Clostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent...

Area of Science:

• Microbiology
• Gastroenterology
• Immunology

Background:

• Antibiotic treatment is a major risk factor for Clostridioides difficile-associated disease (CDAD).
• Some antibiotics increase CDAD risk without direct antimicrobial effects on gut anaerobes, suggesting nonantimicrobial mechanisms.
• The impact of specific antibiotics on host mucosal and immune functions warrants investigation.

Purpose of the Study:

• To investigate the direct cell biological effects of antibiotics on human colon epithelial cells.
• To determine if antibiotics associated with increased CDAD risk alter mucosal barrier and immune functions.
• To assess the impact of antibiotic pretreatment on epithelial cell susceptibility to C. difficile toxins.

Main Methods:

• Utilized an in vitro germfree human colon epithelial culture model.
• Exposed epithelial cultures to CDAD-associated antibiotics (clindamycin, ciprofloxacin) and a non-associated antibiotic (tigecycline).
• Assessed changes in mucosal barrier and innate immune functions; evaluated enteroid monolayer sensitivity to C. difficile toxins after antibiotic pretreatment.

Main Results:

• Clindamycin and ciprofloxacin caused significant loss of mucosal barrier and immune function.
• Tigecycline did not reduce innate immune or mucosal barrier functions.
• Antibiotic pretreatment sensitized mucosal barriers to C. difficile toxin activity in enteroid models.

Conclusions:

• Commensal-independent alterations in gut mucosal barrier function contribute to CDAD risk with specific antibiotics.
• These findings highlight potential host-directed therapeutic targets for CDAD prevention.
• Further in vivo studies are needed to validate these in vitro findings and explore therapeutic avenues.