Background and Aims: 20-30% of patients with a primary episode of Clostridioides difficile infection (CDI) experience recurrence. Fecal microbial transplantation (FMT) is currently the most effective therapy for recurrent CDI (rCDI). Previous work with a mouse model in our lab identified a role for FMT-induced IL-25 in protection from CDI.
Methods: Colon biopsies, stool, and peripheral blood samples were collected from patients (N=19, 74% female) undergoing FMT for rCDI. Samples were also collected for 16 of the patients at a two-month follow-up. Bulk RNAseq of colon biopsies was carried out to determine broad changes in the intestinal tissue following FMT. Plasma antibodies to Toxin B (TcdB) were assessed by ELISA and toxin neutralization assays. Investigation of colon tissue by immunofluorescence microscopy and spatial transcriptomics, and of stool and peripheral blood for soluble and cellular biomarkers is ongoing.
Results: FMT was effective in preventing recurrence out to two months in all cases. PCA analysis of RNAseq results identified distinct colonic transcriptional profiles post-FMT with 3,677 differentially expressed genes between groups. Expression of genes associated with Type 2 immune responses as well as genes associated with tissue remodeling and resolution of inflammation was significantly increased. Gene pathways associated with cell proliferation, including DNA replication, translation, and protein processing and export were up-regulated post-FMT. No significant changes were observed in anti-TcdB antibody levels or neutralization capacity following FMT, indicating that sustained protection from rCDI was not humoral.
Conclusions: These data suggest that FMT therapy works primarily by promoting regeneration of the intestinal barrier. Ongoing work seeks to characterize epithelial and immune-specific pathways that promote these recovery processes and operate in conjunction to protect from recurrence.