to help students with varied interests connect their education with real-world problems. For more advanced courses, I would be especially interested in teaching courses focused on biochemical engineering, metabolic engineering, synthetic biology, engineered food and food systems, or drug design and development.

Teaching and Mentoring Experience:

I have a solid foundation of teaching experience to support my roles as teacher and mentor in my independent career. During my predoctoral training, I served as a teaching assistant and co-head teaching assistant for a biochemistry course in which I gave a guest lecture both terms. As co-head teaching assistant, I managed the entire online class presence which included an online forum for students to ask questions. At the University of Michigan, I have given guest lectures in a course on microbial symbiosis as well as a methods in microbiology and immunology course. I have mentored several undergraduate trainees including a recent graduate who completed her undergraduate thesis under my direct supervision. I also have extensive, albeit less formal, experience mentoring and teaching specific techniques to other trainees.

Scientific Leadership and Outreach

I aspire to be an effective leader and communicator within my scientific and engineering communities. At the University of Michigan, I help run the Data Analysis and Networking Group that brings together trainees to learn from each other and develop personal and professional connections. In 2021, I have independently managed our twice-monthly Microbiome Seminar Series and hosted both internal and external speakers. I have attended and presented at numerous conferences and welcome discussion and collaborations that transcend boundaries. In 2019, I was elected to chair a Gordon Research Seminar originally scheduled for 2021, which will now take place in 2023. For all these activities, I hope to cultivate a welcoming and inclusive environment that makes being part of these communities enjoyable and productive for all members.

I also hope to make science and engineering research accessible to the broader public and pursue this goal through a variety of activities. I have presented my research in public forums including at a University of Michigan Postdoc 180 event and in a 3-minute thesis competition where I was the oral presentation winner. I have written about my personal experience with academic research in “False Dichotomies: Bridging Separate Worlds in Research” and by submitting an essay to the Lasker Essay Contest. I also regularly volunteer with the Huron River Watershed Council as a group leader for citizen-science efforts to collect and identify insects to track and monitor stream health and pollution in our community. As a faculty member, I plan on continuing these or similar activities and to promote science and engineering as approachable, important, and inclusive.