Fecal Microbiota Transplantation: Do We Need Harmonization? Free

To the Editor—We read with great interest the study published by Hota et al [1]. In their single-center, open-label, randomized, controlled trial, the authors compared the effectiveness of 14 days of oral vancomycin followed by a single fecal microbiota transplantation (FMT) by enema to a 6-week taper of oral vancomycin in patients experiencing acute episodes of recurrent Clostridium difficile infection. For the first time and in contrast to 5 clinical, randomized trials [2–6], this study concluded that FMT was not significantly more effective than vancomycin taper, and the study was stopped after an interim analysis. Although there is no single universally accepted FMT protocol, these findings are challenging, and several factors may have contributed to the suboptimal outcome.

First, the FMT preparation specifies that donors provided stools no more than 48 hours before FMT, while in the 5 positive studies previously cited, although no rationale was provided, the time frame was closer to 6 hours. The longer time frame for FMT preparation raises the issue of potential alteration of the harvested microbiota over such a long period of time. The authors performed 16S analysis and showed consistently high diversity in the donor stool. However, 16S shows the diversity of bacterial DNA in the sample without any information on bacterial viability, which might be a key factor in successful FMT. Indeed, although diversity could be preserved with the analysis of dead bacteria, Seekatz et al showed that function was more important than diversity in FMT [7].

The next potential problem is the absence of bowel preparation. In the seminal paper by van Nood et al [2] as well as in the study of Cammarota et al [4], which had high success rates, bowel preparation with macrogol was performed 24 hours prior to FMT. Conversely, in the study by Lee et al [5] without bowel preparation prior to FMT, the success rate after 1 procedure was approximately 50%. These data suggest that bowel preparation is at least indirectly critical to FMT success.

Finally, the enema was administered only once, although several studies have shown that FMT by enema or colonoscopy usually requires more than 1 administration [4, 5]. In an open-label, randomized, controlled study, Cammarota et al showed that the first infusion was associated with only 64% (13/20) success, while multiple administrations reached 90% (18/20) [4]. Lee et al, also using fecal enema, only reached a 50.5% success rate after the first procedure, and 2 to 5 additional procedures were required to reach 85.6% (95/111) [5]. Moreover, Hota et al state that 62.5% (10/16) patients retained at least 80% of the enema, meaning that 37.5% did not receive an optimal transplant.

Taken together, these issues suggest that FMT was not performed optimally, which may explain the negative results.

Notes

Disclaimer. H. S. has received payment for board membership from Enterome and MSD; consultancy fees from Maat, Roche, Abbvie, and Novartis; and payment for lectures or speakers bureaus from Takeda and Biocodez. T. G. has received payment for board membership from Astellas and MDS. B. G. has received payment for board membership from Pfizer and Astellas.

Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

Author notes