Identification of Simplified Microbial Communities That Inhibit Clostridioides difficile Infection through...

Area of Science:

• Microbiology and Immunology
• Gastrointestinal Health
• Microbiome Therapeutics

Background:

• Clostridioides difficile infection (CDI) is a major cause of antibiotic-associated diarrhea and healthcare burden.
• Fecal microbiota transplantation (FMT) is effective for recurrent CDI but has safety concerns due to undefined composition.
• There is a need for simplified, defined microbial communities for safer and more effective CDI treatment.

Purpose of the Study:

• To develop an experimental platform for identifying and screening simplified bacterial communities for Clostridioides difficile colonization resistance.
• To evaluate the efficacy of identified simplified communities in a humanized microbiota mouse model of CDI.
• To understand the microbial dynamics and engraftment of simplified communities during CDI recovery.

Main Methods:

• Developed a dilution-based platform to simplify complex fecal bacterial communities.
• Screened 76 simplified communities in vitro for their ability to inhibit C. difficile colonization.
• Tested the efficacy of seven promising simplified communities in a humanized microbiota mouse model.

Main Results:

• Identified 24 simplified communities that inhibited C. difficile colonization in vitro.
• Four simplified communities significantly reduced CDI severity and disease relapse in mice.
• Simplified communities accelerated indigenous bacteria recovery and led to stable engraftment of 19-22 operational taxonomic units (OTUs).

Conclusions:

• The developed platform effectively identifies simplified bacterial communities with C. difficile colonization resistance.
• Four novel simplified communities show therapeutic potential for treating C. difficile infection and preventing relapse.
• The platform's principles can be adapted for developing therapeutics for other gastrointestinal diseases.