Impaired Th17 immunity in recurrent C. difficile infection is ameliorated by fecal microbial transplantation

Abstract

Background & Aims. Clostridioides difficile is a leading cause of infectious diarrhea and an urgent antimicrobial resistant threat. Symptoms are caused by its toxins, TcdA and TcdB, with many patients developing recurrent C. difficile infection (CDI), requiring fecal microbiota transplant (FMT). Antibody levels have not been useful in predicting patient outcomes, which is an unmet need. We aimed to characterize T cell-mediated immunity to C. difficile toxins and assess how these responses were affected by FMT. Methods. We obtained blood samples from patients with newly acquired CDI, recurrent CDI (with a subset receiving FMT), inflammatory bowel disease with no history of CDI, and healthy individuals (controls). Toxin-specific CD4+ T cell responses were analysed using a whole blood flow cytometry antigen-induced marker assay. Serum antibodies were measured by ELISA. Tetramer guided mapping was used to identify HLA-II-restricted TcdB epitopes and DNA was extracted from TcdB-specific CD4+ T cells for TCR repertoire analysis by Sanger sequencing. Results. CD4+ T cell responses to C. difficile toxins were functionally diverse. Compared to controls, individuals with CDI, or inflammatory bowel disease had significantly higher frequencies of TcdB-specific CD4+ T cells. Subjects with recurrent CDI had reduced proportions of TcdB-specific CD4+ Th17 cells, FMT reversed this deficit and increased toxin-specific antibody production. Conclusions. These data suggest that effective T cell immunity to C. difficile requires the development of Th17 cells. In addition, they show that an unknown aspect of the therapeutic effect of FMT may be enhanced T and B cell-mediated immunity to TcdB.

The adaptive immune response toClostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis

“…investigated how FMT affects CDI immunity. Patients with recurrent CDI have a reduced frequency of circulating TcdB‐specific CD4 + Th17 cells but not CD4 + Th1 and Th2 cells 153 (Fig. 1).…”

“…The authors found a small decrease in Th2 cells and a significant increase in the proportion of TcdB‐specific Th17 cells post‐FMT therapy. The effectiveness of the treatment was further demonstrated by the increase in the levels of anti‐TcdA, TcdB, and TcdBCROPS IgA and IgG in plasma samples from patients with recurrent CDI after FMT therapy 153 …”

“…The effectiveness of the treatment was further demonstrated by the increase in the levels of anti-TcdA, TcdB, and Tcd-BCROPS IgA and IgG in plasma samples from patients with recurrent CDI after FMT therapy. 153 The microbiome plays critical roles in the training and development of major components of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. The positive effects of FMT during CDI has been clearly demonstrated, especially for recurrence.…”