Alteration of the Murine Gastrointestinal Microbiota by Tigecycline Leads to Increased Susceptibility to Clostridium difficile Infection

Abstract

Antibiotics can play dual roles in Clostridium difficile infection (CDI); antibiotic treatment increases the risk of CDI, and antibiotics are used to treat CDI. The glycylcycline antibiotic tigecycline has broad antimicrobial activity, yet it is rarely associated with the development of CDI, presumably due to its activity against C. difficile. In this study, we investigated how tigecycline treatment affects the structure of the gut microbiota and susceptibility to CDI by treating mice with tigecycline (n ‫؍‬ 20) or saline (n ‫؍‬ 8) for 10 days. A sequence analysis of the bacterial 16S rRNA gene amplicons was used to monitor changes in the fecal microbiota. A subset of the mice was followed for 5 weeks after the end of treatment. The remaining mice were challenged with C. difficile strain VPI 10463 spores 2 days after the tigecycline treatment ended. Tigecycline treatment resulted in major shifts in the gut microbiota, including large decreases in Bacteroidetes levels and large increases in Proteobacteria levels. Mice with tigecycline-altered microbial communities were susceptible to challenge with C. difficile spores and developed clinical signs of severe CDI. Five weeks after the cessation of tigecycline treatment, the recovery of the bacterial community was incomplete and diversity was lower than in the untreated controls. Antibiotics with intrinsic activity against C. difficile can still alter the microbiota in a way that leads to susceptibility to CDI after discontinuation of the drug. These results indicate that microbiotic dynamics are key in the development of CDI, and a better understanding of these dynamics may lead to better strategies to prevent and treat this disease.

The structures of the colonic mucosa-associated and luminal microbial communities are distinct and differentially affected by a prolonged murine stressor

“…55,56 The colonic microbiota are known to influence susceptibility and resistance to these attaching and effacing pathogens, 57,58 since disrupting the mucosa-associated populations with antibiotics increased disease severity upon pathogen challenge. 59,60 Stressor induced shifts to luminal populations might also have downstream effects upon host metabolism. The changes to these niches could be inter-related, wherein possible mechanisms such as stressor-induced reductions or exhaustion of mucous secretion, as well as increased motility could affect the composition of both compartments.…”

Clostridium difficile and the microbiota

“…However, even antibiotics that have intrinsic capability against C. difficile are able to change the microbiota, potentially resulting in a loss of colonization resistance (88). The future of CDI treatment will likely include nonantibiotic therapeutic approaches against CDI, which are advantageous since they may be less likely to perturb the microbiota in a detrimental manner.…”

Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease

“…The normal gut microbiota provides colonization resistance (the ability to resist pathogen colonization) against C. difficile (4). In both human studies and animal models, perturbation of the indigenous gut microbiota by antibiotic administration has been correlated to a susceptible community structure, ultimately leading to CDI (5)(6)(7)(8). Although it is clear that antibiotic use is correlated with the majority of CDI cases (9), the standard therapy for CDI is the administration of an antibiotic regimen with activity against C. difficile (typically vancomycin or metronidazole).…”