A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory Clostridioides difficile Infection

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.

Immunological mechanisms of fecal microbiota transplantation in recurrent Clostridioides difficile infection

“…FMT is an effective option for the resolution of rCDI and is being used around the world increasingly. Moreover, recent studies show its efficacy in treating the first episode of CDI as well as its repeated use can treat severe and fulminant CDI forms[ 60 ]. Although the concept of the method is simple, it is a labor-intensive procedure and requires the acceptance of the patient to be treated with this kind of transplant, even if FMT-derived capsules are used.…”

“…Finally, Monaghan et al [ 60 ] performed a systems biology-based study to interrogate the interaction among microbiome-metabolome-immune system in the context of FMT applied to patients with severe or fulminant CDI. They studied four patients unresponsive to antibiotic therapy and treated with sequential FMT.…”

“…The evaluations included microbiome and associated metabolome profile in fecal samples as well as the evaluation of blood samples to access the epigenomic, metabolomic, glycomic, immune proteomic, immunophenotyping, functional immune assays, and the T cell receptor repertoire. Although the small sample size did not allow the authors to draw clear conclusions, they suggest that immunosenescent signals could be associated with non-responsiveness to FMT, since they found strong correlations between peripheral senescent T cells and host factors including butyrate, serum hydroxybutyrate, fecal urso- iso- and hyodeoxycholic acids, serum immunoglobulin G Fc N-glycopeptides, and microbial taxa including Pseudomonas at the genus level[ 60 ]. The main findings of the studies recently discussed are listed in Table 1 .…”

The leaky gut and the gut microbiome in sepsis – targets in research and treatment

“…Several animal studies and case series have reported the ability of faecal microbiota transplantation (FMT) to attenuate sepsis severity, in part through the restoration of butyrate-producing bacteria, gut barrier strengthening, innate immunity enhancement, immune repertoire alteration and pathogen clearance; however, some studies have reported lethal bacteraemia [ 153 ]. Notably, the immune repertoire is a variety of receptors on T cells and B cells that has a large sequence diversity to recognize different organismal molecules as a part of the adaptive immune system [ 154 ] and innate immunity, for example, macrophages, is an important host response against pathogenic gut organisms [ 74 ]. Meanwhile, butyrate is an important short-chain fatty acid that is categorized as an enterocyte energy source and a factor of anti-inflammation and anti-malignancy [ 155 ].…”

The interplay between Helicobacter pylori and the gut microbiota: An emerging driver influencing the immune system homeostasis and gastric carcinogenesis

“…The emergence of FMT application in various ill states is owing to its significant efficacy in treating recurrent Clostridioides difficile infection (rCDI) ( Monaghan et al., 2021 ; Azimirad et al., 2022 ). The engraftment of microbial composition from a healthy donor to an appropriate patient thoroughly modifies the patient’s gut microbiota shifting it toward the donor’s microbial profile ( Wang et al., 2019 ).…”