Fecal Microbial Transplantation and its Expansion into the Treatment of Other Diseases

Abstract

Background: Fecal Microbial Transplantation (FMT) has gained popularity due to its efficacy in the treatment of recurrent Clostridium difficile infection (RCDI). RCDI is associated with prolonged courses of antibiotics with high recurrence rates following the initial resolution of symptoms. The increased use of antibiotics in both healthcare and agriculture has led to increased prevalence of antibiotic-resistant microbes. Therefore, we first tested the hypothesis that patients with RCDI would harbor high numbers of antibiotic-resistant bacteria and secondly, that FMT would reduce the number of antibiotic-resistant gene containing bacteria. Furthermore, the association between microbial dysbiosis and inflammatory bowel disease (IBD) has enhanced interest in therapies targeting the microbiota. For RCDI, resolution of the infection using FMT correlates with efficient engraftment of the donor microbiota. The purpose of our mouse studies was to determine the efficiency of donor microbiota engraftment into the recipient following a short pre-FMT treatment regimen and investigate if this changed the FMTs ability to reduce the development of colitis in Interleukin-10 knockout (IL-10 -/-) mice. Methods: Using shotgun metagenomics, we sequenced the microbiota of 20 RCDI patients. The libraries from the RCDI patients and a healthy cohort (n=87) obtained from the Human Microbiome Project (HMP) were aligned against the NCBI bacterial taxonomy database and the Comprehensive Antibiotic Resistance Database (CARD). Results were corroborated through a DNA microarray containing 354 antibiotic resistance (ABR) genes. In mice, the microbiota was analyzed at baseline (day 0), following treatment (day 3), three days after FMT (day 7) and 31 days following FMT (day 35) using real-time PCR and 16S rRNA sequencing. Sequencing data was processed using the QIIME pipeline. Gastrointestinal inflammation was quantified by measuring cytokines from the stool, cecum tissue, small intestine tissue, and serum, as well as histology scoring of the small intestine and colon. Conclusion: RCDI patients have increased numbers of antibiotic-resistant organisms. FMT is effective in the eradication of pathogenic antibiotic-resistant organisms and elimination of antibiotic-resistance genes. Regardless of the pre-FMT treatment regimen, strong engraftment of the donor microbiota into a healthy recipient was observed and remarkably was maintained after four weeks. In an IBD model, our results indicate that preparation of the host has substantial effects on the efficacy of FMT and should be considered moving forward in FMT research for other diseases.