Author(s): Stephen M Vindigni [*] 1 , Elizabeth K Broussard 2 , Christina M Surawicz 3
Clostridium difficile ; fecal microbiota transplant; intestinal microbiome; probiotics
Clostridium difficile infection (CDI), traditionally a nosocomial, antibiotic-associated, toxin-mediated diarrheal disease, has become increasingly common  . With the emergence of a hypervirulent strain (BI/NAP1/027), cases have been more severe with longer hospitalizations, increased numbers of colectomies and a significant rise in healthcare costs  . A 2008 study showed a CDI prevalence rate of 13.1 out of 1000 inpatients [2,3] . Additionally, there have been community-acquired cases of CDI in overall healthy adults without prior antibiotic exposure. Although in most cases, CDI is adequately treated with antibiotics, up to 30% of patients develop recurrent CDI, which is associated with significant morbidity and mortality  .
The hypothesis for the underlying etiology of severe CDI is disruption in gut microbiota  . The intestinal microbiome makes up a complex interdependent ecosystem responsible for food digestion, immune system activation, vitamin production and protection from invasive nonindigenous bacteria, which is known as colonization resistance  .
Despite antibiotic regimens incorporating pulsed oral vancomycin, fidaxomicin, rifaximin and probiotics for the treatment of recurrent CDI, it is not uncommon for patients to have CDI recurrence, possibly due to persistent spores despite initial elimination of the C. difficile bacteria. Although historically performed without a clear evidence base, multiple studies now demonstrate a role for fecal microbiota transplant (FMT) as a means to restore healthy gut bacteria [6,7] .
Fecal microbiota transplant
The earliest reports of FMT come from the Dong-Jin dynasty in 4th century China. Patients with food poisoning or severe diarrhea were given human feces by mouth with report of positive results, although the details of this intervention are unknown  . FMT has subsequently been described during the 16th century Ming dynasty and in 17th century veterinary medicine by Fabricius Acquapendente, an Italian anatomist [8,9] . Although first reported in US literature by Eiseman in the 1950s for treatment of patients with pseudomembranous colitis, FMT has became more common practice with numerous case reports and case series highlighting its effectiveness [10,11] .
Rather than eradicating the pathogen as has traditionally been the focus of antibiotic treatment, the goal of FMT is to re-establish the diverse normal microbiome within the large intestine. Multiple studies analyzing the intestinal microbiota of healthy people, CDI patients and recurrent CDI patients have demonstrated significant differences [12,13] . Although healthy individuals are colonized with many bacteria including a predominance of bacteroidetes and firmicutes, CDI patients harbor less or none of these bacteria and have decreased microbiome bacterial diversity overall [12-14] . Instead, recurrent CDI patients have high levels of proteobacteria and verrucomicrobia  . These findings support the hypothesis that CDI results from altered intestinal microbiota, which FMT restores. FMT repopulates bacteria relatively quickly and the effect persists. Khoruts assessed the intestinal microbiome of CDI patients pre- and post-FMT  . Two weeks following transplant, and persisting out to 33 days, the recipient's microbiota was similar to that of the donor stool with a dominance of Bacteroides sp . A long-term...