Abstract
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.
Highlights
Clostridioides difficile infection (CDI) remains a significant cause of morbidity and mortality in the health care setting and in the community [1]
In a retrospective human cohort of 102 patients with clinically significant diarrhea (CSD), two groups of patients were identified: those diagnosed with CDI (Cx+/enzyme immunoassay (EIA)+) or those asymptomatically -colonized (Cx+/EIA-), as defined previously [19]
Antibiotic exposure and loss of clostridial niche related to CDI
Summary
Clostridioides difficile infection (CDI) remains a significant cause of morbidity and mortality in the health care setting and in the community [1]. Antibiotic treatments, among other risk factors associated with weakened colonization resistance, increase susceptibility to CDI [2, 3]. C. difficile residence in the human gastrointestinal (GI) tract may result in a spectrum of disease, from asymptomatic colonization to severe and sometimes fatal manifestations of CDI [4]. Diagnosis of CDI relies on detection of the protein toxin, most commonly by enzyme immunoassay (EIA), or the detection of the toxin-encoding genes, by nucleic acid amplification test (NAAT). These diagnostic tools serve as rough benchmarks for assessing severity of disease. Clarifying the biological differences between asymptomatic colonization (Cx+/EIA-) and CDI (Cx+/EIA+) will be critical for identifying mechanisms of colonization resistance, and for defining novel probiotic or prebiotic avenues for treatment or prevention of CDI [5, 6]
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