Long-Term Bacterial and Fungal Dynamics following Oral Lyophilized Fecal Microbiota Transplantation in Clostridioides difficile Infection

Abstract

Oral lyophilized fecal microbiota transplantation (FMT) is effective in recurrent Clostridioides difficile infection (CDI); however, limited data exist on its efficacy in primary CDI and long-term microbial engraftment. Patients with primary or recurrent CDI were prospectively enrolled to receive oral FMT. Changes in the bacterial and fungal communities were characterized prior to and up to 6 months following treatment. A total of 37 patients with CDI (15 primary, 22 recurrent) were treated with 6 capsules each containing 0.35-g lyophilized stool extract. A total of 33 patients (89%) had sustained CDI cure, of whom 3 required a second course. There were no safety signals identified. FMT significantly increased bacterial diversity and shifted composition toward donor profiles in responders but not in nonresponders, with robust donor contribution observed to 6 months following FMT (P < 0.001). Responders showed consistent decreases in Enterobacteriaceae and increases in Faecalibacterium sp. to levels seen in donors. Mycobiome profiling revealed an association with FMT failure and increases in one Penicillium taxon, as well as coexclusion relationships between Candida sp. and bacterial taxa enriched in both donors and responders. Primary CDI was associated with more robust changes in the bacterial community than those with recurrent disease. Oral FMT leads to durable microbial engraftment in patients with primary and recurrent CDI, with several microbial taxa being associated with therapy outcome. Novel coexclusion relationships between bacterial and fungal species support the clinical relevance of transkingdom dynamics. IMPORTANCE Clostridioides difficile infection (CDI) is a substantial health concern worldwide, complicated by patterns of increasing antibiotic resistance that may impact primary treatment. Orally administered fecal microbiota transplantation (FMT) is efficacious in the management of recurrent CDI, with specific bacterial species known to influence clinical outcomes. To date, little is known about the efficacy of FMT in primary CDI and the impact of the mycobiome on therapeutic outcomes. We performed matched bacterial and fungal sequencing on longitudinal samples from a cohort of patients treated with oral FMT for primary and recurrent CDI. We validated many bacterial signatures following oral therapy, confirmed engraftment of donor microbiome out to 6 months following therapy, and demonstrated coexclusion relationships between Candida albicans and two bacterial species in the gut microbiota, which has potential significance beyond CDI, including in the control of gut colonization by this fungal species.

An update on fecal microbiota transplantation for the treatment of gastrointestinal diseases

“…71 Responders to FMT with rCDI were shown in one study to decrease Enterobacteriaceae, and increase Faecalibaterium species. 72 Costello et al found that 10 anaerobic bacteria increased in abundance with FMT for UC, along with the archaea Methanobrevibacter smithii. 17 Increased abundance of Aneorfilum pentosovorans and Bacteroides coprophilus species post-FMT were strongly associated with disease improvement.…”

“…There has been work suggesting fungi also play an important role, for instance with over-representation of Candida albicans among patients with CDI, and poor response to FMT where donors have abundance of C. albicans. 72,81 Fungal and bacterial species appear to be interrelated with trans-kingdom dynamics. 72 In UC, high abundance of Candida pre-FMT has been associated with clinical response post-FMT, with increased bacterial diversity and decreased Candida post-FMT in these patients.…”

“…72,81 Fungal and bacterial species appear to be interrelated with trans-kingdom dynamics. 72 In UC, high abundance of Candida pre-FMT has been associated with clinical response post-FMT, with increased bacterial diversity and decreased Candida post-FMT in these patients. 82 The virome.…”

Encapsulated Fecal Microbiota Transplantation: Development, Efficacy, and Clinical Application

“…Methods were refined to assess correlations between donor and recipient fecal communities ( Weingarden et al., 2015 ; Jalanka et al., 2016 ), which provided a statistical evaluation of engraftment while still suffering from similar technical limitations. More recently, our group and others have utilized Bayesian approaches to infer levels of engraftment and invasion by specific taxa following FMT or animal cohousing ( Ridaura et al., 2013 ; Khanna et al., 2017 ; Staley et al., 2017b ; Le Bastard et al., 2018 ; Sokol et al., 2020 ; Haifer et al., 2021 ). Packages like SourceTracker ( Knights et al., 2011 ) that employ this approach have been shown to be able to differentiate individual donor samples ( Staley et al., 2018 ), determine taxa associated with engraftment ( Ridaura et al., 2013 ; Staley et al., 2017b ), and may be applied to emerging metagenomics datasets for use with high resolution taxonomic data.…”

Intraspecies strain exclusion, antibiotic pretreatment, and donor selection control microbiota engraftment after fecal transplantation

“…From a microbiome research perspective, FMT represents an intriguing experimental model to establish causality in reported human microbiota/disease associations, which are currently mostly studied using controversial germ-free mice experiments (Walter et al 2020). Yet, the mechanism of action of FMTs and their specific and long-term effects on the recipient microbiota remain poorly understood (Khoruts, Staley, and Sadowsky 2021;Haifer et al 2021).…”