Abstract
Many cases of Clostridioides difficile infection (CDI) are poorly responsive to standard antibiotic treatment strategies, and often patients suffer from recurrent infections characterized by severe diarrhea. Our group previously reported the successful cure of two patients with recurrent CDI using a standardized stool-derived microbial ecosystem therapeutic (MET-1). Using an in vitro model of the distal gut to support bacterial communities, we characterized the metabolite profiles of two defined microbial ecosystems derived from healthy donor stool (DEC58, and a subset community, MET-1), as well as an ecosystem representative of a dysbiotic state (ciprofloxacin-treated DEC58). The growth and virulence determinants of two C. difficile strains were then assessed in response to components derived from the ecosystems. CD186 (ribotype 027) and CD973 (ribotype 078) growth was decreased upon treatment with DEC58 metabolites compared to ciprofloxacin-treated DEC58 metabolites. Furthermore, CD186 TcdA and TcdB secretion was increased following treatment with ciprofloxacin-treated DEC58 spent medium compared to DEC58 spent medium alone. The net metabolic output of C. difficile was also modulated in response to spent media from defined microbial ecosystems, although several metabolite levels were divergent across the two strains examined. Further investigation of these antagonistic properties will guide the development of microbiota-based therapeutics for CDI.
Highlights
Clostridioides difficile is an anaerobic, exotoxin-producing, sporulating bacterial pathogen that is one of the most common causes of antibiotic-associated diarrhea[1,2]
A third ecosystem representative of a dysbiotic gut microbial community was formulated through the application of a physiologically relevant dose of ciprofloxacin, a clinically important broad-spectrum antibiotic associated with Clostridioides difficile infection (CDI), to bioreactor-cultured defined experimental community of 58 bacterial isolates (DEC58)
Given the importance of the normal gut microbiota in the context of Recurrent CDI (rCDI), this study aimed to examine the influence of microbiota-derived components on C. difficile growth and virulence determinants
Summary
Clostridioides difficile is an anaerobic, exotoxin-producing, sporulating bacterial pathogen that is one of the most common causes of antibiotic-associated diarrhea[1,2]. While the reconstitution of metabolic imbalances through FMT has been shown to influence C. difficile growth and germination[31], the effects on sporulation and toxin production are less characterized. This is an important knowledge gap considering the importance of these virulence determinants in the pathophysiology of CDI. FMT is highly effective for rCDI, the use of stool as a therapeutic presents many logistical, regulatory, and safety challenges To address these issues, our group previously developed a defined microbial ecosystem therapeutic (MET-1), derived from the stool of a healthy fecal donor, which was used to cure two patients with rCDI32. The precise mechanism through which health is restored in rCDI patients after MET-1 treatment is not fully understood, preliminary evidence of host-associated protective effects and direct antagonistic mechanisms against C. difficile TcdA have been described[33,34]
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