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

Abstract

A significant proportion of individuals develop recurrent Clostridium difficile infection (CDI) following initial disease. Fecal microbiota transplantation (FMT), a highly effective treatment method for recurrent CDI, has been demonstrated to induce microbiota recovery. One of the proposed functions associated with restoration of colonization resistance against C. difficile has been recovery of bile acid metabolism. In this study, we aimed to assess recovery of short chain fatty acids (SCFAs) in addition to bile acids alongside microbial community structure in six patients with recurrent CDI following treatment with FMT over time. Using 16S rRNA gene-based sequencing, we observed marked similarity of the microbiota between recipients following FMT (n = 6, sampling up to 6 months post-FMT) and their respective donors. Sustained increases in the levels of the SCFAs butyrate, acetate, and propionate were observed post-FMT, and variable recovery over time was observed in the secondary bile acids deoxycholate and lithocholate. To correlate these changes with specific microbial taxa at an individual level, we applied a generalized estimating equation approach to model metabolite concentrations with the presence of specific members of the microbiota. Metabolites that increased following FMT were associated with bacteria classified within the Lachnospiraceae, Ruminococcaceae, and unclassified Clostridiales families. In contrast, members of these taxa were inversely associated with primary bile acids. The longitudinal aspect of this study allowed us to characterize individualized patterns of recovery, revealing variability between and within patients following FMT.

IdentifyingClostridioides difficile-inhibiting gut commensals using culturomics, phenotyping, and combinatorial community assembly

“…Many strains in our culture collection shown in Figures 4 inhibit C. difficile at varying levels. Several phenotypes—particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol or succinate—correlated with the C. difficile -inhibitor phenotype, consistent with previous reports that restoration of depleted SCFAs in the gut resolved CDI [42, 43] and competition between C. difficile and commensals for nutrients and increased availability of mannitol, sorbitol or succinate allowed C. difficile invasion of the gut [27, 28]. Top inhibiting species in our collection were also depleted in the CDI patient gut, indicating their role in providing colonization resistance against C. difficile (Figure 7).…”

Fecal Microbiota Transplantation: Restoring the Injured Microbiome after Allogeneic Hematopoietic Cell Transplantation

“…It can be hypothesized that a similar mechanism is operative when FMT is used to correct the dysbiosis seen after allo-HCT and treat GVHD. FMT also has been associated with restoration of short-chain fatty acids (eg, butyrate, acetate, propionate) in patients with rCDI [21]. This may be important for allo-HCT recipients, given that butyrate has recently been identified as a potentially important microbial metabolite with beneficial effects on immune and epithelial cells that mitigate GVHD severity [22].…”

Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids promote gastrointestinal colonization ofCandida albicans

“…Commensal bacteria produce a variety of bioactive molecules; however, SCFAs have emerged as key regulators of gut homeostasis for colonization resistance against enteric pathogens 25,28,33,44 . Several preliminary studies have highlighted the antifungal potential of select SCFAs, including the inhibition of C. albicans germination by butyric acid 52,53 , a dose-dependent fungicidal effect with acetic, butyric, and propionic acid treatment 2,54 , an increase in programmed cell death with acetic acid 55 , an increase in mitochondrial-mediated apoptosis with propionic acid 56 , and an upregulation of transcriptional stress responses with acetic, butyric, and propionic acids 54,57 .…”

“…Antibiotic treatment in mice and humans alters the composition of gut microbiota, ultimately leading to changes in the levels of microbial-derived gut metabolites, mainly bile acids and short-chain fatty acids (SCFAs) 24–28 . Alterations in the normal levels of microbial-derived bile acids and SCFAs have been implicated in the growth, colonization, and pathogenesis of enteric pathogens including C. difficile 24,25,28 . Moreover, we have recently demonstrated that microbial-derived bile acids play an important role in the GI colonization of C. albicans 29 30 .…”