Abstract
Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI); increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies.
Highlights
Clostridioides difficile infection (CDI) is the most common cause of diarrhea acquired in acute healthcare settings
Four patients treated with sequential Fecal microbiota transplantation (FMT) and concurrent antibiotics for severe or fulminant Clostridioides difficile infection (SFCDI) were included
Our results hint that non-response may be associated with immunosenescent signals in the non-responder, including: a higher frequency of circulating senescent T cells characterized by loss of CD28 surface antigen and acquisition of CD57; lower B cell and regulatory B cell frequencies; and higher levels of MMP-2, TWEAK, IL-26, sTNF-R1, sTNF-R2, and effector memory CD8 T cells
Summary
Clostridioides difficile infection (CDI) is the most common cause of diarrhea acquired in acute healthcare settings. Severe infection is defined by an elevated white blood cell count of over 15,000 cells/mL or serum creatinine level >1.5 mg/dL, while fulminant infection is characterized by hypotension or shock, ileus or toxic megacolon [3]. These patients usually require hospital admission for treatment with oral vancomycin and intravenous metronidazole or surgery if refractory to medical therapy. In patients with antibiotic-refractory severe or fulminant CDI (SFCDI) who are poor surgical candidates, treatment options are limited and sequential FMT by colonoscopy with concomitant vancomycin has been shown to be effective in several small case series and a single randomized trial [7,8,9,10]. Despite its effectiveness, significant knowledge gaps remain in our understanding of how FMT exerts these beneficial effects, and what molecular features, immunological, may predict treatment outcomes in this unique population of antibiotic refractory SFCDI [11]
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