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Clostridioides difficile  infection (CDI) imposes a substantial burden on the health care system in the United States. Understanding the biological basis for the spectrum of  C. difficile -related disease manifestations is imperative to improving treatment and prevention of CDI. Here, we investigate the correlates of asymptomatic  C. difficile  colonization using a multi-omics approach. We compared the fecal microbiome and metabolome profiles of patients with CDI versus asymptomatically colonized patients, integrating clinical and pathogen factors into our analysis. We found that CDI patients were more likely to be colonized by strains with the binary toxin (CDT) locus or strains of ribotype 027, which are often hypervirulent. We find that microbiomes of asymptomatically colonized patients are significantly enriched for species in the class Clostridia relative to those of symptomatic patients. Relative to CDI microbiomes, asymptomatically colonized patient microbiomes were enriched with sucrose degradation pathways encoded by commensal Clostridia, in addition to glycoside hydrolases putatively involved in starch and sucrose degradation. Fecal metabolomics corroborates the carbohydrate degradation signature: we identify carbohydrate compounds enriched in asymptomatically colonized patients relative to CDI patients. Further, we reveal that across  C. difficile  isolates, the carbohydrates sucrose, rhamnose, and lactulose do not serve as robust growth substrates in vitro, consistent with their enriched detection in our metagenomic and metabolite profiling of asymptomatically colonized individuals. We conclude that pathogen genetic variation may be strongly related to disease outcome. More interestingly, we hypothesize that in asymptomatically colonized individuals, carbohydrate metabolism by other commensal Clostridia may prevent CDI by inhibiting  C. difficile  proliferation. These insights into  C. difficile  colonization and putative commensal competition suggest novel avenues to develop probiotic or prebiotic therapeutics against CDI.

Multi-omics investigation of Clostridioides difficile -colonized patients reveals pathogen and commensal correlates of C. difficile pathogenesis