<i>Clostridioides difficile</i> infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease
Steven J. Mileto, Thierry Jardé, Kevin O. Childress, Jaime L. Jensen, Ashleigh P. Rogers, Genevieve Kerr, M. Hutton, Michael J. Sheedlo, Sarah C. Bloch, John A. Shupe, Katja Horvay, Tracey J. Flores, Rebekah Engel, Simon Wilkins, Paul McMurrick, D. Borden Lacy, Helen E. Abud, Dena Lyras
Abstract
we show that infection disrupts murine intestinal cellular organization and integrity deep into the epithelium, to expose the otherwise protected stem cell compartment, in a TcdB-mediated process. Exposure and susceptibility of colonic stem cells to intoxication compromises their function during infection, which diminishes their ability to repair the injured epithelium, shown by altered stem cell signaling and a reduction in the growth of colonic organoids from stem cells isolated from infected mice. We also show, using both mouse and human colonic organoids, that TcdB from epidemic ribotype 027 strains does not require Frizzled 1/2/7 binding to elicit this dysfunctional stem cell state. This stem cell dysfunction induces a significant delay in recovery and repair of the intestinal epithelium of up to 2 wk post the infection peak. Our results uncover a mechanism by which an enteric pathogen subverts repair processes by targeting stem cells during infection and preventing epithelial regeneration, which prolongs epithelial barrier impairment and creates an environment in which disease recurrence is likely.