In recent years scientists studying genital microbiomes have focused on the possible connection between HIV incidence in men and the penile microbiome, the community of microorganisms living on the penis.

A number of studies have investigated how circumcision affects HIV incidence in men, but few have focused on the penile microbiome. A 2007 study showed an association between male circumcision and reduced HIV incidence in Ugandan men and a 2010 paper found that circumcision was associated with a decrease of anaerobic bacteria—microbes that thrive in areas deprived of oxygen such as what you might find underneath the foreskin—on the penises of HIV-negative men. In a study published this week in mBio, researchers sought to follow up on these studies by investigating and quantifying the relationship between anaerobic bacteria in the penile microbiome and HIV risk. The findings suggest certain microbial strains likely increase the risk of uncircumcised men contracting HIV.

In the new study a team of researchers from The George Washington University (G.W), Johns Hopkins University, Northern Arizona University, the University of Toronto and the Rakai Health Sciences Program used penile swabs collected from 182 uncircumcised, heterosexual men whose ages ranged from 15 to 49 in Rakai, Uganda, as part of a larger, two-year clinical study. During the study period 46 of the men who were swabbed became infected with HIV whereas 136 remained uninfected. Lead author Cindy Liu, an epidemiologist at G.W., says that for their study population (low-income country, female-to-male transmission), the absolute risk of a man becoming infected with HIV after a single instance of vaginal intercourse with an HIV-positive partner is estimated to be one in 263, which is 950 times greater than the absolute risk for the same demographics in developed countries (one in 2,380).

The researchers focused on 10 strains of anaerobic bacteria living under the penile foreskin, which made up an average of 62 percent of the subjects’ penile bacteria. The scientists compared the baseline anaerobic bacteria populations in men who later contracted HIV infections with those of men who remained HIV-negative, adjusting for risk factors including condom use and number of sexual partners. At the the beginning of the study, the men who would go on to contract HIV during the two-year-period had larger populations of eight penile anaerobic organisms—including Prevotella, Dialister, Mobiluncus, Murdochiella and Peptostreptococcus—compared with those who did not contract the virus during that period, the team found. The team analyzed the relationship between penile microbiomes and HIV risk, finding that, on average, for every 10-fold increase in population of each bacterial strain, the risk of a subject contracting HIV increased by an amount ranging from 29 percent (for Murdochiella) to 63 percent (for Prevotella).

The researchers think the higher rates of HIV infection among some men is connected to an observed link between increased numbers of certain penile anaerobes and greater production of cytokines, biochemical “distress calls” from immune cells. According to Liu, “the cytokines can play roles such as recruiting immune cells to foreskin, and the immune cells themselves are what HIV infects.”

The bacterial strains associated with a greater risk of HIV infection may not be confined to the penis. Lance Price, a genetic epidemiologist at G.W., and one of the study’s senior authors, says that in addition to highlighting an association between an increased risk of HIV with high populations of anaerobic bacteria on the foreskin that spur the production of cytokines, he believes these populations of anaerobic bacteria may be passed between partners during intercourse. A 2015 paper, also co-authored by Liu and Price, supported the possibility that many of the same anaerobic bacteria found under the male foreskin, like Prevotella and Dialister, are also associated with bacterial vaginosis, an infection caused by an imbalance of vaginal bacteria. Thus, the microbes may be transmitted between partners during sexual intercourse. “We know that bacterial vaginosis is associated with HIV transmission as well,” Price says. “Now you have this potentially sexually transmitted risk factor for HIV.”

Jared Baeten, a professor of global health at the University of Washington, who was not involved in the study, says the paper has implications for the association between circumcision and HIV infection risk: “[The researchers] help us understand the multiplicity of mechanisms by which being uncircumcised puts a man at risk for HIV, and by which circumcision resulted in improvements in a series of health risks, most prominently HIV.” (Further studies will be needed, however, as this study only involved uncircumcised men.)

Clive Gray, an HIV immunologist at the University of Cape Town, who was also not part of the research, says the new work generated data that allows researchers to hypothesize that “the microbiome around the penis, especially around the coronal sulcus [the top groove behind the head of the penis], is potentially a risk factor.” He adds that Liu and her colleagues still need to identify a biological connection between the anaerobic bacteria and inflammatory cytokines. He thinks they could do this by culturing the anaerobic bacteria “and identifying [in] in vitro experiments whether these cultural bacteria can stimulate the production of the cytokines.”