Fecal microbiota transplantation to fight Clostridium difficile infections and other intestinal diseases

Abstract

We have analyzed fecal bacterial and viral communities of a patient with recurrent C. difficile infection (rCDI) who was cured by fecal microbiota transplantation (FMT). The "Zürich Patient" experienced immediate cure and has remained free of symptoms for now over 5 y. Donor-similar bacterial compositions after 4.5 y post-FMT demonstrated sustainable engraftment of donor microbiota predominated by Bacteroidetes and Firmicutes bacteria. Appearance of beneficial species Faecalibacterium prausnitzii and Akkermansia municiphila was detected while disease-related Proteobacteria decreased. Stabilization of the microbiota took longer than expected from the rapidly improving clinical symptoms, suggesting the need for longer-lasting patient observation. The virome was mainly composed of Caudovirales bacteriophages but surprisingly also contained sequences related to a Chlorella giant virus that normally infects green algae not known to inhabitate the human intestine. FMT is highly effective against rCDI and is presently broadening its application to other conditions including inflammatory bowel disease (IBD). Here, we discuss the prospects and challenges of FMT against rCDI and other indications including a focus on bacteriophages.

Keywords: Chlorella giant virus; Clostridium difficile; clinical trial; fecal microbiota transplantation; microbiota; phage therapy; virome.

Figure 1.

Microbiota changes of the Zürich Patient. (A) Bacterial compositions determined by 16S sequencing shown as pie charts with indicated color code. (B) Relative abundances of butyrate-producing bacteria shown as bars. (C) Virome compositions determined by metagenomic sequencing shown as pie charts with indicated color code.

Figure 2.

Proposed phage-assisted therapy for rCDI. Left: Natural phages frequently have narrow host ranges that may be altered through genetic engineering. Alternatively, isolated endolysins may be used. Right: Bacteroidetes and Firmicutes predominate healthy gut microbiota. C. difficile infection and antibiotic treatment causes detrimental Proteobacteria to expand. Both C. difficile and Proteobacteria may be targeted by engineered phages and/or endolysins, allowing for the microbiota to return to the healthy state, further facilitated by transferring beneficial bacterial species such as F. prausnitzii.