Abstract
There is a current need for enhancing our insight in the effects of antimicrobial treatment on the composition of human microbiota. Also, the spontaneous restoration of the microbiota after antimicrobial treatment requires better understanding. This is best addressed in well-defined animal models. We here present a model in which immune-competent or neutropenic mice were administered piperacillin-tazobactam (TZP) according to human treatment schedules. Before, during and after the TZP treatment, fecal specimens were longitudinally collected at established intervals over several weeks. Gut microbial taxonomic distribution and abundance were assessed through culture and molecular means during all periods. Non-targeted metabolomics analyses of stool samples using Quadrupole Time of Flight mass spectrometry (QTOF MS) were also applied to determine if a metabolic fingerprint correlated with antibiotic use, immune status, and microbial abundance. TZP treatment led to a 5–10-fold decrease in bacterial fecal viability counts which were not fully restored during post-antibiotic follow up. Two distinct, relatively uniform and reproducible restoration scenarios of microbiota changes were seen in post TZP-treatment mice. Post-antibiotic flora could consist of predominantly Firmicutes or, alternatively, a more diverse mix of taxa. In general, the pre-treatment microbial communities were not fully restored within the screening periods applied. A new species, closely related to Eubacterium siraeum, Mageeibacillus indolicus, and Saccharofermentans acetigenes, became predominant post-treatment in a significant proportion of mice, identified by 16S rRNA gene sequencing. Principal component analysis of QTOF MS of mouse feces successfully distinguished treated from non-treated mice as well as immunocompetent from neutropenic mice. We observe dynamic but distinct and reproducible responses in the mouse gut microbiota during and after TZP treatment and propose the current murine model as a useful tool for defining the more general post-antibiotic effects in the gastro-intestinal ecosystem where humanized antibiotic dosing may ultimately facilitate extrapolation to humans.
Highlights
To understand the effects of antibiotic treatment on the gut microbiome, two experiments were conducted in which TZP was administered to mice in a dosing regimen designed to mimic the human clinical dosing levels (Bulik et al, 2012)
TZP1 consisted of 6 days pre-TZP monitoring, 7 days of TZP treatment, and 7 days post-TZP treatment follow-up
The overall bacterial loads in both experiments decreased upon antibiotic exposure, up to 5–10fold, and began to increase again upon termination of the antibiotic administration, though the bacterial loads in both experiments did not return to their respective pre-antibiotic levels
Summary
Antimicrobial agents are crucial for protection against and cure of infectious processes. Overall antibiotic effectivity seems to be waning due to the global development of antimicrobial resistance (AMR) and a reduced developmental pipeline for new antibiotics (D’Atri et al, 2019). This trend is worrisome and one that needs vigorous attention. The use of bacteriolytic enzymes, clever nucleic acid constructs, or bacteriophages for combatting infections are currently being examined as alternative approaches that target specific pathogenic species and spare colonizing bacterial populations present in human microbiota and not involved in the actual disease process (Gordillo Altamirano and Barr, 2019; López-Jácome et al, 2019). The effect of antibiotic treatment on mixed bacterial populations needs further clarification (Galera-Laporta and Garcia-Ojalvo, 2020)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
