Sunday, February 9, 2025

Doxycycline increases antimicrobial resistance in the gut without disrupting microbiome diversity


New research reveals that doxycycline post-exposure prophylaxis increases levels of resistance genes in the gut, but lets the overall balance of the gut slip away. microbiota largely intact, marking a crucial step in understanding antibiotic resistance and prevention of STIs.

Study: Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome. Image credit: Kateryna Kon/ShutterstockStudy: Impact of Doxycycline Post-Exposure Prophylaxis for Sexually Transmitted Infections on the Gut Microbiome and Antimicrobial Resistome. Image credit: Kateryna Kon/Shutterstock

In a recent study published in the journal Natural medicineResearchers studied the effects of doxycycline post-exposure prophylaxis (doxy-PEP) on the gut microbiome and antimicrobial resistance genes (ARG) in men who have sex with men (MSM) and women transgender. They found that the use of doxy-PEP increased the proportion and expression of tetracycline ARGs in the gut resistome, but did not significantly change the diversity or composition of the gut microbiome.

Background

Doxy-PEP is known to be effective in preventing sexually transmitted infections (STIs) caused by bacteria in MSM and transgender women. It is now included in the US Centers for Disease Control and Prevention guidelines and is expected to be included in upcoming World Health Organization guidelines. However, concerns exist about the potential of doxy-PEP to increase antimicrobial resistance, particularly among Neisseria gonorrhoeaewhich could complicate treatment and promote resistance to other antibiotics. Increasing antimicrobial resistance globally is due to misuse of antibiotics, and concerns exist over the selection of doxy-PEP due to resistance in pathogens and commensal organisms. Previous studies on the impact of doxycycline on the human microbiome have been limited, focusing primarily on daily use and employing less comprehensive methods. Advanced techniques such as metagenomic deoxyribonucleic acid sequencing (DNA-seq) and meta-transcriptomic ribonucleic acid sequencing (RNA-seq) can now provide deeper insights into the resistome and gene activity , thereby helping to assess the broader impact of doxy-PEP. In the current study, researchers analyzed rectal swabs from participants in the DoxyPEP clinical trial to investigate the potential effects of doxy-PEP on the gut microbiome and resistome in MSM and transgender women.

About the study

The DoxyPEP trial compared doxy-PEP to standard care in participants at HIV and sexual health clinics in San Francisco and Seattle. Participants were eligible if they were adults, assigned male at birth, diagnosed with human immunodeficiency virus (HIV) infection or taking HIV pre-exposure prophylaxis and had a recent bacterial STI, including gonorrhea, chlamydia, or early syphilis. . The study focused on individuals with the highest use of doxycycline. Participants were randomized 2:1 to receive doxy-PEP (n=100) or standard care (n=50). Rectal swabs were self-collected at enrollment and after six months, and data on demographics and doxycycline use were also collected. Metagenomic sequencing was performed, with a focus on gut microbiome and ARG analysis using DNA sequencing and RNA sequencing.

Metagenomic sequencing involved the extraction of nucleic acids from rectal swabs, followed by microbial and ARG detection using CZ ID (short for Chan Zuckerberg Initiative for Discovery) analysis pipelines and tools. . Microbial mass and ARG mass were calculated and environmental contaminants were monitored using negative controls. Statistical analyzes focused on resistome diversity, ARG class distribution, and microbiome changes, including tetracycline resistance. Significant correlations between microbial taxa and ARGs were analyzed.

Results and discussion

Significant tetracycline resistance genes (ARGs) were detected among the analyzed samples, revealing that tetracycline ARGs were the most prevalent in the resistome, accounting for a substantial portion of the mass. The proportion of tetracycline ARGs increased from 46% to 51% in DNA-seq analysis (P = 0.023) and from 4% to 15% in RNA-seq analysis (P = 0.0000045) during of the six-month study period. Although no overall differences in resistome mass or alpha diversity were noted between the doxy-PEP and standard care groups, significant compositional differences in the expressed resistome were detected by RNA-seq at month six. (P=0.018). The proportion of tetracycline ARGs was found to increase in the doxy-PEP arm over time, while no change in ARG richness was observed.

Additionally, doxycycline doses were found to be positively correlated with the richness and proportion of tetracycline ARG expressed, particularly in participants taking more than 25 doses. Only participants who took more than 25 doses of doxycycline over the six-month period demonstrated a significant increase in tetracycline ARG richness. There was no significant difference in the gut microbiome or its transcriptome between the two arms at any time point, although a possible reduction in Chlamydia trachomatis abundance (P = 0.06) was observed. Positive correlations between tetracycline ARGs and various bacterial genera increased over time, indicating interactions between the resistome and microbiome when using doxy-PEP.

The present study is the largest doxycycline antimicrobial resistome study to date, strengthened by its extensive evaluation, detailed dose-response data, and combined use of metagenomics and meta-transcriptomics. However, the study is limited by the selection of participants with higher use of doxy-PEP, which may have biased the results. There is also potential for confusion from participants in the standard care group receiving doxycycline for other indications, quality issues with self-collected samples, lack of temporal data for doxy-PEP doses compared to sample collection, a focus only on the gut microbiome, a short follow-up period of six months, and the inability to definitively associate tetracycline ARGs with specific bacterial species due to read-sequencing limitations short.

Conclusion

In conclusion, the study found that the use of doxy-PEP resulted in an increase in the relative expression and proportion of tetracycline ARGs, with minimal effects on gut microbiome ecology. However, significant differences were observed in the composition of the resistome expressed by RNA-seq, indicating potential impacts at the transcriptional level. Results highlight the ecological impact of doxy-PEP on the gut microbiome and antimicrobial resistome in humans, highlighting the need for further research and population-based surveillance to monitor the emergence of resistant pathogens.

Journal reference:

  • Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome. Chu, VT et al., Natural medicine (2024), DOÏ: 10.1038/s41591-024-03274-2, https://www.nature.com/articles/s41591-024-03274-2



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