Circumcision is known to reduce a man's risk of HIV infection by at least half, but scientists don't know why. A new study offers support for the theory that removing the foreskin deprives troublesome bacteria of a place to live, leaving the immune system in much better shape to keep the human immunodeficiency virus at bay.
Anyone who has ever lifted a rock and watched as the earth beneath it was quickly vacated by legions of bugs and tiny worms would be familiar with the principle, said study leader Dr. Cindy Liu: After the foreskin is cut away, the masses of genital bacteria that once existed beneath it end up disappearing.
"It's the same as if you clear-cut a forest," said Liu, a pathologist at the Translational Genomics Research Institute in Flagstaff, Ariz. "The community of animals that once lived in that forest is going to change."
Of particular note is that circumcision undercuts anaerobic bacteria, the microbes that thrive in oxygen-deprived environments, she said. By reducing the number of anaerobic bacteria, the body's immune cells may be better able to destroy the virus — and less likely to fall prey to its Trojan horse-style of attack, the authors suggest.
Liu and her colleagues present their case in a paper published Tuesday in the journal mBio.
Numerous studies conducted over the last two decades have shown that male circumcision reduces the risk of HIV infection in men who have heterosexual intercourse by 50% to 60%. Some researchers have speculated that the foreskin is prone to tearing, giving the virus more routes of entry. Others have argued that removal of the foreskin simply reduces the surface area available to be infected.
Liu and coauthor Lance Price, a professor of environmental health sciences at George Washington University in Washington, suspected it had to do with the bacterial species that inhabit the coronal sulcus, the shallow groove behind the head, or glans, of the penis.
To establish a possible connection, study authors enrolled 156 Ugandan men in a randomized trial in which half of them were circumcised and the other half were not.
Study participants ranged in age from 15 to 49. While the prospect of undergoing circumcision as an adult might not appeal to many American men, 5,000 Ugandan males volunteered for the study. In a region where 1 in 6 people are infected with HIV, circumcision's "powerful potential" to reduce the risk of infection was strong motivation, said coauthor Dr. Aaron Tobian, a health epidemiologist and pathologist who teaches at Johns Hopkins University School of Medicine.
On average, there was an 81% reduction in bacteria in the circumcised men one year after surgery, the researchers reported. Some of the biggest drops were recorded for anaerobic bacteria, they said.
Bacteria on the coronal sulcus fell by more than 33% in the circumcised men, Liu said.
Interestingly, the men in the uncircumcised control group also experienced a reduction in bacteria, but not to the degree that the circumcised men did, Liu said. This was probably because of health and hygiene information that was given to all study participants.
"That's not an uncommon outcome," she said. "Just being in a trial can confer some benefits."
The study only examined the effect of circumcision on reducing or altering bacterial colonies on the penis. Further research must be done to draw a direct connection between these changes in the microbiome and subsequent HIV infection.
However, the study offers strong support for the idea that bacteria — particularly anaerobic bacteria — can cause inflammation that will trigger the body's immune system and summon a variety of cells to fight a threat. Among those fighters are T4 cells, which are infected by HIV. The virus needs those cells to survive and replicate over time.
The study authors argue that the large populations of bacteria in uncircumcised men attract these T4 cells, giving the virus a means of entry during intercourse with an infected person. However, circumcised men are much less likely to mobilize these susceptible cells; therefore, the virus can be destroyed by other types of immune cells.
Dr. Alexandra Levine, chief medical officer at the City of Hope Cancer Center in Duarte, said scientists have long been searching for the connection between circumcision and reduced HIV infection. The authors of the new study make a convincing argument, she said.
"This is an important paper in beginning to document what the reason might be," said Levine, who was not involved in the research. "Their data are convincing to me."
Price said that colleagues were already working on follow-up studies. If the connection can be proved, there might be less-invasive ways of altering bacterial populations that do not rely on circumcision.
"As a society, we've gotten used to thinking about alterations to the microbiome as having negative outcomes," said Price, who is married to study leader Liu. "We think about the person who takes antibiotics in the hospital and ends up with an infection in their gut because we've knocked out the natural microbiota. But here's a situation where we're flipping that notion on its head. The disturbance of the microbiome could have a positive effect."