Current Projects
Insults to the intestinal tract such as infections with pathogenic organisms, excess inflammation, or
chemotherapy treatment cause significant damage to the epithelial barrier and increases in regulated
mammalian cell death. Regulated mammalian cell death is an important host defense mechanism;
however, we uncovered a previously unappreciated mechanism in which intestinal bacteria directly exploit the metabolites released by dying intestinal epithelial cells to promote growth.
Our findings have launched a novel line of research within the realm of host-microbe interactions. The
primary focus of the research program is to understand the cellular and molecular processes at the
host-microbe interface that originate within the dying mammalian cell, fuel bacterial growth, and
culminate in intestinal disease. Going further, the lab will focus on the added interplay with tissue
repair and regeneration. We combine the power of bacterial and mammalian genetics to:
1. Determine the impact of metabolites from pathogen-induced lytic cell death on bystander bacteria and immune cells.
2. Define the bacterial inducers of intestinal mucositis.
3. Interrogate the factors responsible for prolonged susceptibility to infection following intestinal injury.
Ultimately, we seek to identify death-dependent mechanisms that influence bacterial outgrowth and modify the repair of injured tissue in the intestine.
Our Research
Publications
Metabolite-based inter-kingdom communication controls intestinal tissue recovery following chemotherapeutic injury
Cytotoxic chemotherapies have devastating side effects, particularly within the gastrointestinal tract. Gastrointestinal toxicity includes the death and damage of the epithelium and an imbalance in the intestinal microbiota, otherwise known as dysbiosis. Whether dysbiosis is a direct contributor to tissue toxicity is a key area of focus. Here, from both mammalian and bacterial perspectives, we uncover an intestinal epithelial cell death-Enterobacteriaceae signaling axis that fuels dysbiosis. Specifically, our data demonstrate that chemotherapy-induced epithelial cell apoptosis and the purine-containing metabolites released from dying cells drive the inter-kingdom transcriptional re-wiring of the Enterobacteriaceae, including fundamental shifts in bacterial respiration and promotion of purine utilization-dependent expansion, which in turn delays the recovery of the intestinal tract. Inhibition of epithelial cell death or restriction of the Enterobacteriaceae to homeostatic levels reverses dysbiosis and improves intestinal recovery. These findings suggest that supportive therapies that maintain homeostatic levels of Enterobacteriaceae may be useful in resolving intestinal disease.
Microbes exploit death-induced nutrient release by gut epithelial cells
Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.