Community dynamics drive punctuated engraftment of the fecal microbiome following transplantation using freeze-dried, encapsulated fecal microbiota

Abstract

Fecal microbiota transplantation (FMT) is a highly effective treatment of recurrent and recalcitrant Clostridium difficile infection (rCDI). In a recent study oral-delivery of encapsulated, freeze-dried donor material, resulted in comparable rates of cure to colonoscopic approaches. Here we characterize shifts in the fecal bacterial community structure of patients treated for rCDI using encapsulated donor material. Prior to FMT, patient fecal samples showed declines in diversity and abundance of Firmicutes and Bacteroidetes, with concurrent increases in members of the Proteobacteria, specifically Enterobacteriaceae. Moreover, patients who experienced recurrence of CDI within the 2-month clinical follow-up had greater abundances of Enterobacteriaceae and did not show resolution of dysbioses. Despite resolution of rCDI following oral-administration of encapsulated fecal microbiota, community composition was slow to return to a normal donor-like assemblage. Post-FMT taxa within the Firmicutes showed rapid increases in relative abundance and did not vary significantly over time. Conversely, Bacteroidetes taxa only showed significant increases in abundance after one month post-FMT, corresponding to significant increases in the community attributable to the donors. Changes in the associations among dominant OTUs were observed at days, weeks, and months post-FMT, suggesting shifts in community dynamics may be related to the timing of increases in abundance of specific taxa. Administration of encapsulated, freeze-dried, fecal microbiota to rCDI patients resulted in restoration of bacterial diversity and resolution of dysbiosis. However, shifts in the fecal microbiome were incremental rather than immediate, and may be driven by changes in community dynamics reflecting changes in the host environment.

Restoration of short chain fatty acid and bile acid metabolism following fecal microbiota transplantation in patients with recurrent Clostridium difficile infection

“…Our data in human patients supports this trend; however, levels of secondary bile acid recovery were variable across individuals. Variation in the levels of detected bile acids following FMT in patients has also been observed in other studies both cross-sectionally and longitudinally (21, 24). Approximate levels of DCA and LCA immediately following FMT, secondary bile acids that are associated with attenuating or delaying C. difficile colonization in mice (20, 22), have also not been able to predict which individuals fail FMT (24).…”

“…Variation in the levels of detected bile acids following FMT in patients has also been observed in other studies both cross-sectionally and longitudinally (21, 24). Approximate levels of DCA and LCA immediately following FMT, secondary bile acids that are associated with attenuating or delaying C. difficile colonization in mice (20, 22), have also not been able to predict which individuals fail FMT (24). This correlation does not necessarily discount the role of secondary bile acids in clearance of C. difficile , as many physiological factors, such as host response, diet, and gut transit time, can impact bile acid production at a given time point (42).…”

“…Supplementation of a single organism has not been successful in preventing or clearing C. difficile in mice (20, 23), and a recent phase 2 clinical trial with SER-109, a mixture of bacterial spores isolated from healthy human donors, failed to outperform placebo treatment for the treatment of recurrent CDI (49, 50). It is possible that easily preserved encapsulated spore treatments (24, 49) or even traditional FMT treatments that fail in individuals (51) is due to a lack of microbes in the baseline gut microbiota of these individuals that provide a necessary intermediate step in recovery of microbial functions. In our current study, we observed variability in the microbiota before and after FMT, as well as variability in the types of microbes that were ‘engrafted’, or transplanted.…”

“…Lawley et al have previously demonstrated that a six-member community of bacteria that did not contain a bacterium with 7-alpha dehydroxylase activity was able to clear C. difficile in a murine model, resulting in a shift in short chain fatty acids (SCFAs) (23). Furthermore, levels of secondary bile acids in patients treated with FMT, while increased overall, do not necessarily predict failure of FMT to clear C. difficile (24). It is likely that the host response as well as additional metabolic pathways, provided by a healthy community with bacteria other than C. scindens , also contribute to clearance of C. difficile and subsequent recovery from CDI.…”

Computational Modeling of the Gut Microbiota Predicts Metabolic Mechanisms of RecurrentClostridioides difficileInfection

“…By contrast, both abundance data and model-processed abundance data derived from post-index samples identified high Enterobacteriaceae, low Bacteroides clusters as having disproportionate numbers of recurrent samples. Numerous studies have identified Enterobacteriaceae as positively associated and Bacteroides as negatively associated with primary CDI (63)(64)(65) and to a lesser extent with subsequent reinfection (72,73). The analyses presented here suggest CDI recurrence is more dependent on community response to antibiotic therapy than on the community composition entering therapy.…”