Clostridium scindens colonization of gnotobiotic mice promotes a chronic unresolving infection with Clostridioides difficile

The commensal Clostridium scindens has been regarded as a promising bacteriotherapeutic against Clostridioides difficile infection due to its ability to consume host factors that can promote C. difficile growth, and its production of the antimicrobial compound 1-acetyl-β-carboline. We investigated C. scindens’ protective effects against C. difficile using defined colonization studies in gnotobiotic mice. Mice infected with C. difficile develop lethal infection within 48 hours. In contrast, 88% of mice pre-colonized with C. scindens survived acute infection with delayed C. difficile colonization, lower biomass, and toxin B levels at 24 hours after infection. However, two weeks post-challenge, surviving mice showed comparable levels of cecal C. difficile vegetative and spore biomass and toxin B, as seen during acute infection. After two weeks, co-colonized mice exhibited mucosal colonic hyperplasia with focal pseudomembranes, modeling a chronic and recurrent infection state. Our findings illustrate how the commensal microbiota can modulate host and pathogen interactions leading to chonic C. difficile carriage and infection. ### Competing Interest Statement LB is an inventor on patents for C. difficile microbiota therapeutics, and is the founder, SAB chair and a stock holder in ParetoBio Inc. Remaining authors declare no competing interests.