The gut microbiota produces a vast and structurally diverse array of small molecules. Remarkably, bacterial processing of ingested food and drug compounds alone accounts for the production of thousands of metabolites, many of which are not well studied despite possessing disease connections. Among these, microbiota-dependent metabolites (MDMs) are significant predictors of kidney disease progression, yet their mechanistic roles in kidney signaling and disease remain largely unexplored. Our research investigates how these microbial metabolites mediate inter-nephron and inter-organ signaling that governs fibrosis and repair in the kidney. We develop and use microbiome-focused metabolomics platforms to identify and quantify diverse MDMs. We employ a kidney organoid model system to study the impact of these molecules on inter-nephron signaling and fibrosis. We also employ cheminformatics and network topology methods to decode microbial production dynamics. By understanding these microbial chemical interactions, we aim to design targeted microbiome interventions to protect and restore kidney health.
Upcoming PMB Seminars
For a schedule of all Plant & Microbial Biology events, seminars, and lectures visit our calendar.
Redesigning plants with synthetic biology: from carbon fixation to natural products
Our limited understanding of plant systems and the dearth of genetic tools constrain our ability to engineer plants effectively for diverse applications, including agriculture, sustainability, human health, and bioenergy. However, the field of synthetic biology has opened the door to new possibilities, enabling us to introduce heterologous metabolic pathways or create entirely new-to-nature compounds that don't naturally exist in plants. As future endeavors in plant metabolic engineering become increasingly complex, we have also developed a suite of synthetic biology tools to enhance our ability to modify and manipulate plant genomes. Finally, we also leverage synthetic biology approaches to study the origins and evolution of rubisco in order to provide novel insights into the biophysical and evolutionary constraints potentially limiting photosynthesis.
Temperature-responsive circuitry that drives fungal pathogenesis
We are interested in the biology of a small, evolutionarily related group of fungi that cause disease in healthy humans. These environmental fungi are exquisitely responsive to mammalian body temperature, which triggers drastic changes in cell shape and the induction of virulence properties. We dissect temperature-dependent signaling in these organisms to reveal fundamental molecular paradigms with broad significance to our understanding of cellular circuits. We study the circuitry used to establish and maintain thermosensation in these simple eukaryotic pathogens and elucidate how temperature-induced fungal effectors manipulate the biology of innate immune cells. Ultimately we hope fundamental discoveries can be applied to a variety of biological contexts, including generating synthetic temperature-response circuits and harnessing fungal effectors as immunomodulatory agents during disease.
Past PMB Seminars
Tsujimoto Lecture: Changing Paradigms in Natural Product Discovery: A Molecule to Microbe Approach
Microbial natural products remain an important source of lead compounds for drug discovery. Traditional approaches to microbial natural product discovery take a microbe first approach in which individual strains are cultured in the lab and bioassays used to guide the isolation of active compounds. While once productive, the limitations to this approach are now well documented and include the recognition that only a small percentage of the bacteria present in the environment are readily obtained in culture. We have developed a new approach to microbial natural product discovery in which compounds are isolated directly from the environments in which they are produced thus bypassing the initial need for laboratory cultivation. This culture independent approach, which we call Small Molecule In Situ Resin Capture (SMIRC), is agnostic to the biological source of the compounds and requires no up-front knowledge of cultivation requirements or the cues needed to induce biosynthesis. Initial SMIRC deployments have yielded extensive, biome specific chemical diversity including compounds previously reported from marine plants, invertebrates, and bacteria. Mining compounds that could not be identified has yielded unprecedented carbon skeletons and demonstrated that sufficient yields can be obtained for bioactivity testing and NMR-based structure elucidation. These results suggest a path forward to access new chemical space for drug discovery and to address the ecological functions of marine natural products.
Molecular mechanism of jasmonate signaling: A delicate balance between growth and defense
Sessile organisms face unique challenges in acquiring and allocating resources to various cellular processes. In plants, competition for limited resources such as light and nutrients drives transcriptional programs that maximize growth. Conversely, herbivores and pathogens activate the expression of defense-related genes at the expense of plant growth. Research in the Howe lab seeks to elucidate the molecular mechanisms by which the lipid-derived hormone jasmonate controls transcriptional programs that modulate growth-defense balance. This line of investigation may inform biotechnological strategies to engineer plants that maintain stress resilience in the absence of growth and yield penalties.