The mechanisms of in vivo commensal control of Clostridioides difficile virulence

Abstract

We define multiple mechanisms by which commensals protect against or worsen Clostridioides difficile infection. Leveraging new systems-level models we show how metabolically distinct species of Clostridia modulate the pathogens colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survived infection while mice colonized with the butyrate- producer, Clostridium sardiniense, more rapidly succumbed. Systematic in vivo analyses revealed how each commensal altered the gut nutrient environment, modulating the pathogens metabolism, regulatory networks, and toxin production. Oral administration of P. bifermentans rescued conventional mice from lethal C. difficile infection via mechanisms identified in specifically colonized mice. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile infections using systems biologic approaches to define host-commensal-pathogen interactions in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/894915v2_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@15a6940org.highwire.dtl.DTLVardef@b4290borg.highwire.dtl.DTLVardef@1f2af49org.highwire.dtl.DTLVardef@1d1e6b9_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG