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We present predictive models for comprehensive systems analysis of Clostridioides difficile , the etiology of pseudomembranous colitis. By leveraging 151 published transcriptomes, we generated an EGRIN model that organizes 90% of C. difficile genes into a transcriptional regulatory network of 297 co-regulated modules, implicating genes in sporulation, carbohydrate transport, and metabolism. By advancing a metabolic model through addition and curation of metabolic reactions including nutrient uptake, we discovered 14 amino acids, diverse carbohydrates, and 10 metabolic genes as essential for C. difficile growth in the intestinal environment. Finally, we developed a PRIME model to uncover how EGRIN-inferred combinatorial gene regulation by transcription factors, such as CcpA and CodY, modulates essential metabolic processes to enable C. difficile growth relative to commensal colonization. The C. difficile interactive web portal provides access to these model resources to support collaborative systems-level studies of context-specific virulence mechanisms in C. difficile. [Display omitted] • The EGRIN model uncovers regulatory responses of C. difficile in multiple contexts • Genes and pathways needed to support C. difficile growth in vivo are identified • PRIME predicts in vivo synergistic epistasis between transcription factor networks • The C. difficile portal makes all tools and resources available to the public C. difficile is one of the leading causes of hospital-acquired infections. Arrieta-Ortiz et al. report three predictive models (with extensive validations) for dissecting interplay of regulation and metabolism that underlies host-pathogen interactions of C. difficile. The C. difficile interactive web portal provides access to these models, compiled datasets, and algorithms. [ABSTRACT FROM AUTHOR]

Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense , succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen's metabolism, gene regulatory networks, and toxin production. Oral administration of P. bifermentans rescues conventional, clindamycin-treated mice from lethal C. difficile infection in a manner similar to that of monocolonized animals, thereby supporting the therapeutic potential of this commensal species. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo. [Display omitted] • Systems biology models identify complex host and inter-microbe interactions in vivo • P. bifermentans alone protects the murine host against lethal C. difficile disease • C. sardiniense worsens disease through cross-feeding and growth enhancement • Findings inform successful bacteriotherapeutic development against C. difficile Girinathan et al. define complex mechanisms by which individual gut commensals limit or worsen Clostridioides difficile pathogenicity. Integrated, high-resolution analyses of metabolomic, metatranscriptomic and phenotypic outcomes identify complex intermicrobe interactions in vivo to delineate how commensals uniquely shape the intestinal environment to impact microbial programs, which may enlighten bacteriotherapeutic approaches. [ABSTRACT FROM AUTHOR]