Mammalian apoptotic factors regulate bacterial gene expression

Regulated cell death is an integral part of life, having broad impacts on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3–6, but the direct impact 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 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, murine and human cell lines, multiple 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, where death induced nutrient release (which we term DINNR) acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment. Overall design: The experiment consisted of two conditions: Salmonella grown in live cell supernatants or FADD induced apoptotic supernatants. Each condition consisted of four biological replicates.