Dataset Information

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.

SUBMITTER: Monaghan TM

PROVIDER: S-EPMC8624539 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Monaghan Tanya M TM Duggal Niharika A NA Rosati Elisa E Griffin Ruth R Hughes Jamie J Roach Brandi B Yang David Y DY Wang Christopher C Wong Karen K Saxinger Lynora L Pučić-Baković Maja M Vučković Frano F Klicek Filip F Lauc Gordan G Tighe Paddy P Mullish Benjamin H BH Blanco Jesus Miguens JM McDonald Julie A K JAK Marchesi Julian R JR Xue Ning N Dottorini Tania T Acharjee Animesh A Franke Andre A Li Yingrui Y Wong Gane Ka-Shu GK Polytarchou Christos C Yau Tung On TO Christodoulou Niki N Hatziapostolou Maria M Wang Minkun M Russell Lindsey A LA Kao Dina H DH

Cells 20211119 11

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 ...[more]

PMID: 34831456

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Project description:Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients.A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT.Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT.This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Project description:ObjectiveFecal microbiota transplantation (FMT) is a highly effective treatment for Clostridioides difficile infection (CDI). However, the fecal transplant's causal components translating into clearance of the CDI are yet to be identified. The commensal bacteria Faecalibacterium prausnitzii may be of great interest in this context, since it is one of the most common species of the healthy gut microbiota and produces metabolites with anti-inflammatory properties. Although there is mounting evidence that F. prausnitzii is an important regulator of intestinal homeostasis, data about its role in CDI and FMT are relatively scarce.MethodsStool samples from patients with recurrent CDI were collected to investigate the relative abundance of F. prausnitzii before and after FMT. Twenty-one patients provided fecal samples before the FMT procedure, at 2 weeks post-FMT, and at 2-4 months post-FMT. The relative abundance of F. prausnitzii was determined using quantitative polymerase chain reaction.ResultsThe abundance of F. prausnitzii was elevated in samples (N = 9) from donors compared to pre-FMT samples (N = 15) from patients (adjusted P<0.001). No significant difference in the abundance of F. prausnitzii between responders (N = 11) and non-responders (N = 4) was found before FMT (P = 0.85). In patients with CDI, the abundance of F. prausnitzii significantly increased in the 2 weeks post-FMT samples (N = 14) compared to the pre-FMT samples (N = 15, adjusted P<0.001). The increase persisted 2-4 months post-FMT (N = 15) compared to pre-FMT samples (N = 15) (adjusted P<0.001).ConclusionsFMT increases the relative abundance of F. prausnitzii in patients with recurrent CDI, and this microbial shift remains several months later. The baseline abundance of F. prausnitzii in donors or recipients was not associated with future treatment response, although a true predictive capacity cannot be excluded because of the limited sample size. Further studies are needed to discern whether F. prausnitzii plays an active role in the resolution of CDI.

Project description:Fecal communities transplanted into individuals can eliminate recurrent Clostridioides difficile infection (CDI) with high efficacy. However, this treatment is only used once CDI becomes resistant to antibiotics or has recurred multiple times. We sought to investigate whether a fecal community transplant (FCT) pretreatment could be used to prevent CDI altogether. We treated male C57BL/6 mice with either clindamycin, cefoperazone, or streptomycin and then inoculated them with the microbial community from untreated mice before challenge with C. difficile. We measured colonization and sequenced the V4 region of the 16S rRNA gene to understand the dynamics of the murine fecal community in response to the FCT and C. difficile challenge. Clindamycin-treated mice became colonized with C. difficile but cleared it naturally and did not benefit from the FCT. Cefoperazone-treated mice became colonized by C. difficile, but the FCT enabled clearance of C. difficile. In streptomycin-treated mice, the FCT was able to prevent C. difficile from colonizing. We then diluted the FCT and repeated the experiments. Cefoperazone-treated mice no longer cleared C. difficile. However, streptomycin-treated mice colonized with 1:102 dilutions resisted C. difficile colonization. Streptomycin-treated mice that received an FCT diluted 1:103 became colonized with C. difficile but later cleared the infection. In streptomycin-treated mice, inhibition of C. difficile was associated with increased relative abundance of a group of bacteria related to Porphyromonadaceae and Lachnospiraceae. These data demonstrate that C. difficile colonization resistance can be restored to a susceptible community with an FCT as long as it complements the missing populations. IMPORTANCE Antibiotic use, ubiquitous with the health care environment, is a major risk factor for Clostridioides difficile infection (CDI), the most common nosocomial infection. When C. difficile becomes resistant to antibiotics, a fecal microbiota transplant from a healthy individual can effectively restore the gut bacterial community and eliminate the infection. While this relationship between the gut bacteria and CDI is well established, there are no therapies to treat a perturbed gut community to prevent CDI. This study explored the potential of restoring colonization resistance to antibiotic-induced susceptible gut communities. We described the effect that gut bacterial community variation has on the effectiveness of a fecal community transplant for inhibiting CDI. These data demonstrated that communities susceptible to CDI can be supplemented with fecal communities but that the effectiveness depended on the structure of the community following the perturbation. Thus, a reduced bacterial community may be able to recover colonization resistance in patients treated with antibiotics.

Dataset Information

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

Publications

A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory <i>Clostridioides difficile</i> Infection.

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Dataset Information

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

Publications

A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory &lt;i&gt;Clostridioides difficile&lt;/i&gt; Infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory <i>Clostridioides difficile</i> Infection.