Impact of drug-microbiome interactions on the intestinal colonization with pathogenic Gammaproteobacteria

Abstract

The human gut microbiome has garnered scientific interest due to its key role in health. Maintaining a balanced microbiome is crucial for preventing harmful pathogens from colonizing the intestine and causing disease. It has been shown that drugs beyond classical antibiotics, inhibit growth of gut bacteria in monoculture. To translate these findings to a community context, we developed the synthetic model community Com20, consisting of 20 prevalent and abundant species of the human gut microbiome for which the individual direct growth effects of over 1000 non-antibiotic drugs have already been described. We identified S. perfringens as a key member required for Com20 community stability in vitro and explored the impact of individual community members when challenged with diverse pathogenic Gammaproteobacteria. Among them, Salmonella typhimurium showed the greatest variability in growth when a single strain was absent from the community. Com20 was able to colonize mice long-term, making the model suitable for investigating a chronic treatment regimen followed by a subsequent pathogen challenge. This allows us to explore the impact of non-antibiotic drugs on disrupting colonization resistance. To identify drugs which affect the community in vitro, we used Com20 and human stool-derived communities and treated them for 24h with >50 non-antibiotic drugs in different concentrations, before challenging the drug-treated communities with Salmonella typhimurium. Approximately 35% of the tested drugs increased the growth of the pathogen, which can be explained by shifts in community composition or a decrease in community biomass. We then challenged drug-treated communities with various other pathogenic Gammaproteobacteria and observed an increase in pathogen growth. We tested 5 drugs in our chronic treatment animal model in both defined colonized and conventional mice to demonstrate the risk of non-antibiotic drugs in disrupting colonization resistance. Drugs that promoted the growth of Salmonella typhimurium and other Gammaproteobacteria in the in vitro screen resulted in an increase of fecal Salmonella counts in both animal models, suggesting a possible influence of non-antibiotics on infection risk. In summary, our study provides a model which allows for a detailed examination of the effects of non-antibiotic drugs within a controlled context and highlights a critical and overlooked issue regarding the implications of non-antibiotic drug usage on microbial dynamics and pathogen proliferation.

Dissertation ist gesperrt bis 9. April 2027 !