Circumcision: The Biology Behind the Benefits

Circumcision -- the surgical removal of foreskin from the penis -- is a touchy subject. Some say the procedure is an unnecessary surgery foisted upon infants and youths. Supporters, however, argue that male circumcision offers myriad health benefits, including protection from HIV and other sexually transmitted infections and a reduced risk of cervical cancer in female partners.

If science were to decide the debate, there would be a clear winner: epidemiological studies strongly point to the perks of a shorn shaft. Among men, circumcision has been shown to reduce acquisition of HIV by as much as 80 percent, herpes simplex virus type 2 by 28-34 percent and human papillomavirus by 32-35 percent (Tobian and Gray et al, 2010). Studies have also linked male circumcision to a 40 percent reduction in bacterial vaginosis among their female partners (Tobian and Gray et al, 2010).

But for Dr. Lance B. Price--director of the Center for Microbiomics and Human Health at the Translational Genomics Research Institute (TGen)--the epidemiological studies present an incomplete picture: "We have this great evidence that circumcision is reducing the risk [of disease]," he said. "But now the question is, "What is the underlying biological explanation?"

In recent years, Price and his TGen team have made unprecedented strides towards an answer. Working with Dr. Ronald Gray--a Johns Hopkins University reproductive epidemiologist and pioneering researcher into circumcision and HIV prevention--Price has completed the world's first-ever molecular analysis of the penile microbial population.

For the initial trial, the results of which were published in 2010 in the journal PLoS ONE, Dr. Gray submitted two sets of penile swabs from 12 HIV-negative Ugandan men, ranging from ages 15 to 49; the first set was taken prior to circumcision, and the second set was taken one year after the men were circumcised. By sequencing the samples, the researchers discovered the penis microbiome had radically changed following circumcision: "We found that once you remove the foreskin and expose the tissue to oxygen, anaerobic bacteria virtually disappear," explains Dr. Gray.

Although this preliminary finding was groundbreaking, Price confesses that, in retrospect, it was not surprising. The area between foreskin and glans is warm, moist and low in oxygen -- exactly the kind of place anaerobic (oxygen-averse) bacteria can thrive. "Open the environment to a lot more oxygen and of course the anaerobic bacteria will have a hard time," he explained.

But by analyzing more than 40 bacterial families in the samples, Price spotted intriguing pre- and post-circumcision trends: "Anaerobic bacteria are associated with causing inflammation and exacerbating the immune response," says Price. For example, Clostridiales and Prevotellaceae, two anaerobic organisms linked to bacterial vaginosis, were present in large numbers on swab samples taken pre-circumcision but virtually absent on those taken after circumcision. Price and Gray feel that this may explain why women with circumcised partners have lower rates of bacterial vaginosis than those with uncircumcised partners.

By exciting the body's inflammation response, the anaerobic bacteria that thrive on the uncircumcised penis may also play a key role in HIV transmission. Dendritic cells called Langerhans cells reside just below the surface skin of the head of the penis, known as the mucosal layer. In their inactive state, the Langerhans cells will engulf and destroy HIV, should they come into contact with it. But when the Langerhans cells have too many viruses and bacteria to combat, they enter their active state and behave very differently. Instead, they engulf the virus and deliver it to lymph node T-cells intact--a process that allows the body to develop adaptive immunity, the ability recognize and respond to a pathogen faster should it invade again.

But this spells trouble when it comes to HIV: "The problem is that the T-cells are actually target cells for HIV," Price explains. "The Langerhans cells are inadvertently acting as a Trojan horse, carrying the bad guy to the very site that it wants to be." Because circumcision creates a less-hospitable environment for these inflammation-causing bacteria, it may reduce HIV's access to its target cells, according to Price.

Price and Gray are not the only researchers examining how circumcision impacts our health. For example, others are investigating how anatomical aspects of the penis play a role in disease transmission. The skin of the inner foreskin of the penis is delicate, with only a thin layer of the protein keratin serving as a protective barrier. During intercourse, the foreskin is pulled back over the glans of the penis, rendering it susceptible to microtears which provide an entry portal for pathogens. After circumcision, however, the tissue strengthens, making the area less vulnerable to abrasions and unwanted microbial visitors.

Price and Gray are working now on a larger, controlled study of the penis microbiome, this time following 70 participants. Price is keeping mum about their subsequent findings, although he confirmed that the data supported their 2010 findings. They have identified a reduction in the overall bacterial load on the penis following circumcision. As for the implications of this, we'll all just have to stay tuned...