Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study

Abstract

Objectives: Fecal microbiota transplantation (FMT) is increasingly being used for treatment of recurrent Clostridium difficile infection (R-CDI) that cannot be cured with antibiotics alone. In addition, FMT is being investigated for a variety of indications where restoration or restructuring of the gut microbial community is hypothesized to be beneficial. We sought to develop a stable, freeze-dried encapsulated preparation of standardized fecal microbiota that can be used for FMT with ease and convenience in clinical practice and research.

Methods: We systematically developed a lyophilization protocol that preserved the viability of bacteria across the taxonomic spectrum found in fecal microbiota and yielded physicochemical properties that enabled consistent encapsulation. We also treated a cohort of R-CDI patients with a range of doses of encapsulated microbiota and analyzed the associated changes in the fecal microbiome of the recipients.

Results: The optimized lyophilized preparation satisfied all our preset goals for physicochemical properties, encapsulation ease, stability at different temperatures, and microbiota viability in vitro and in vivo (germ-free mice). The capsule treatment was administered to 49 patients. Overall, 43/49 (88%) of patients achieved a clinical success, defined as no recurrence of CDI over 2 months. Analysis of the fecal microbiome demonstrated near normalization of the fecal microbial community by 1 month following FMT treatment. The simplest protocol using the lowest dose (2.1-2.5 × 10¹¹ bacteria in 2-3 capsules) without any colon purgative performed equally well in terms of clinical outcomes and microbiota engraftment.

Conclusions: A single administration of encapsulated, freeze-dried fecal microbiota from a healthy donor was highly successful in treating antibiotic-refractory R-CDI syndrome.

Figure 1

Changes in the fecal bacterial composition associated with capsule FMT. (a) Distribution of phyla in fecal samples from successfully treated patients and donors. Samples were collected before fecal microbial transplantation (pre-FMT), within the first 6 days post-FMT (days), between 7 and 21 days post-FMT (weeks), between 30 and 60 days post-FMT (months), or after 2 months post-FMT (>2 months). (b) Phylum-level classification of operational taxonomic units (OTUs) that were associated with donor contribution as estimated by SourceTracker. Error bars reflect s.e.m.