How doxycycline for STI prevention affects the gut microbiome

Taking a dose of the oral antibiotic doxycycline after a high-risk sexual encounter has dramatically reduced the incidence of sexually transmitted infections (STIs) in places where the strategy is being tried.

Despite its effectiveness, the new strategy, known as doxy-PEP, may come with risks, especially with chronic use. Experts worry about the impact on the community of gut bacteria, also known as the microbiome, and the potential that the antibiotic will give rise to resistant strains of bacteria.

Now, using metagenomic sequencing to see the impact of doxycycline on the gut microbiome of those who took it frequently for six months, UC San Francisco researchers have found both reassurance and possible cause for concern.

Doxy-PEP did not have much impact on the overall composition of bacterial communities in gastrointestinal tracts. But scientists noted signs of resistance building against tetracycline, the class of antibiotic that doxycycline belongs to, which could make it less effective.

The study appears in Nature Medicine.

“While doxy-PEP did not appear to have global impacts on the gut microbiome, it did have impacts on the antimicrobial resistance of gut bacteria, both in terms of the proportion of tetracycline class resistance genes and the amount that were turned on, or expressed,” said Chaz Langelier, MD, Ph.D., an associate professor of medicine in UCSF’s Division of Infectious Diseases and senior author of the paper. “So, it’s not totally innocuous.”

San Francisco’s high-profile STI prevention role

Doxy-PEP is short for doxycycline post-exposure prophylaxis, and it involves taking two 100-milligram pills within 72 hours of condomless sex.

Prompted by early promising clinical trial results, San Francisco became the first city in the country in October of 2022 to recommend doxy-PEP to gay and bisexual men and transgender women with a history of having unprotected encounters with multiple partners.

In March of 2024, the San Francisco Department of Public Health released results showing that after about a year, the approach halved the incidence of chlamydia and early syphilis. In June, the U.S. Centers for Disease Control and Prevention (CDC) issued guidelines recommending doxy-PEP for these groups. It was the first new STI prevention tool to be adopted in decades.

But the widespread use of antibiotics raises concerns about resistance and the potential harmful impact on gut health, specifically the balance of bacteria and other microbes. Disruption can lead to diarrhea, nausea, fever and abdominal pain; and until now, there had been very limited research into these side effects.

Working with the Chan Zuckerberg Biohub and scientists in Washington and Georgia, UCSF researchers studied participants from the recent doxy-PEP clinical trial in San Francisco and Seattle, led by Annie Luetkemeyer, MD, a professor of medicine in the Division of Infectious Diseases at UCSF.

The study included 100 individuals who used doxy-PEP and 50 individuals who received standard-of-care and did not use doxy-PEP. Researchers analyzed rectal swabs collected at enrollment and after six months to study the presence of DNA and RNA from gut bacteria and their antibiotic resistance genes.

“While we found no major changes to the community of gut bacteria in doxy-PEP users, we saw that doxy-PEP users over time had increasing amounts of tetracycline resistance genes present in their gut,” said Victoria T. Chu, MD, MPH, an assistant professor of pediatrics in the Division of Global Health and Infectious Diseases at UCSF and a first author of the study. “It also appeared to be dose dependent, meaning the more doxy-PEP they used, the larger the increase was.”

More research is needed to determine which gut bacteria are turning on these tetracycline-resistant genes to know whether this will lead to more doxycycline-resistant infections among both individuals taking doxy-PEP and in the greater community.

“Right now, it looks like the pros outweigh the cons,” Langelier said. “Especially given the dramatic rise in STIs, in particular syphilis, over the past decade.”