Bacterial Community Modeling Allows Metabolic Differentiation of Recurrent and Nonrecurrent Clostridioides Difficile Infections in the Human Gut

The anaerobic bacterium Clostridioides difficile is an opportunistic human pathogen responsible for infections of the colon of the human gastrointestinal tract. Recurrence is a major challenge associated with C. difficile infection (CDI), as approximately 30% of patients develop a least one occurrence of reinfection. A recent study compared the microbial communities of 275 stool samples collected from 93 patients with recurrent and nonrecurrent CDI. Bacterial taxa abundance data showed that patients who suffered from recurrent CDI harbored less diverse communities that were less likely to recover following treatment compared to patients with nonrecurrent CDI.

We hypothesized that integrating abundance data within community models could provide insights into the metabolic signatures of recurrent CDI. We assigned 16S rRNA-encoding gene sequence reads for the top 100 operational taxonomic units to 48 taxa (genera and families) and normalized the reads to produced taxa abundances for each sample. Direct analysis of these normalized abundances showed significant differences in five taxa, including elevated Peptostreptococcaceae (contains C. difficile) in recurrent samples and elevated Bacteroides in nonrecurrent samples. To better understand the functional impact of these compositional differences, the mgPipe metagenomics modeling tool was used to create and simulate 275 sample-specific community models with taxa abundances imposed as constraints. Model predictions showed significant differences in the ability of communities from untreated recurrent and nonrecurrent patients to produce 13 metabolites. Five degradation products from Stickland metabolism of aromatic amino acids were elevated in recurrent patient samples, including the potent bacteriostat para-cresol known to be secreted by C. difficile and toxic to gram-negative commensals such as Bacteroides. Conversely, the intermediate chorismite from the shikimate pathway for aromatic amino acid synthesis was elevated in nonrecurrent samples. These in silico predictions support recent studies suggesting aromatic amino acid metabolism as a key community function for understanding and potentially treating CDI.