Clostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms
Name
Antimicrobial Agents and Chemotherapy-2020-Kester-AAC.01404-19.full.pdf
Description
Accepted version
Size
2.01 MB
Format
Adobe PDF
Checksum (MD5)
28b6dc93a445b95352b713c3482272e6
Author(s)
Kester, Jemila C.
Brubaker, Douglas K.
Velazquez, Jason
Wright, Charles
Lauffenburger, Douglas A.
Griffith, Linda G.
Date Issued
January 27, 2020
Journal
Antimicrobial agents and chemotherapy
Publisher
American Society for Microbiology
Citation
Kester, Jemila C. et al. “Clostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms.” Antimicrobial agents and chemotherapy 64 (2020): e01404-19 © 2019 The Author(s)
Version
Author's final manuscript
Abstract
A clinically relevant risk factor forClostridioides difficile-associated dis-ease (CDAD) is recent antibiotic treatment. Although broad-spectrum antibioticshave been shown to disrupt the structure of the gut microbiota, some antibioticsappear to increase CDAD risk without being highly active against intestinal anaerobes, suggesting direct nonantimicrobial effects. We examined cell biological effectsof antibiotic exposure that may be involved in bacterial pathogenesis using aninvitrogermfree human colon epithelial culture model. We found a marked loss of mucosal barrier and immune function with exposure to the CDAD-associated antibiotics clindamycin and ciprofloxacin, distinct from the results of pretreatment with anantibiotic unassociated with CDAD, tigecycline, which did not reduce innate immuneor mucosal barrier functions. Importantly, pretreatment with CDAD-associated antibi-otics sensitized mucosal barriers to C. difficiletoxin activity in primary cell-derived enteroid monolayers. These data implicate commensal-independent gut mucosal barrier changes in the increased risk of CDAD with specific antibiotics and warrantfurther studies inin vivosystems. We anticipate this work to suggest potential ave-nues of research for host-directed treatment and preventive therapies for CDAD.
Subjects
Pharmacology (medical)
Pharmacology
Infectious Diseases
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1128/aac.01404-19
