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. [Display omitted] •Epithelial apoptosis fuels dysbiosis and intestinal disease following chemotherapy•Caspase-dependent metabolites boost growth and reprogram E. coli transcription•Apoptotic metabolites act as secondary signals to regulate bacterial respiration•E. coli abundance, rather than presence, prolongs intestinal mucositis Anderson et al. demonstrate that host cell death drives dysbiosis and disease following chemotherapy. Intestinal epithelial cell apoptosis and the release of soluble metabolites promote Enterobacteriaceae expansion and reprogramming, which subsequently delay host intestinal recovery from injury. Maintenance of homeostatic levels of Enterobacteriaceae is sufficient to improve disease outcome.